TURKU CENTRE FOR BIOTECHNOLOGY REPORT 2011

Transcription

TURKU CENTRE
FOR BIOTECHNOLOGY
REPORT 2011
AnnuAl RepoRt 2011
Turku Centre for Biotechnology
Published by:
P.O. Box 123, FI-20521 Turku, Finland
Tel. int. +358-2-333 8603, fax int. +358-2-333 8000
http://www.btk.fi
Editorial Board
Riitta Lahesmaa (Chair)
Daniel Abankwa
Tero Aittokallio
Eleanor Coffey
Garry Corthals
Michael Courtney
Konstantin Denessiouk
Laura Elo
John Eriksson
Attila Gyenesei
David Hawkins
Jyrki Heino
Johanna Ivaska
Panu Jaakkola
Patrik R. Jones
Marko Kallio
Olli Kallioniemi
Päivi Koskinen
Linnéa Linko
Harri Lähdesmäki
Matti Nykter
Tassos Papageorgiou
Cecilia Sahlgren
Mikko Savontaus
Lea Sistonen
Juha Strandén
Eero Vuorio
Mikael Wasberg
Jukka Westermarck
Andrey Zavialov
Photographs:
KUV@TEHDAS Roni Lehti, Photograph archives of the Centre for Biotechnology
Front cover image: Patrik Jones, “Tasapainoilua” by Reima Nurmikko
(Turku/Åbo – European Capital of Culture 2011).
Graphic Design: Anne Asplund, Finepress Oy
Printed by: Finepress Oy, Turku
ISSN 1237-5217
CONTENTS
Organization.............................................................................. 2
Chairman’s Foreword................................................................. 3
From the Director....................................................................... 4
Year 2011 in a Nutshell.............................................................. 6
Funding and Statistics............................................................... 10
Publications 2011...................................................................... 13
Personnel 2011......................................................................... 20
Finnish Microarray and Sequencing Centre................................ 24
Cell Imaging Core...................................................................... 28
Proteomics Facility..................................................................... 31
Protein Crystallography Core Facility ........................................ 34
Bioinformatics Core................................................................... 35
Virus Vector Facility ................................................................... 37
Coordination of European Biobanking........................................ 38
Mechanisms and Biosensors of GTPases.................................. 40
Protein Kinase Regulation of Brain Development and Disease... 44
Translational Proteomics............................................................ 49
Organisation of Neuronal Signaling Pathways............................ 52
Structural Bioinformatics............................................................ 56
Data Mining and Modelling........................................................ 58
Cytoskeletal and Survival Signaling............................................ 63
Epigenomics.... .......................................................................... 69
Cell Adhesion and Cancer......................................................... 72
Hypoxia in Cell Survival.............................................................. 75
Bioenergy........ .......................................................................... 78
Mitosis and Drug Discovery ...................................................... 80
Canceromics Research Programme.......................................... 83
Signaling Pathways Regulated by Oncogenic Pim Kinases ..........87
Molecular Immunology and Systems Biology of Cell.................. 90
Differentiation... .......................................................................... Computational Systems Biology................................................ 96
Complex Biosystems Modeling.................................................. 98
Metabolome in Health and Disease............................................ 100
Protein Crystallography.............................................................. 103
Cell Fate.......... .......................................................................... 107
Targeting Strategies for Gene Therapy....................................... 110
Regulation and Function of Heat Shock Transcription Factors........ 112
Cancer Cell Signaling................................................................. 116
Adenosine Deaminases............................................................. 119
Ph.D. Defences......................................................................... 122
Life outside the Lab................................................................... 127
1
ORGANIZATION
CHAIRMAN’S FOREWORD
Board of Trustees 2011
When assessing the present state of Finnish life science one cannot
avoid very controversial feelings. Never in the history of this country
have the quality of science and the resources for research been
better, still there are increasing concerns about the future. The
daily huge media interest on the economic crises in Europe has
raised the anxiety to unprecedented and, hopefully, exaggerated
levels. Nevertheless, budget cuts will also be inevitable in Finland.
How much they will affect life science research remains to be
seen. Despite the positive trends in the development of Finnish
research infrastructure the future of this fundamental construction
work is uncertain. Biocenter Finland has done excellent work in
reorganizing national core services and promoting the division of
labour between the Finnish biocentres. The job is not yet done
and clearly worth of continuing. There are also great expectations
related to the national research infrastructure roadmap and the
potential Finnish participation in the European ESFRI processes.
These important tasks have now been delegated to the new national
research infrastructure policy committee that will be nominated
later this spring by the Academy of Finland. Thus, many critical and
far-reaching decisions will be made during the year 2012.
Recent good news include the new strategy of TEKES. Previous
criteria set for the various funding instruments were very difficult to
fulfil by a typical life science or molecular medicine research project.
The new policy of TEKES has not yet been tested in practice but
there is a clear promise for a change to better. Presently, far too
many interesting preliminary observations and innovative ideas
become abandoned in the lack of suitable financing mechanisms.
The total absence of proof-of-concept funding has led to
unacceptable waste of potential innovations. This problem is far
from being solved in Finland, but there is room for optimism that we
are finally moving to right direction.
Chairman
HEINO Jyrki, Professor, University of Turku,
Department of Biochemistry and Food Chemistry,
Scientific Director, BioCity Turku
Vice-chairman
ERIKSSON John, Professor, Åbo Akademi University,
Department of Biology
Secretary
LAHESMAA Riitta, Professor, Director,
Assistant Secretary
ALANKO Satu, Coordinator,
Turku Centre for Biotechnology and BioCity Turku
Members
ARO Eva-Mari, Professor, University of Turku,
Department of Biochemistry and Food Chemistry
BUCHERT Johanna, Vice President, Strategic research, VTT
HAAPALINNA Antti, Vice President, Research, R&D,
Orion Corporation ORION PHARMA
JALKANEN Sirpa, Professor, University of Turku,
Department of Medical Microbiology and Immunology
JOHNSON Mark, Professor, Åbo Akademi University,
Department of Biosciences
POUTANEN Matti, Professor, University of Turku,
Institute of Biomedicine
SAVILAHTI Harri, Professor, University of Turku,
TERHO Perttu, Project Engineer, Turku Centre for Biotechnology
TÖRNQUIST Kid, Professor, Åbo Akademi University,
WILLFÖR Stefan, Professor, Åbo Akademi University,
Department of Chemical Engineering
Vice-members
FARDIM Pedro, Professor, Åbo Akademi University,
Department of Chemical Engineering
HÄNNINEN Pekka, Professor, University of Turku,
Institute of Biomedicine
JAAKKOLA Ulla-Marjut, Director, Central Animal Laboratory,
LASSILA Olli, Professor, University of Turku,
Department of Medical Microbiology and Immunology
PETTERSSON Kim, Professor, University of Turku,
Department of Biochemistry and Food Chemistry
PRIMMER Craig, Professor, University of Turku,
SLOTTE J. Peter, Professor, Åbo Akademi University,
VUORELA Pia, Professor, Åbo Akademi University,
2
Looking at the recent achievements of the Turku Centre for
Biotechnology it is delightful to notice that the uncertainties of the
future have not discouraged the Turku scientists. Funding from the
Biocenter Finland, the Academy of Finland (FIRI programme) and the
University of Turku (strategic funding) have enabled the acquisition
of up-to-date instruments. Based on that the core facilities have
been able to establish novel technologies and offer new services.
Recently also many outstanding young scientists have joined the
Turku life science community. Importantly, many of the new recruits
have moved to Turku from abroad. Turku Centre for Biotechnology
has always been a forerunner in the internationalization of the
Universities. One more reason
to congratulate Turku Centre for
Biotechnology is that the recent
list of published papers is really
impressive. Thus, even in the
rapidly changing world, the Centre
and its staff seem to have all critical
elements needed for the continuing
success also in the future.
Jyrki Heino, M.D., Ph.D.,
Professor of Biochemistry,
Scientific Director of the BioCity Turku
and Chairman of the Board of the Turku
Centre for Biotechnology
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FROM THE DIRECTOR
In 2011 the City of Turku was the cultural capital of Europe, which
is also reflected in this Annual Report. The annual BioCity Turku
symposium was also flavored by this theme. In addition to culture,
also science flourished in Turku. The researchers of Turku Centre of
Biotechnology (CBT) organized a number of international meetings,
workshops and seminars, including the Sigrid Juselius symposium on
“Post-translational modification networks as survival determinants”
and ESF epigenomics meeting “Epigenomics and Gene Regulatory
Networks Controlling Cellular Responses” in Turku. CBT actively
developed its strengths in research and core competence in research
infrastructure in molecular biosciences. The Centre provided stateof the-art core facilities, education and training for BioCity Turku
research groups and six research programs featuring altogether
seven Academy of Finland Centers of Excellence.
In 2011 research focused in cell signalling, regulation of gene and
protein expression, and systems biology resulted in 61 papers,
including articles published in top ranked journals such as Nature
Neuroscience, Nature Cell Biology, PNAS and Nature. Altogether
11 Ph.D. students presented their dissertations, which is a great
achievement. A new international group leader Andrey Zavialov
became an Academy Fellow, a highly competitive award by the
Academy of Finland (AoF), and started his research group at the
Centre. Also, Daniel Abankwa became an Academy Fellow. Our
group leaders succeeded well in obtaining national and international
funding, including 11 grants from the AoF. Among these were the
AoF FiRI grant to Daniel Abankwa to support development of cuttingedge cell imaging infrastructure. A new Centre of Excellence (CoE) in
“Molecular Systems Immunology and Physiology” was selected by
the AoF for 2012-17. In this AoF CoE Riitta Lahesmaa is responsible
for molecular systems immunology, and CBTs affiliated group leaders
Matej Oresic (VTT) and Harri Lähdesmäki (Aalto) play central roles in
leading the CoE and directing the computational systems biology,
respectively. Johanna Ivaska was awarded the distinguished Anders
Jahre young investigator’s award and Jukka Westermarck received
a highly competitive professorship of the Finnish Cancer Institute for
a 2nd term. CBT nominated a new scientific advisory board, that is
led by Dr. Doreen Cantrell (Dundee University, Scotland, UK) and has
the following distinguished members: Dr. Martin Eilers, (University
of Marburg, Germany), Dr. Ron Germain (NIH, Bethesda, MD, US)
,Dr. Carlos Ibanez (Karolinska Institute, Stockholm, Sweden and
Dr.Tomas Mustelin (Medimmune, Gaithersburg, MD, US). We are
looking forward to exciting discussions with this expert panel.
The animal core facility continued to take up a sizeable portion
of basic resources in serving researchers and Turku Centre for
disease modeling. Substantial efforts were made to raise and assign
resources to further develop the cutting-edge platforms in genomics,
epigenomics and functional genomics, proteomics, cell imaging and
bioinformatics. Funding from the host organisations and AoF was
supplemented by competitive funding through the Biocenter Finland.
Biocenter Finland was established in 2006 to facilitate national
collaboration between the Finnish biocenters, and to coordinate
development of research infrastructures in Finland. The Ministry of
Education special funding for 2010-2012 has made it possible to
significantly improve the research infrastructure in Finland. Several of
CBT’s group leaders are actively engaged in these Biocenter Finland
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infrastructure networks and were able to raise altogether 3 185 536 €
through a competitive call. Accordingly, CBT now further develops
and provides national services in a wide range of platforms within the
Biocenter Finland infrastructure network. Bioimaging and systems
biology infrastructures are at the core of the research strategy of
both our universities and central infrastructures in the research
strategy of BioCity Turku.
The Biocenter Finland networks have made outstanding progress
in developing the Finnish infrastucture for research and providing
Finnish scientists access to the state-of-the-art technology. The
key to this success has been the division of tasks between the
biocenters and tight networking to share the knowledge and provide
critical mass in this rapidly developing field. Most importantly, the
additional resources have enabled Finnish biocenters to update
their technology infrastructure and knowledge because funding
has been provided not only for instruments, but also to hire and
further train key personnel. One of the most important goals for
2012 is to secure the continuation of Biocenter Finland funding from
the Ministry of Education. The results of the two years out of the
period of three years are excellent and should speak for themselves.
The international scientific advisory board who has evaluated the
networks and the midterm results also clearly state this in their report.
Our results during the first two years of this budget period (2010-12)
have been outstanding and record breaking in many aspects. I wish
to congratulate our scientists for their excellent accomplishments! I
am deeply grateful to our administrative and technical personnel for
your special commitment - without your contributions such results
would not have been possible!
Riitta
Riitta Lahesmaa, M.D., Ph.D.,
Professor Director Turku Centre
for Biotechnology University of Turku
and Åbo Akademi University
5
YEAR 2011 IN A NUTSHELL
RESEARCH AND EDUCATION 2011
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61 scientific papers were published (p.
11 new Ph.D.´s graduated
Johanna Ivaska was granted Anders Jahre young investigator
award
Jukka Westermarck’s professorship of the Finnish Cancer
Institute was renewed (2012-14)
A new “Center of Excellence in Molecular Systems
Immunology and Physiology” was chosen by the Academy
of Finland for years 2012-17. The five CoE groups include
Riitta Lahesmaa’s group and those led by two affiliated
CBT group leaders, Harri Lähdesmäki and Matej Oresic.
Two new Academy Fellows, Daniel Abankwa and Andrey
Zavialov were awarded by The Academy of Finland
David Goodlett was selected as a new Finnish Distinguished
Professor by TEKES for years 2012-15
CBT was awarded a substantial 1,034,812 € funding through
Biocenter Finland
The Academy of Finland granted 873,810 € infrastructure
funding (FIRI) to Daniel Abankwa and coapplicants Eleanor
Coffey, Johanna Ivaska and Jukka Westermarck
For undergraduate training, CBT organized lecture courses
and practical demonstrations including a laboratory course
on “Functional Genomics” for Health Bioscience and Biology
students (4 study points), “Medical Biotechnology” for
Medical students (5 study points) and a lecture course
(4 study points) on “Quality Systems” for Biochemistry and
Health Bioscience students.
12 M.Sc. theses were completed
DEVELOPMENT OF INFRASTRUCTURE, RESEARCH
SERVICES AND CORE FACILITIES 2011
Finnish Microarray and Sequencing Centre 2011
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The Centre got substantial competitive funding through
Biocenter Finland to develop and provide national services
in the area of gene expression, regulation of gene expression
and epigenetics
Next-generation sequencing instrument: ABI SOLiD 4 was
upgraded to SOLiD 5500 XL in August
Acquisition of the following instruments to expand our services:
Affymetrix GeneTitan microarray system, Illumina HiSeq2000
next-generation sequencing platform and Diagenode
SX-8G IP-Star automated system for epigenetics platform
development
An ESF symposium “Epigenomics and Gene Regulatory
Networks Controlling Cellular Responses” was organized in
October with top speakers from US, Europe and Finland
Altogether 38 publications, including papers in very high
impact journals such as Nature, Nature Immunology,
Immunity and Cell Stem Cell were published with contribution
from the FMSC
Proteomics and Mass spectrometry Laboratory 2011
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Cell Imaging Core 2011
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Additional funding received to the Facility through Biocentre
Finland for instrument purchases and laboratory personnel
Continued upgrades to important software for quantitative
analysis
Development of new procedures for label-free quantitation
and phosphorylation analysis
Two new mass spectrometers were ordered for PTM
analysis and targeted quantitative proteomics
A 23% increase to 4300 hours of MS service operation
Several trainings courses were organised ranging from
3 day targeted courses on bioinformatics procedures
including Scaffold, ProteinPilot, Mascot and MS courses for
sample handling for iTRAQ analysis as well as week long
courses on basic MS and Protein Phosphorylation 4th)
Summer School in “Mass Spectrometry in Biotechnology
and Medicine” in Dubrovnik
Dorota Muth was recruited in May to spearhead targeted
quantitative MS
Pekka Haapaniemi (MSc) was recruited in November as a
laboratory technician to assist in day to day running of the
MS instruments
Firouz Saedi completed his Masters degree in bioinformatics
and Avinash Jadav, Thaman Chand and Santhosh
Thatikonda started their Masters degree.
Darshana Kottahachi started as a new Ph.D. student in
quantitative MS.
Throughout the year, a dozen microscopes and other
instrumentation were tested by CIC staff locally and
internationally to evaluate them for future purchase
CIC staff helped in courses and gave lectures e.g. for Health
Biosciences (TerBio) and BioImaging Masters students
April 27-29: Zeiss on Campus and BioImageXD workshop
Two big tender procedures were successfully concluded for
microscope purchases
Jouko Sandholm returns from research stay in the US
Pasi Kankaanpää will replace Daniel Abankwa as the head of CIC
CIC is a test site for the preparatory phase of the
Euro-BioImaging initiative
8500 downloads of “Flowing Software”, flow cytometry
analysis software developed by Perttu Terho at the Cell
Imaging Core. http://www.flowingsoftware.com/
New CIC-instrumentation:
Zeiss LSM780 confocal microscope with FCS capability
Leica STED upgrade for STED-FCS, SymPhoTime software
and analysis computer
FLIM-FRET/ FRAP fast confocal unit from Lambert
Instruments and VisiTech
Evos fl cell culture fluorescence microscope
Zeiss AxioVert 200M fluorescence microscope second
hand purchase from Hormos Medical Oy
BioTek Synergy H1 multimodal plate reader
New powerful public image analysis computer and
computers for CIC staff
New computers for two flow cytometer
New computer and Zen Software upgrade on LSM 510;
hardware upgrades on LSM 510
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Various smaller upgrades, such as a new light source for a
fluorescence microscope etc.
Viral vector facility 2011
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The viral vector facility produced 115 viral preps as a service
and hosted 50 registered users of the BSL2 lab
The BSL2 lab was equipped with a Zeiss Axiovert 40
inverted fluorescence microscope with CCD camera for
digital imaging of fluorescence reporters
New infrastructure was purchased to expand the capacity of
the BSL2 lab to accommodate the increase in user base.
This was made possible because of additional funding from
the Biocenter Finland organisation that was allocated
during 2011
Bioinformatics Unit 2011
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Two new computational clusters were acquired, one dedicated
to genome sequencing efforts (supporting BF Genomics),
funded by the Center for Biotechnology (CBT), and a second
cluster partly funded by Åbo Akademi
IT support has integrated dedicated disks and software tools
into the high-capacity server to support BF Biological Imaging.
Workstations and software (modeling, computational
chemistry, chemical structure databases, etc.) supporting BF
Structural Biology and BF Translational Activities (DDCB) have
been set up.
Structural bioinformatics projects (funded from research funds)
and using BF-funded infrastructure supports researchers in
Bergen (1 project), Heidelberg (2), Stockholm (1), Tampere (1)
and Turku (10).
High-throughput bioinformatics group analyzed 23 Next
Generation Sequences and 11 microarray projects (20 local;
13 domestic; 1 international).
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Individual training for graduate and post-graduate students
A M.Sc. thesis of Eeva Mäki was completed
QA inspections for the Central Animal Laboratory and Forensic
Medicine in GLP quality system
Internal audits of CBT
Linnéa Linko is a member in the Advisory Commission for
Metrology and the chairman in its Education group as well as
a member of The Eurachem Education and Training Working
Group
PhD and MSc Theses
PhD Theses (p. 13)
Name
Björk Johanna
Dhavala Prathusha
Supervisor
Sistonen Lea
Papageorgiou Tassos
Gupta Santosh
Kallioniemi Olli
Haikarainen Teemu
Papageorgiou Tassos
Jokilehto Terhi
Jaakkola Panu
Ketola Kirsi
Kallioniemi Olli
Mai Anja
Ivaska Johanna
Nevo Jonna
Ivaska Johanna
Nikula Tuomas
Lahesmaa Riitta
Rantala Juha
Kallioniemi Olli
Vainio Paula
Kallioniemi Olli
Protein crystallography facility 2011
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Participation in several courses (Medical Biochemistry,
TERBIO, Protein Crystallography and Structural Genomics’,
‘How to solve a protein structure’, Master’s degree program
in Autonomous University of Barcelona) with lectures and
demonstrations.
New X-ray generator was installed. Training and demonstrations
were arranged.
BioXLabs-Turku
(http://www.sci.utu.fi/projects/biokemia/
bioxlabs/) was launched with other crystallographic groups in
Turku to facilitate training, share of resources, and exchange of
information.
Participation in the road show organized by Biocenter Finland
Structural Biology Network.
New projects at various stages were initiated in collaboration
with other groups in Finland and abroad.
All major crystallographic programs were kept updated to latest
versions. New computers and 3D-monitors were purchased.
Site besides CBT
ÅA/Department of Biosciences
UTU/Department of Medical
Biochemistry and Genetics
UTU/Department of Biochemistry
and Food Chemistry
and Food Chemistry
and Food Chemistry
UTU/Department of
Pharmacology, Drug
Development and Therapeutics
and Food Chemistry
UTU/Department of
Pharmacology, Drug
Development and Therapeutics
MSc / M.D. Advanced Study Theses
Name
Fors Daniela
Laajala Essi
Heikelä Hanna
Supervisor
Lea Sistonen
Henna Kallionpää
and Harri Lähdesmäki
Eleanor Coffey
Hurme Miikka
Lundgren Jolanta
Muleta Adbi
Eleanor Coffey
John Eriksson
Tassos Papageorgiou
Mäki Eeva
Linnéa Linko and
Susanna Työppönen
Nuutila Maiju
Heidi Högel and
Panu M. Jaakkola
Rajavuori Anna
Riitta Lahesmaa
Quality Assurance Unit 2011
Salo Verna
Riitta Lahesmaa
Organized courses for the university on quality assurance and
metrology and how to assure the reliability of laboratory test
results
Seijas Biel Hanser Jose Lea Sistonen
Subedi Bishwa
Tassos Papageorgiou
Site besides CBT
Aalto University/
School of Electrical Engineering
University of Turku/
University of Turku/ICT
University of Turku/Department
of Information Technology
of Biochemistry and Food
Chemistry
of Biochemistry and Food
Chemistry
University of Turku/Medical
Faculty
University of Turku/Health
Biosciences
of Information Technology
99
FUNDING AND STATISTICS
Number of graduates 2006-2011
Sources of funding received
by Centre for Biotechnology in 2011 (12.3 Million €)
Biocenter
Finland 9%
EU
12%
Others,
TEKES 6%
Services
17%
Academy of
Finland
20%
Universities 36%
Publication impact factors
8 publications
with IF > 10
30 publications
with IF < 5
External funding 2006-2011
23 publications
with IF 5-10
Citations per year
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11
PUBLICATIONS
Ph.D. Theses 2011
1. Björk, Johanna: Role and regulatory mechanisms of
heat shock factor 2. Åbo Akademi University, 146 p.
2. Dhavala, Prathusha. Structural studies on Enzymes
of Biotechnical and Biomedical Interest, University of
Turku, 99 p.
3. Jokilehto, Terhi: The Cellular oxygen Sensor PHD2 in
Cancer Growth. University of Turku, 133 p.
4. Nevo, Jonna: Novel Players in the Integrin Signaling
Orchestra: TCPTP and MDGI University of Turku, 146 p.
5. Nikula, Tuomas: Transcriptional profiling of organspecific autoimmunity in human, University of Turku,
139 p.
6. Mai, Anja: In The Footsteps Of Migrating Cancer Cells,
University of Turku, 145 p.
7. Haikarainen, Teemu: Dps-like Peroxide Resistance
protein: Structural and functional studies on a
versatile nanocontainer, University of Turku, 121 p.
8. Vainio, Paula: High-Throughput Screening for Novel
prostate Cancer Drug Targets -Getting Personal, 74 p.
9. Ketola, Kirsi: Chemical Biology Screen for Prostate
Cancer Therapeutics, University of Turku. 177 p.
10.Gupta, Santosh: Functional Study of Oncogenic
Transcription Factor ERG and its Signaling in Prostate
Cancer University of Turku, 40 p.
11. Rantala, Juha: A cell spot microarray method for highthroughput biology, University of Turku, 48 p.
From left to right: First row: Markku Saari, Riitta Lahesmaa, Hannele Vuori, Marjo
Hakkarainen, Virpi Korpiranta, Elina Pietilä, Sarita Heinonen and Terhi Jokilehto
Second row: Perttu Terho, Pasi Viljakainen, Petri Vahakoski, Mikael Wasberg,
Juha Strandén, Mårten Hedman, Bogata Fezazi, Aila Jasmavaara, Susanna Pyökäri
and Anne Rokka
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PUBLICATIONS 2011
12. Grouneva I., Rokka A. and Aro E.M. (2011) The thylakoid
membrane proteome of two marine diatoms outlines
both diatom-specific and species-specific features of the
photosynthetic machinery. J. Proteome Res. 10: 53385353. IF: 5.460.
Publications 2011
1. Anckar J. and Sistonen L. Regulation of HSF1 function in
the heat stress response: implications in aging and disease
(2011) Annu. Rev. Biochem. 80: 1089-1115. Review. IF:
29.742.
13. Haapa-Paananen S., Kiviluoto S., Waltari M., Puputti
M., Mpindi J.P., Kohonen P., Tynninen O., Haapasalo
H., Joensuu H., Perälä M. and Kallioniemi O. (2011)
HES6 gene is selectively overexpressed in glioma and
represents an important transcriptional regulator of glioma
proliferation. Oncogene. [Epub ahead of print]. IF: 7.414.
2. Annala M., Laurila, K., Lähdesmäki, H. and Nykter, M.
(2011) A linear model for transcription factor binding affinity
prediction in protein binding microarrays. PLoS One 6:
e20059. IF: 4.411.
3. Arjonen A., Kaukonen R. and Ivaska J. (2011) Filopodia and
adhesion in cancer cell motility. Cell Adh. Migr. 5: 421430.
14. Haikarainen T., Paturi P., Lindén J., Haataja S., MeyerKlaucke W., Finne J. and Papageorgiou A.C. (2011)
Magnetic properties and structural characterization of iron
oxide nanoparticles formed by Streptococcus suis Dpr
and four mutants. J. Biol. Inorg. Chem. 16: 799-807. IF:
3.287.
4. Asaoka T., Kaunisto A., Eriksson J.E. (2011) Regulation
of cell death by c-FLIP phosphorylation. Adv. Exp. Med.
Biol. 691: 625-630. IF: 1.379.
5. Björkman M., Ostling P., Härmä V., Virtanen J., Mpindi
J.P., Rantala J., Mirtti T., Vesterinen T., Lundin M., Sankila
A., Rannikko A., Kaivanto E., Kohonen P., Kallioniemi O.
and Nees M. (2011) Systematic knockdown of epigenetic
enzymes identifies a novel histone demethylase PHF8
overexpressed in prostate cancer with an impact on cell
proliferation, migration and invasion. Oncogene. [Epub
ahead of print]. IF: 7.414.
15. Haikarainen T., Thanassoulas A., Stavros P., Nounesis G.,
Haataja S. and Papageorgiou A.C. (2011) Structural and
thermodynamic characterization of metal ion binding in
Streptococcus suis Dpr. J. Mol. Biol. 405: 448-460. IF:
4.008.
16. Heinonen J., Taipaleenmäki H., Roering P., Takatalo M.,
Harkness L., Sandholm J., Uusitalo-Järvinen H., Kassem
M., Kiviranta I., Laitala-Leinonen T. and Säämänen A.M.
(2011) Snorc is a novel cartilage specific small membrane
proteoglycan expressed in differentiating and articular
chondrocytes. Osteoarthritis Cartilage 19: 1026-1035.
IF: 3.953.
6. Böckelman C., Lassus H., Hemmes A., Leminen A.,
Westermarck J., Haglund C., Bützow R. and Ristimäki
A. (2011) Prognostic role of CIP2A expression in serous
ovarian cancer. Br. J. Cancer 105:989-995. IF: 4.831.
7. Chouhan B., Denesyuk A., Heino J., Johnson M.S. and
Denessiouk K. (2011) Conservation of the Human IntegrinType Beta-Propeller Domain in Bacteria. PLos One 6:
e25069. IF: 4.411.
17. Härmä V., Knuuttila M., Virtanen J., Mirtti T., Kohonen
P., Kovanen P., Happonen A., Kaewphan S., Ahonen
I., Kallioniemi O., Grafström R., Lötjönen J. and Nees
M. (2011) Lysophosphatidic acid and sphingosine-1phosphate promote morphogenesis and block invasion
of prostate cancer cells in three-dimensional organotypic
models. Oncogene. [Epub ahead of print]. IF: 7.414.
8. Corthals G.L., Dunn M., James P., Gil C., Penque D., Albar
J.P., Andrén P., Rabilloud T. and Marko-Varga G. (2011) The
transition of the European Proteomics Association into the
future. J. Proteomics. [Epub ahead of print]. IF: 5.074.
9. Chrusciel M., Bodek G., Kirtiklis L., Lewczuk B., Hyder C.L.,
Blitek A., Kaczmarek M.M., Ziecik A.J., Andronowska A.
(2011) Immortalization of swine umbilical vein endothelial
cells (SUVECs) with the simian virus 40 large-T antigen.
Mol. Reprod. Dev. 78: 597-610. IF: 2.395.
18. Hussein S.M., Batada N.N., Vuoristo S., Ching R.W., Autio
R., Närvä E., Ng S., Sourour M., Hämäläinen R., Olsson
C., Lundin K., Mikkola M., Trokovic R., Peitz M., Brüstle O.,
Bazett-Jones D.P., Alitalo K., Lahesmaa R., Nagy A. and
Otonkoski T. (2011) Copy number variation and selection
during reprogramming to pluripotency. Nature 471: 5862. IF: 36.104.
10. Edgren H., Murumagi A., Kangaspeska S., Nicorici
D., Hongisto V., Kleivi K., Rye I.H., Nyberg S., Wolf M.,
Borresen-Dale A.L. and Kallioniemi O. (2011) Identification
of fusion genes in breast cancer by paired-end RNAsequencing. Genome Biol. 12:R6. IF: 6.885.
19. Hyder C.L., Isoniemi K.O., Torvaldson E.S. and Eriksson J.E.
(2011) Insights into intermediate filament regulation from
development to ageing. J. Cell Sci. 124: 1363-1372. IF: 6.290.
20. Högel H., Rantanen K., Jokilehto T., Grenman R. and
Jaakkola P.M. (2011) Prolyl hydroxylase PHD3 enhances
the hypoxic survival and G1 to S transition of carcinoma
cells. PLoS One 6: e27112. IF: 4.411.
11. Eriksson J.E. and Vandenabeele P. (2011) Workshop
summary: cell death mechanisms controlled by the TNF
family. Adv. Exp. Med. Biol. 691: 585-588. IF: 9.379.
21. Högnäs, G., Tuomi, S., Veltel, S., Mattila, E., Murumägi,
A., Edgren, H., Kallioniemi, O. and Ivaska, J. (2011)
13
14
14
15
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aneuploidy and oncogenic transformation in vitro and in
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22. Ivaska J. and Heino J. (2011) Cooperation between integrins
and growth factor receptors in signaling and endocytosis.
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biological analysis of their functional impact. Mol. Cell
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33. Li, D.-C., Li., A.-N. & Papageorgiou, A.C. (2011).
Cellulases from thermophilic fungi: Recent insights and
biotechnological potential. Enzyme Res. 2011: 308730.
23. Ivaska J. (2011) Vimentin; Central hub in EMT induction?
Small GTPases 2: 51-53.
34. Lindén, R. O., Eronen, V.P. and Aittokallio T. (2011)
Quantitative maps of genetic interactions in yeast
Comparative evaluation and integrative analysis. BMC
Systems Biology 5: 45. IF: 3.565.
24. Kakko T., Jaakkola U., Raitakari O.T. and Kallio J. (2011)
Inflammatory effects of blood leukocytes: association with
vascular function in neuropeptide Y proline 7-genotyped type 2
diabetes patients. Diab. Vasc. Dis. Res. 8: 221-228. IF: 2.468.
35. Mai A., Veltel S., Pellinen T., Padzik A., Coffey E., Marjomäki
V. and Ivaska J. (2011) Competitive binding of Rab21 and
p120RasGAP to integrins regulates receptor traffic and
migration. J. Cell Biol. 194: 291-306. IF: 9.921.
25. Khanna A., Okkeri J., Bilgen T., Tiirikka T., Vihinen M.,
Visakorpi T. and Westermarck J. (2011) ETS1 mediates
MEK1/2-dependent overexpression of cancerous inhibitor
of protein phosphatase 2A (CIP2A) in human cancer cells.
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36. Mamaeva V., Rosenholm J.M., Bate-Eya L.T., Bergman L.,
Peuhu E., Duchanoy A., Fortelius L.E., Landor S., Toivola
D.M., Lindén M. and Sahlgren C. (2011) Mesoporous
silica nanoparticles as drug delivery systems for targeted
inhibition of Notch signaling in cancer. Mol. Ther. 19:
1538-1546. IF: 7.149.
26. Koh K.P., Yabuuchi A., Rao S., Huang Y., Cunniff K., Nardone
J., Laiho A., Tahiliani M., Sommer C.A., Mostoslavsky G.,
Lahesmaa R., Orkin S.H., Rodig S.J., Daley G.Q. and Rao
A. (2011) Tet1 and Tet2 regulate 5-hydroxymethylcytosine
production and cell lineage specification in mouse embryonic
stem cells. Cell Stem Cell 8: 200-213. IF: 25.943.
27. Kouvonen P., Rainio E.M., Suni V., Koskinen P. and
Corthals G.L. (2011) Enrichment and sequencing of
phosphopeptides on indium tin oxide coated glass slides.
Mol. Biosyst. 7: 1828-1837. IF: 3.825.
37. Mathiasen D.P., Egebjerg C., Andersen S.H., Rafn B.,
Puustinen P., Khanna A., Daugaard M., Valo E., Tuomela
S., Bøttzauw T., Nielsen C.F., Willumsen B.M., Hautaniemi
S., Lahesmaa R., Westermarck J., Jäättelä M. and Kallunki
T. (2012) Identification of a c-Jun N-terminal kinase-2dependent signal amplification cascade that regulates
c-Myc levels in ras transformation. Oncogene 31: 390401. IF: 7.414.
28. Kukkonen-Macchi A., Sicora O., Kaczynska K., OetkenLindholm C., Pouwels J., Laine L. and Kallio M.J. (2011) Loss
of p38gamma MAPK induces pleiotropic mitotic defects and
massive cell death. J. Cell Sci. 124: 216-227. IF: 6.290.
38. Mattila E. and Ivaska J. (2011) High-throughput methods
in identification of protein tyrosine phosphatase inhibitors
and activators. Anticancer Agents Med. Chem. 11:
141-150. Review. IF: 3.144.
29. Lahti L., Elo, L.L., Aittokallio, T. and Kaski, S. (2011)
Probabilistic analysis of probe reliability in differential gene
expression studies with short oligonucleotide arrays.
IEEE/ACM Transactions on Computational Biology
and Bioinformatics 8: 217-225. IF: 1.664.
39. Mohseni P., Sung H.K., Murphy A.J., Laliberte C.L., Pallari
H.M., Henkelman M., Georgiou J., Xie G., Quaggin S.E.,
Thorner P.S., Eriksson J.E. and Nagy A. (2011) Nestin is
not essential for development of the CNS but required for
dispersion of acetylcholine receptor clusters at the area of
neuromuscular junctions. J. Neurosci. 31: 11547-11552.
IF: 7.271.
30. Landor S.K., Mutvei A.P., Mamaeva V., Jin S., Busk M., Borra
R., Grönroos T.J., Kronqvist P., Lendahl U. and Sahlgren
C.M. (2011) Hypo- and hyperactivated Notch signaling
induce a glycolytic switch through distinct mechanisms.
Proc Natl Acad Sci U S A 108: 18814-18819. IF: 9.771.
40. O’Shea J.J., Lahesmaa R., Vahedi G., Laurence A. and
Kanno Y. (2011) Genomic views of STAT function in CD4+
T helper cell differentiation. Nat. Rev. Immunol. 11: 239250. Review. IF: 35.196.
31. Legrain P., Aebersold R., Archakov A., Bairoch A., Bala
K., Beretta L., Bergeron J., Borchers C., Corthals G.L.,
Costello C.E., Deutsch E.W., Domon B., Hancock W., He
F., Hochstrasser D., Marko-Varga G., Salekdeh G.H., Sechi
S., Snyder M., Srivastava S., Uhlen M., Hu C.H., Yamamoto
T., Paik Y.K. and Omenn G.S. (2011) The human proteome
project: Current state and future direction. Mol. Cell
Proteomics. [Epub ahead of print]. IF: 8.354.
41. Pallari H.M., Lindqvist J., Torvaldson E., Ferraris S.E., He T.,
Sahlgren C. and Eriksson J.E. (2011) Nestin as a regulator
of Cdk5 in differentiating myoblasts. Mol. Biol. Cell. 22:
1539-1549. IF: 5.861.
42. Petre I., Mizera A., Hyder C.L., Meinander A., Mikhailov
A.., Morimoto R.I., Sistonen L., Eriksson J.E. and Back
R.J. (2011) A simple mass-action model for the eukaryotic
heat shock response and its mathematical validation.
Natural Computing 10: 595-612.
32. Leivonen S.K., Rokka A., Ostling P., Kohonen P., Corthals
G.L., Kallioniemi O. and Perälä M. (2011) Identification
16
15
16
17
53. Vainio P., Lehtinen L., Mirtti T., Hilvo M., Seppänen-Laakso
T., Virtanen J., Sankila A., Nordling S., Lundin J., Rannikko
A., Orešic M., Kallioniemi O. and Iljin K. (2011) Phospholipase
PLA2G7, associated with aggressive prostate cancer,
promotes prostate cancer cell migration and invasion and
is inhibited by statins. Oncotarget 2: 1176-1190.
43. Pihlaja R., Koistinaho J., Kauppinen R., Sandholm J.,
Tanila H. and Koistinaho M. Multiple cellular and molecular
mechanisms Are involved in human AÎ² clearance by
transplanted adult astrocytes. Glia 59: 1643-1657. IF: 5.186.
44. Pollari S., Käkönen S.M., Edgren H., Wolf M., Kohonen
P., Sara H., Guise T., Nees M., and Kallioniemi O. (2011)
Enhanced serine production by bone metastatic breast
cancer cells stimulates osteoclastogenesis. Breast
Cancer Res. Treat. 125: 421-430. IF: 4.859.
54. Vainio P., Wolf M., Edgren H., He T., Kohonen P., Mpindi
J.P., Smit F., Verhaegh G., Schalken J., Perälä M., Iljin K. and
Kallioniemi O. (2011) Integrative genomic, transcriptomic,
and RNAi analysis indicates a potential oncogenic role
for FAM110B in castration-resistant prostate cancer.
Prostate. [Epub ahead of print]. IF: 3.377.
45. Rantala J.K., Mäkelä R., Aaltola A.R., Laasola P., Mpindi
J.P., Nees M., Saviranta P. and Kallioniemi O. (2011) A
cell spot microarray method for production of high density
siRNA transfection microarrays. BMC Genomics 12:
162. IF: 4.206.
55. Vuoriluoto K., Haugen H., Kiviluoto S., Mpindi J.P., Nevo
J., Gjerdrum C., Tiron C., Lorens J.B. and Ivaska J. (2011)
Vimentin regulates EMT induction by Slug and oncogenic
H-Ras and migration by governing Axl expression in breast
cancer. Oncogene 30: 1436-1448. IF: 7.414.
46. Rantala J.K., Pouwels J., Pellinen T., Veltel S., Laasola P.,
Mattila E., Potter C.S., Duffy T., Sundberg J.P., Kallioniemi
O., Askari J.A., Humphries M.J., Parsons M., Salmi M. and
Ivaska J. (2011) SHARPIN is an endogenous inhibitor of
b1-integrin activation. Nat. Cell Biol. 13: 1315-1324. IF:
19.407.
56. Vuoriluoto K., Högnäs G., Meller P., Lehti K. and Ivaska J.
(2011) Syndecan-1 and -4 differentially regulate oncogenic
K-ras dependent cell invasion into collagen through a2b1
integrin and MT1-MMP. Matrix Biol. 30: 207-217. IF:
3.328.
47. Rodrigues A.J., Neves-Carvalho A., Teixeira-Castro A.,
Rokka A., Corthals G., Logarinho E. and Maciel P. (2011)
Absence of ataxin-3 leads to enhanced stress response in
C. elegans. PLoS One 6: e18512. IF: 4.411.
57. Vuoriluoto M., Laine L.J., Saviranta P., Pouwels J. and Kallio
M.J. (2011) Spatio-temporal composition of the mitotic
Chromosomal Passenger Complex detected using in situ
proximity ligation assay. Mol. Oncol. 5: 105-111. IF: 4.250.
48. Rosenholm J.M., Sahlgren C. and Lindén M. (2011)
Multifunctional mesoporous silica nanoparticles for combined
therapeutic, diagnostic and targeted action in cancer
treatment. Curr. Drug Targets 12:1166-1186. IF: 3.061.
58. Vähämaa H., Koskinen V.R., Hosia W., Moulder R., Nevalainen
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59. Westerlund N., Zdrojewska J., Padzik A., Komulainen E.,
Björkblom B., Rannikko E., Tararuk T., Garcia-Frigola C.,
Sandholm J., Nguyen L., Kallunki T., Courtney M.J. and
Coffey E.T. (2011) Phosphorylation of SCG10/stathmin-2
determines multipolar stage exit and neuronal migration
rate. Nat. Neurosci. 14: 305-313. IF: 14.191.
50. Tripathi P., Sahoo N., Ullah U., Kallionpää H., Suneja A.,
Lahesmaa R. and Rao K.V. (2011) A novel mechanism
for ERK-dependent regulation of IL4 transcription during
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60. Yang J., Dominguez B., de Winter F., Gould T.W., Eriksson
J.E. and Lee K.F. (2011) Nestin negatively regulates
postsynaptic differentiation of the neuromuscular synapse.
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51. Tyurina Y.Y., Kisin E.R., Murray A., Tyurin V.A., Kapralova
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Alanen K.A., Kallioniemi O. and Iljin K. (2011) Arachidonic
acid pathway members PLA2G7, HPGD, EPHX2, and
CYP4F8 identified as putative novel therapeutic targets in
prostate cancer. Am. J. Pathol. 178: 525-536. IF: 9.865.
18
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PERSONNEL 2011
Administration
LAHESMAA Riitta, Director, Professor,
Group Leader
ALANKO Satu, Coordinator
GRÖNROOS Sirkku, Senior
Administrative Assistant
HIRVENSALO Eva, Clerical Official
JASMAVAARA Aila, Clerical Official
JOKILEHTO Terhi, Coordinator
Protein Crystallography Core
PAPAGEORGIOU Tassos, Group Leader,
Adjunct Professor
HEDMAN Mårten, Systems Manager
STRANDÉN Juha, Laboratory Engineer
VAHAKOSKI Petri, Systems Manager
VILJAKAINEN Pasi, Senior Technician
Bioinformatics core
DENESSIOUK Konstantin, Group Leader
(Structural Bioinformatics)
GYENESEI Attila, Senior Scientist
(High-throughput Bioinformatics)
CHOUHAN Bhanupratap Singh,
Graduate Student
GHIMIRE Bishwa, Undergraduate Student
ISOJÄRVI Janne, Undergraduate Student
JUNTTILA Sini, Graduate Student
KYTÖMÄKI Leena, Project Engineer
LAIHO Asta, Project Engineer
BioCity Turku
HEINO Jyrki, Biocity Turku Scientific
Director, Professor
HEINO Ilona, Student
ALANKO Satu, Coordinator
Technical Staff
HEDMAN Mårten, Systems Manager
KORPIRANTA Virpi, Instrument Maintenance
STRANDÉN Juha, Laboratory Engineer
VAHAKOSKI Petri, Systems Manager
VILJAKAINEN Pasi, Senior Technician
VUORI Hannele, Instrument Maintenance Virus Vector facility
WASBERG Mikael, Laboratory Manager COFFEY Eleanor, Group Leader,
Coordinator
ADEL Ketlin, Laboratory Technician
Finnish Microarray and
Sequencing Centre
GYENESEI Attila, Senior Scientist
HAWKINS David, Group Leader
LUND Riikka, Senior Scientist
PURSIHEIMO Juha-Pekka, Senior Scientist
ALA Kulju Ritva, Student
HEININEN-BROWN Mari,
Undergraduate Student
ISOJÄRVI Janne, Undergraduate Student
JUNNI Päivi, Laboratory Technician
JUNTTILA Sini, Project Engineer
KAUKO Leni, Researcher
KIRALY Andras, Graduate Student
KYTÖMÄKI Leena, Project Engineer
LAIHO Asta, Project Engineer
RISSANEN Oso, Laboratory Technician
SUNDSTRÖM Robin, Undergraduate
Student
VENHO Reija, Laboratory Technician
VIRTANEN Eveliina, Project Engineer
VUORIKOSKI Sanna, Researcher
Cell Imaging Core
ABANKWA Daniel, Academy of Finland
Research Fellow, Coordinator of the
Cell Imaging Core
COFFEY Eleanor, Academy of Finland
Research Fellow, Head of the Cell
Imaging Core
ERIKSSON John, Group Leader, Professor
KORHONEN Jari, Project Engineer
SANDHOLM Jouko, Research Engineer
SAARI Markku, Project Engineer
TERHO Perttu, Project Engineer
Proteomics Facility
CORTHALS Garry, Group Leader, Head
of Proteomics
HAAPANIEMI Pekka, Laboratory Technician
HEINONEN Arttu, Project Engineer
IMANISHI Susumu, Postdoctoral Fellow
KOUVONEN Petri, Researcher
MUTH Dorotha, Senior Scientist
NEES Susanne, Coordinator
ROKKA Anne, Senior Scientist
20
Biobanking and Biomolecular
Resources Research Infrastructure
(BBMRI)
VUORIO Eero, Professor, BBMRI
Executive Manager
SALMINEN-MANKONEN Heli,
Project manager, Adjunct professor
GRÖNROOS Sirkku, Project assistant
Mechanisms and Biosensors of
GTPases
ABANKWA Daniel, Group Leader,
Academy of Finland Research Fellow
GUZMAN Camilo, Postdoctoral Fellow
KOUHI Reihaneh, Undergraduate
Student
LO Rebecca, Graduate Student
NAJUMUDEEN Arafath, Graduate
Student
SOLMAN Maja, Graduate Student
Protein Kinase Regulation of Brain
Development and Disease
COFFEY Eleanor, Group Leader,
ADUSUMALLI Ravi, Undergraduate Student
DESHPANDE Prasannakumar,
Graduate Student
FLINKMAN Dani, Undergraduate Student
HOLLOS Patrik, Undergraduate Student
KOMULAINEN Emilia, Graduate Student
MOHAMMAD Hasan, Graduate Student
MYSORE Raghavendra, Graduate Student
PADZIK Artur, Graduate Student
ZDROJEWSKA Justyna, Graduate
student Translational Proteomics
CORTHALS Garry, Group Leader,
Head of Proteomics
BULBUL Ahmed, Undergraduate Student
CHAND Thaman, Undergraduate Student
EEROLA Sini, Laboratory Technician
HAAPANIEMI Pekka, Laboratory Technician
HAKANEN Emmi, Laboratory Technician
HEINONEN Arttu, Project Engineer
IMANISHI Susumu, Postdoctoral Fellow
JAAKKOLA Noora, Undergraduate Student
KANNASTE Olli, Graduate Student
KOTTAHACHCHI Darshana, Graduate
Student
KOUVONEN Petri, Researcher
KUMAR Santosh, Undergraduate Student
MUTH Dorotha, Senior Scientist
NEES Susanne, Coordinator
ROKKA Anne, Senior Scientist
SAEIDI Firouz, Undergraduate Student
DE SANTOS Hugo, Graduate Student
SUNI Veronika, Graduate Student
Organisation of Neuronal Signaling
Pathways
COURTNEY Michael, Group Leader,
Professor
GASCOGNE Esther, Undergraduate Student
HO Franz, Postdoctoral Researcher
HOLME Andrea, Senior Scientist
LI Lili, Graduate Student
LIU Xiaonan, Graduate Student
MARTINSSON Peter, Postdoctoral
Researcher
MIN Jungah, Senior Scientist
RAI Surya, Undergarduate Student
SEPPÄNEN Aila, Laboratory Technician
VERGUN Olga, Postdoctroal Researcher
WANG Xijun, Graduate Student
Structural Bioinformatics
DENESSIOUK Konstantin, Docent,
Group Leader
CHOUHAN Bhanupratap Singh,
Graduate Student
HEININEN-BROWN Mari, Bioinformatician
Data Mining and Modeling
ELO Laura, Group Leader, Adjunct Professor
AITTOKALLIO Tero, Group Leader,
Adjunct Professor
NEVALAINEN Olli, Group Leader, Professor
ERONEN Ville- Pekka, Undergraduate
Student
GAO Bin, Undergraduate Student
HEISKANEN Marja, Graduate Student
HIISSA Jukka, Graduate Student
JÄRVINEN Aki, Undergraduate Student
KOSKINEN Ville, Undergraduate Student
LAAJALA Essi, Undergraduate Student
LAAJALA Teemu Daniel, Undergraduate
Student
LINDEN Rolf, Graduate Student
OKSER Sebastian, Graduate Student
SALMI Jussi, Postdoctoral Fellow
SANTA Harri, Undergraduate Student
SUOMI Tomi, Graduate Student
TUIKKALA Johannes, Graduate Student
VÄHÄMAA Heidi, Graduate Student
Cytoskeletal and Survival Signaling
ERIKSSON John, Group Leader, Professor
ASAOKA Tomoko, Graduate Student
CHENG Fang, Post-doctoral fellow
FERRARIS Saima, Graduate Student
GULLMETS Josef, Undergraduate Student
HYDER Claire, Graduate Student
LINDQVIST Julia, Graduate Student
LUNDGREN Jolanta, Undergraduate
Student
MOHANASUNDARAM Ponnuswamy,
Graduate Student
ISONIEMI Kimmo, Graduate Student
PALLARI Hanna-Mari, Post-doctoral fellow
PAZIEWSKA Beata, Secretary
PAUL Preethy, Undergraduate Student
PEUHU Emilia, Graduate Student
PRASEET Poduval, Postdoctoral Fellow
PYLVÄNÄINEN Joanna, Undergraduate
Student
RAJENDRAN Senthil Kumar,
Postdoctoral Fellow
REMES Mika, Postdoctoral Fellow
ROBERTS Maxwell, Undergraduate Student
RUSSELL John, Undergraduate Student
SAARENTO Helena, Research Associate
TORVALDSON Elin, Graduate student Epigenomics
HAWKINS David, Group Leader
PASUMARTHY Kalyan, Postdoctoral Fellow
VALENSISI Cristina, PostdoctoralFellow
Cell Adhesion and Cancer
IVASKA Johanna, Group Leader, Professor
ALANKO Jonna, Graduate Student
ARJONEN Antti, Graduate Student
DE FRANCESCHI Nicola, Graduate Student
HÖGNÄS Gunilla, Graduate Student
KAUKONEN Riina, Graduate Student
LAHTINEN Laura, Graduate Student
MATTILA Elina, Postdoctoral Fellow
MUHARRAM Ghaffar, Postdoctoral Fellow
POUWELS Jeroen, Postdoctoral Fellow
SAARI Markku, Coordinator
SIIVONEN Jenni, Laboratory Technician
TUOMI Saara, Postdoctoral Fellow
VELTEL Stefan, Postdoctoral Fellow
VIRTAKOIVU Reetta, Graduate Student
Hypoxia in Cell Survival
JAAKKOLA Panu, Group Leader,
Adjunct Professor
HEIKKINEN Pekka, Graduate Student
HÖGEL Heidi, Graduate Student
JOKILEHTO Terhi, Graduate Student
KALEVO-MATTILA Taina, Laboratory
Technician
MIIKKULAINEN Petra, Laboratory
Technician
NUUTILA Maiju, Undergraduate Student
RANTANEN Krista, Graduate Student
Bioenergy
JONES Patrik, Group Leader
AKHTAR M. Kalim, Researcher
CARBONELL Veronica, Graduate Student
CORREDU Danilo, Undergraduate Student
DAPANDANI Hariharan, Undergraduate
Student
EL SOUKI Francy, Graduate Student
GUERRERO Fernando, Researcher
KÄMÄRÄINEN Jari, Graduate Student
OTANI Yumi, Coordinator
PASZTOR Andras, Graduate Student
PELTONEN Sanna, Graduate Student
TALLIHÄRM Artur, Undergraduate
Student
VUORIJOKI Linda, Graduate Student
WELDENGODGUAD Melak,
21
Mitosis and Drug Discovery
KALLIO Marko, Group Leader, Senior
Research Scientist, Adjunct Professor
ASGHAR Adel, Undergraduate Student
JAAKKOLA Kimmo, Postdoctoral Fellow
KUKKONEN-MACCHI Anu,
Postdoctoral Fellow
LAINE Leena, Postdoctoral Fellow
MÄKI-JOUPPILA Jenni, Graduate Student
NARVI Elli, Postdoctoral Fellow
OETKEN-LINDHOLM Christina,
Postdoctoral Fellow
SALMELA Anna-Leena, Graduate Student
TAMBE Mahesh, Graduate Student
TOIVONEN Pauliina, Laboratory Technician
WINSEL Sebastian, Postdoctoral Fellow
Canceromics Research Programme
KALLIONIEMI Olli, Group Leader, Director
PLOSILA Riina, Coordinator
AAKULA Anna, Graduate Student
BUCHER Elmar, Graduate Student
BJÖRKMAN Mari Graduate Student
GUPTA Santosh, Graduate Student
KETOLA Kirsi, Graduate Student
KOHONEN Pekka, Graduate Student
POLLARI Sirkku, Graduate Student
VAINIO Paula, Graduate Student
Signaling Pathways Regulated by
Oncogenic Pim Kinases
KOSKINEN Päivi, Group Leader,
Adjunct Professor
EEROLA Sini, Undergraduate Student
EKMAN Heidi, Undergraduate Student
RAINIO Eeva-Marja, Postdoctoral Fellow
SANDHOLM Jouko, Graduate Student
SANTIO Niina, Undergraduate Student
VAHAKOSKI Riitta, Graduate Student
VIRTANEN Juho, Undergraduate Student
Molecular Immunology and
Systems Biology of Cell
Differentiation
LAHESMAA Riitta, Director, Professor,
Group Leader
BALA Kanchan, Senior Scientist
CHEN Zhi Jane, Senior Scientist
EDELMAN Sanna, Postdoctoral Fellow
ELO-UHLGREN Laura, Adjunct
Professor, Senior Scientist
FEZAZI Bogata, Laboratory Technician
HAKANEN Emmi, Undergraduate Student
HAKKARAINEN Marjo, Laboratory Technician
HEINONEN Mirkka, Graduate Student
HEINONEN Sarita, Laboratory Technician
KALLIONPÄÄ Henna, Graduate Student
KANDURI Kartiek, Graduate Student
KHAN MOHN Moin, Graduate Student
KORHONEN Juha, Graduae Student
KYLÄNIEMI Minna, Graduate Student
LAAJALA Essi, Undergraduate Student
LUND Riikka, Senior Scientist
LÖNNBERG Tapio, Graduate Student
MAURINEN Krista, Undergraduate Student
MOULDER Robert, Senior Scientist
MYLLYVIITA Johanna, Undergraduate
Student
NÄRVÄ, Elisa, Graduate Student
OIKARI Lotta, Undergraduate Student
PIETILÄ Elina, Laboratory Technician
RAHKONEN Nelly, Undergraduate Student
RAJAVUORI Anna, Undergraduate Student
22
RAO Anjana, Visiting Professor
RAO Kanury, Visiting Professor
RASOOL Omid, Adjunct Professor,
Senior Scientist
REDDY Emaheswa, Postdoctoral fellow
SALO Verna, Graduate Student
SARAPULOV Alexey, Graduate Student
STOCKINGER Brigitta, Visiting Professor
TAHVANAINEN Johanna, Postdoctoral
fellow
TRIPATHI Subhash, Graduate Student
TUOMELA Soile, Graduate Student
ÖLING Viveka, Postdoctoral Fellow
Quality Assurance Unit
LINKO Linnéa, Group Leader, Adjunct
Professor
Computational Systems Biology
LÄHDESMÄKI Harri, Group Leader,
Professor
ALASOO Kaur, Undergraduate Student
ERKKILÄ Timo, Graduate Student
INTOSALMI Jukka, Post-doctoral Fellow
KANDURI Kartiek, Graduate Student
KONG Lingjia, Graduate Student
KÄHÄRÄ Juhani, Undergraduate Student
LARJO Antti, Graduate Student
MALONZO Maia, Undergraduate Student
MANNERSTRÖM Henrik, Graduate
Student
NOUSIAINEN Kari, Graduate Student
OSMALA Maria, Graduate Student
RAUTIO Sini, Undergraduate Student
SEPPÄLÄ Janne, Undergraduate Student
SOMANI Juhi, Undergraduate Student
ÄIJÖ Tarmo, Graduate Student
Complex Biosystems Modeling
NYKTER Matti, Group Leader
ANNALA Matti, Graduate Student
GRANBERG Kirsi, Post-doctoral Fellow
KARTASALO Kimmo, Undergraduate
Student
KESSELI Juha, Post-doctoral Fellow
KIVINEN Virpi, Graduate Student
LEPPÄNEN Simo-Pekka,
LIUKSIALA Thomas, Undergraduate
Student
SARBU Septimia, Graduate Student
SOININEN Tero, Undergraduate Student
SORSA Saija, Undergraduate Student
WALTERING Kati, Post-doctoral Fellow
YLIPÄÄ Antti, Graduate Student
RUSKEEPÄÄ Anna-Liisa, Technician
Sysi-Aho Marko, Team Leader
VELAGAPUDI Vidya R., Research
scientist
YETUKURU Laxman, Research scientist
ZHAO Han, Technician
ÖHRNBERG Leena, Technician
Protein Crystallography
PAPAGEORGIOU Tassos, Group
Leader, Adjunct Professor
BATTULA Pradeep, Undergraduate
Student
BRUNEAU Morgane, Undergraduate
Student
DHAVALA Prathusha, Graduate Student
HERNANDEZ David, Undergraduate
Student
HAIKARAINEN Teemu, Graduate Student
MATTSSON Jesse, Graduate Student
MULETA Abdi, Undergraduate Student
SIVARAMAN Chamundeeswari,
SUBEDI Bishwa, Undergraduate Student
Cell fate
SAHLGREN Cecilia, Group Leader,
ANTFOLK Daniel, Undergraduate Student
ANTILA Christian, Graduate Student
BAGHINOV Habib, Graduate Student
BAGHIRO Habib, Undergraduate Student
LANDOR Sebastian, Graduate Student
MAMAEVA Veronika, Postdoctoral Fellow
PRABHAKAR Neeraj, Undergraduate
Student
SAARENTO, Helena, Laboratory Technician
SARINKO Sara, Undergraduate Student
SJÖQVIST Marika, Graduate Student
THATIKONDA Santosh Kumar,
Graduate Student
Targeting Strategies for
Gene Therapy
SAVONTAUS Mikko, Group Leader,
Adjunct Professor
EEROLA Kim, Graduate Student
MATTILA Minttu, Undergraduate Student
TOIVONEN Raine, Graduate Student Regulation and Function of Heat
Shock Transcription Factors
SISTONEN Lea, Group Leader, Professor
AALTO, Anna, Undergraduate Student
AHLSKOG Johanna, Postdoctoral Fellow
BERGMAN Heidi, Undergraduate Student
BJÖRK Johanna, Graduate Student
BLOM Malin, Undergraduate Student
BUDZYNSKI Marek, Graduate Student
ELSING Alexandra, Graduate Student
HENRIKSSON Eva, Postdoctoral Fellow
HUDD Joachim, , Undergraduate Student
JOUTSEN Jenny, Undergraduate Student
LUNDSTEN Emine, Undergraduate Student
PUUSTINEN Mikael, Undergraduate
Student
ROOS-MATTJUS Pia, Senior Scientist
SAARENTO Helena, Research Associate
SANDQVIST Anton, Postdoctoral Fellow
SEIJAS BIEL Hanser Jose,
VAINIO Petra, Graduate Student
VASARA Jenni, Student
VIHERVAARA Anniina, Graduate Student
ÅKERFELT Malin, Postdoctoral Fellow Cancer Cell Signaling
WESTERMARCK Jukka, Group Leader,
Professor
ANCHIT Khanna, Graduate Student
CVRLSEVIC Anna, Postdoctoral Fellow
HALONEN Tuuli, Graduate Student
KALEVO-MATTILA Taina, Laboratory
Technician
KAUKO Otto, Graduate Student
KAUR Amanpreet, Graduate Student
LAINE Anni, Graduate Student
NIEMELÄ Minna, Graduate Student
OKKERI Juha, Postdoctoral Fellow
POKHAREL Yuba, Postdoctoral Fellow
PUKONEN Inga, Laboratory Technician
SITTIG Eleonora, Laboratory
Technician
VENTELÄ Sami, Postdoctoral Fellow
XI Qiao, Graduate Student
Adenosine Deaminases
ZAVIALOV Andrey, Group Leader,
REZA Salim, Graduate Student
SKALDIN Maksym, Graduate Student
Metabolome in Health and Disease
OrešiC Matei, Group Leader, Professor
Bondia Pons Isabel, Research scientist
Castillo Sandra, Research scientist
Hilvo Mika, Research scientist
Hyötyläinen Tuulia, Team Leader
JÄNTTI Sirkku, Research scientist
KIVILOMPOLO Maarit, Research scientist
KOIVUNIEMI Artturi, Research scientist
LAHTINEN Ulla, Technician
LANKINEN Maria, Research scientist
LINDFORS Erno, Research scientist
LÖNNBERG Tapio, Research scientist
MARINKOVIć Tijana, Research scientist
MATTILA Ismo, Research scientist
NYGREN Heli, Research scientist
PEDDINTI Gopal, Research scientist
23
Our Centre also provides services on commercial microarray
platforms for genome-wide RNA expression profiling, SNP
genotyping and comparative genomic hybridization needs. These
platforms include Affymetrix GeneChip©, Illumina Sentrix Bead Array©
and Agilent DNA technology services for all of which we have been
granted the Certified Service Provider status. All platforms have
dedicated scanners and software for array data analysis. Diverse
aspects of the microarray techniques are continuously developed
and tested. Additionally, Affymetrix GeneTitan microarray system
was purchased to automate sample processing.
The Microarray and Sequencing Centre also offers a number of
other genomic analysis technologies for gene expression, SNP
and genotyping studies including a sequencing facility and realtime PCR service. Services include BioRad Experion and Agilent
Bioanalyzer runs for verifying the RNA quality.
FINNISH MICROARRAY AND
SEQUENCING CENTRE
http://fmsc.btk.fi
Scientists in charge:
Attila Gyenesei, Ph.D., Senior Scientist
– FMSC services and operation, bioinformatics
David Hawkins, Ph.D., Group Leader
– Epigenetics and emerging technologies
Riikka Lund, Ph.D., Senior Scientist – Epigenetics
Juha-Pekka Pursiheimo, Ph.D., Senior Scientist – SOLID NGS
Contact information:
Turku Centre for Biotechnology, BioCity,
Tykistökatu 6A, P.O. Box 123, FIN-2050 Turku, Finland.
Tel. +358-2-333 8634 Fax +358-2-333 8000.
Email: fmsc@btk.fi
http://fmsc.btk.fi
Bioinformatics data analysis and data mining are included in the
data analysis service that is provided for microarray and nextgeneration sequencing customers. The data handling is done by
our bioinformaticians, using both commercial and R/Bioconductor
software tools.
Personnel:
Päivi Junni, Sini Junttila, Andras Kiraly, Leena Kytömäki, Asta Laiho,
Oso Rissanen, Reija Venho, Eveliina Virtanen, Sanna Vuorikoski,
Leni Kauko, Ritva Ala-Kulju, Janne Isojärvi, Bishwa Ghimire, Robin
Sundström.
Steering Committee:
Prof. Olli Carpén, Chair (University of Turku), Prof. Eva-Mari Aro
(University of Turku), Prof. Klaus Elenius (University of Turku), Prof.
Riitta Lahesmaa (University of Turku), Prof. Tarja Laitinen (University
of Turku), Prof. Harri Lähdesmäki (University of Turku, Aalto
University), Prof. Craig Primmer (University of Turku), Prof. Harri
Savilahti (University of Turku), Prof. Lea Sistonen (Åbo Akademi
University), Prof. Stina Syrjänen (University of Turku)
General description:
The Finnish Microarray and Sequencing Centre (FMSC), an
internationally recognised Functional Genomics Core Facility
belongs to the Turku Centre for Biotechnology. As a national core
facility, we provide state-of-the-art research technologies and
services in the areas of genomics, epigenomics, transcriptomics
and bioinformatics for the Finnish as well as the international
scientific community. Our services include next-generation
sequencing and microarray based services mainly focusing on gene
expression and regulation as well as epigenetics, Real-Time PCR
and traditional DNA sequencing. Our service covers all the steps
from experimental planning and design to sample processing and
bioinformatics data analysis. The Centre also regularly organizes
courses, symposia and training for its users.
FMSC hosts a high-throughput
next-generation sequencing
TM
(NGS) instruments SOLiD 5500 XL from Life Technologies and
HiSeq2000 from Illumina. The systems support a wide range of
genetics applications covering genomics, transcriptomics and
epigenomics and they have high accuracy and capability of
generating more than 100 gigabases of mappable sequence data
per run. The combination of increased throughput, shorter run
times, and improved data analysis make both SOLiD and HiSeq
technologies ideal choices for research applications in a wide
range of projects.
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Seminars and practical courses on microarrays, next-generation
sequencing and related bioinformatics are held frequently to
facilitate knowledge transfer within the field, often this is done in
collaboration with graduate schools.
Major achievements in 2011:
According to the division of tasks Turku node focuses on developing
technologies in the areas of gene expression and its regulation.
FMSC services according to the BF application:
•· Sequencing of immunoprecipitated DNA/RNA (ChIP-seq,
PAR-CLIP, ChIP-chip)
•· RNA sequencing
•· Gene expression microarrays
Additionally, in response to the increasing demands in the
epigenetic field one of the key goals in the Centre has been to
develop advanced techniques and optimizing reagents and set
up a service for Epigenomic applications.To achieve the goals the
following was accomplished in 2011:
•· 79 service projects were carried out in 2011. These
included 50 microarray platform based projects and 29
next-generation sequencing projects (including ChIP-seq,
FAIRE-seq, whole transcriptomics, small RNA, targeted
resequencing, whole genome de-novo sequencing,
methylation analysis, whole genome resequencing)
•· PAR-CLIP technique has been set up. First sample sets
were sequenced with SOLID 4 and analyzed by our
affiliated group leader Prof Harri Lähdesmäki and his
group. The technology development continues with a goal
to provide PAR-CLIP through research collaboration from
the second half of 2012.
•· Chromatin Immunoprecipitation (ChIP) application has
been set up in the Centre. This started with the optimization
of the chromatin fragmentation to a size distribution
optimal for genome-wide sequencing. In particular, the
optimization was carried out also for challenging sample
types. In the next phase a panel of good quality antibodies
was selected for the ChIP application to enable genomewide profiling of the histone marks for active and inactive
promoters and enhancers. The ChIP protocol was
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25
optimized and the amount of starting material needed
for ChIP was scaled down 25 times. Also the amount of
antibodies and beads used for ChIP reactions were scaled
down. We have successfully generated ChIP-Seq histone
modification maps from Illumina sequencing. With the
Biocentre Finland funding automated system for epigenetic
sample preparation, SX-8G IP-Star® from Diagenode was
purchased. The IP-Star robot enables epigenetic sample
preparation in a standardized and quality controlled
manner, which is crucial for the service. The internal quality
control steps for monitoring the sample quality and sample
preparation process were established.
• Reduced Representative Bisulfite Sequencing (RRBS)
·
assay has been set up to for DNA methylation profiling.
This technique enables global profiling of DNA methylation
at the CpG islands and shores with single base pair
resolution from a starting material as low as 500 ng of
genomic DNA. In comparison to whole genome bisulfite
sequencing, in RRBS enzymatic treatment is used to
enrich the CpG-rich regions enabling cost efficient profiling
of DNA methylome. We have established the entire
pipeline from sample preparation and data acquisition
to visualizing the results on UCSC browser. The Illumina
TruSeq multiplexing/sample indexing library preparation kit
has been optimized for compatability with low amounts
of RRBS DNA to provide commercially, quality controlled
reagents for library generation. Sequencing capacity
and mapping efficiency (45-65%) are equivalent to or
surpassing recently published results. Bisulfite conversion
controls have been implemented to ensure accurate
calling of methylation status.
·
• As the Helicos instrument, tested by the Centre in 2010,
is not available for use, a HiSeq2000 instrument from
Illumina was purchased (U. Turku funding) and installed in
November 2011, in particular for epigenomic applications,
as it supports both the RRBS and ChIP assay. Preparation
of the ChIP samples for sequencing with SOLID platform
was found to be challenging partly due to narrow chromatin
fragment size distribution required for sequencing SOLID
instrument. The RRBS and RNA-Seq applications
have already been successfully run with the instrument.
Currently, the work is carried out to set up the multiplexing
of the ChIP samples for sequencing, which is currently not
supported by commercial kits from Illumina. Multiplexing
of the ChIP samples will significantly reduce the cost of
ChIP-Seq analysis. In addition, the next focus areas are
to explore possibilities and develop methods for analysis
of challenging sample material, such as clinical sample
material from FFPE tissues or with restricted starting
amounts.
•· The bioinformatics team of the Centre has set up a new
computer cluster to increase the computation power and
storage capacity the new next generation sequencing
instrument requires. Development of data analysis pipeline
for various next-generation sequencing applications
including RNA-seq, Chip-seq and methylation analysis
has been completed and applied to 23 NGS projects.
Funding:
University of Turku
Biocenter Finland
Users:
Finnish Microarray and Sequencing Centre has national and
international customers from universities, biocenters and research
institutes in the field of biosciences.
From left to right: Asta Laiho, Attila Gyenesei, Juha-Pekka Pursiheimo, Reija Venho,
Leni Mannermaa, Eveliina Virtanen, Leena Kytömäki, Sini Junttila, Riikka Lund, Päivi
Junni, Cristina Valensisi and Kalyan Pasumarthy
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CELL IMAGING CORE
http://www.btk.fi/cell-imaging/
Coordinator and Group Leader:
Daniel Abankwa, PhD, PI, Turku Centre for Biotechnology, BioCity,
5th floor, Tykistökatu 6B, FI-20520, Finland. Tel. +358-2-3336969,
Fax. +358-2-3338000. Email: daniel.abankwa@btk.fi
Technical Team/Technical Team leaders:
Perttu Terho, M.Sc., Technical Engineer Flow Cytometry, Email:
perttu.terho@btk.fi, Markku Saari, M.Sc., Researcher Microscopy,
Email: msaari@btk.fi, Jari Korhonen, M.Sc., Researcher
Microscopy, Email: jari.korhonen@abo.fi, Jouko Sandholm, M.Sc.,
Senior Researcher Microscopy, Email: jouko.sandholm@btk.fi
Steering Committee:
Prof. Olli Carpén, M.D., Ph.D., University of Turku, Prof. John Eriksson
(chairman), Ph.D., Åbo Akademi University, Prof. Jyrki Heino, M.D.,
Ph.D., University of Turku, Prof. Pekka Hänninen, Ph.D., University
of Turku, Prof. Sirpa Jalkanen, M.D., Ph.D., University of Turku, Prof.
Riitta Lahesmaa, M.D., Ph.D., University of Turku, Prof. Olli Lassila,
M.D., Ph.D., Prof. Matti Poutanen, Ph.D., University of Turku, Prof.
Lea Sistonen, Ph.D., Åbo Akademi University, Kid Törnquist, Ph.D.,
Åbo Akademi University
Core facility description:
The mission of Cell Imaging Core (CIC) is to provide state-of-theart cell imaging and flow cytometry technologies and to make
them available to scientists and students mainly coming from the
University of Turku, Åbo Akademi University and VTT Technical
Research Centre for Medical Biotechnology. Importantly, CIC is
open to both academic and industrial researchers.
One major goal of CIC is to enhance the research and teaching
environment locally, nationally and internationally. Therefore, CIC
·
• provides numerous instruments (microscopes, flow
cytometers etc.) for research and teaching use
·
• provides technical training to local and visiting researchers
and to industries
·
• offers consultation on experimental design and image
analysis
·
• evaluates new methods and fluorescence tools and
communicates acquired knowledge to users
·
• implements advances in hardware and software relevant
for biomedical sciences
·
• provides ongoing education in theory and practice
by organizing training courses and international
workshops
Our staff includes a coordinator and experienced application
specialists, who maintain the instruments, learn new technologies
and most importantly, provide personal training to users. Our areas
of technical expertise are STED superresolution microscopy, live
cell imaging, F-techniques (FRET and FRAP imaging), confocal
microscopy (including timelapse and spectral detection), highcontent imaging, widefield fast CCD imaging, laser-capture
microdissection, high throughput cell sorting, flow cytometry FRET
and advanced flow cytometry software development. The STED
technique was developed by Stefan Hell in the group of Prof.
Pekka Hänninen in the mid 1990s in Turku. Complementary to this
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27
From left to right: Perttu Terho, Markku Saari, Daniel Abankwa, Jari Korhonen,
Pasi Kankaanpää
29
superresolution technology, we have two Atomic Force Microscopy
(AFM) setups, which are coupled to a Zeiss LSM510 and the Leica
STED microscope.
Most of the instruments are provided in two facility areas of the
CBT, while others are housed nearby within BioCity. Thanks to
great funding success and local support in 2010/2011, we have
significantly expanded our instrumentation to feature two new
confocal microscopes with fluorescence lifetime imaging and
fluorescence correlation spectroscopy capabilities (see list below). In
addition, image analysis workstations that run the locally developed
BioImageXD image analysis software have become available.
We organize local and national training programs, service existing
equipment, sustain research on new imaging techniques, and
implement the latest technological advances demanded by the
research community. A number of international leaders in the field of
microscopic imaging have visited Turku for scientific presentations
and lectures, such as Stefan Hell (MPI bpc Göttingen, Germany).
Current information on events, services and pricing can be found
on the facility webpages.
CIC has succeeded both as a service provider and as a point of
integration of emerging imaging technologies. In the Turku scientific
community, added value is achieved by the first-class expertise
in the fields of fluorescence-activated cell sorting, fluorescencebased screening, high-content screening, in vivo animal imaging,
and viral gene transfer.
CIC is nationally and internationally networked (e.g. through the
Nordic Network on Imaging in Medicine and Biology). Importantly,
CIC is one of the major contributors to Turku BioImaging, an
umbrella organization, which aims at organizing and supporting
bioimaging expertise in the Turku area. Through this activity,
Turku BioImaging sites have become one of the first three test
sites for the Euro-BioImaging initiative. Euro-BioImaging aims at
providing access, service and training to state-of-the-art imaging
technologies in Europe. To this end, a harmonized infrastructure
deployment is planned in the next few years, which is meant to
facilitate excellence in research.
Funding:
The Academy of Finland, University of Turku, Åbo Akademi
University, BioCity Turku Research Groups, Biocenter Finland,
Health and Welfare Ministry
PROTEOMICS
PROTEOMICS FACILITY
FACILITY
http://www.btk.fi/proteomics
Coordinator and Group Leader:
Garry Corthals, Ph.D. (2005).
Address: Turku Centre for Biotechnology, BioCity, Tykistökatu 6,
P.O. Box 123, FI-20521 Turku, Finland.
Tel. +358-2-333 8889, Fax. +358-2-333 8000.
E-mail: garry.corthals@btk.fi
Personnel:
Senior scientists: Dr. Anne Rokka, Ph.D.; Dorota Muth, Ph.D.;
Susumu Imanishi, Ph.D.; Project Engineer: Arttu Heinonen;
Laboratory Technician: Pekka Haapaniemi; Researcher: Petri
Kouvonen; Coordinator: Susanne Nees.
Steering Committee:
Prof. Eva-Mari Aro (University of Turku), Dr. Eleanor Coffey (Åbo
Akademi University), Prof. John Eriksson (Åbo Akademi University),
Prof. Jyrki Heino (University of Turku), Prof. Riitta Lahesmaa (CBT),
Prof. Matti Poutanen, Prof. Craig Primmer (University of Turku),
Prof. Jukka Westermarck (CBT) and Prof. Johanna Ivaska (VTT &
CBT)
General description:
The Turku Proteomics Facility is engaged in the development
and application of proteomics and mass spectral methods
in key areas of life science research. In doing so we have
developed a wide basis of operation and expertise in Quantitative
proteomics, Post-translational modification analysis, Imaging mass
spectrometry, Biological mass spectrometry, Protein separation
and Bioinformatics.
The Mission of the Facility is to advance MS methods and instrumentation
to meet the needs in molecular biotechnology and medicine. Our goals
are to identify new areas appropriate for MS in biological sciences and
to develop new approaches involving MS, to apply cutting-edge MS
to tackle critical questions in biological sciences, and train students,
postdoctoral fellows and practicing scientists in the use of MS and
encourage its wide and appropriate use.
The facility receives funding locally through the University of Turku.
National funding is provided for the facility to serve as a technology
platform through financial support of Biocentre Finland. Nationally
the facility spearheads mass spectrometric developments, training
and application in quantitative analysis of proteins and proteomes,
and analyses of PTMs.
Analytical services:
The facility offers access to advanced methods and sophisticated
instrumentation that enable high-content protein and proteome
measurements. Most services involve mass spectral methods
integrated with services ranging from protein and peptide
enrichment workflows for large-scale analysis of proteomes to
detailed characterisation of single proteins. We aim to offer the best
possible analytical proteomics services to bioscience researchers
in academia and industry, both locally and nationally through
Biocentre Finland coordinated activities.
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31
A full representation of our services in 2011 were as follows:
·• Shotgun / discovery proteomics – ‘-omic-scale’ analysis of
cells, tissues and fluids is available in all life sciences. Several
integrated fractionation techniques have been developed
to provide deep proteome coverage from exquisite sample
amounts.
·• Quantitative proteomics – Analysis of proteomes following
isobaric or isotopic labelling with reagents such as iTRAQ and
SILAC.
·• Label-free quantitation – We have established a framework
for label-free quantitative analysis, particularly useful for largescale clinical studies.
·• Post-translational modifications –a long standing history
with phosphorylation analysis exists on campus, and we
have expanded our ‘PTM tool set’ through newly developed
methods by various closely affiliated groups, including
sumoylation analysis.
·• Imaging mass spectrometry – imaging of tissues is offered as
a collaborative service with the proteomics research group.
·• Biological mass spectrometry – various analytical
measurements for protein, peptide and small molecule
structure determination, mass determination and peptide and
protein purity are offered.
·• Protein separation – numerous separation technologies including
liquid chromatography and a variety of gel based methods
such as 1-DE, 2-DE, peptide-IPG and blue native gel
electrophoresis.
·• Bioinformatics – in all areas of proteomics bioinformatics
services are offered including identification, quantitation and
validation studies, reporting and software development.
Major mass spectrometry instrumentation:
For ESI-MS/MS – Q-Star Pulsar, Q-Star Elite and LTQ Velos
Orbitrap with ETD
For MALDI-MS/MS – Ultrafelx II ToF ToF system
Funding:
University of Turku and Åbo Akademi University, Biocenter Finland,
The Academy of Finland, City of Turku, Ministry of Education,
Centre of Expertise of Southwest Finland, Bruker Daltonics, the
Systems Biology Research Program.
Users:
The University of Turku, Åbo Akademi University, Biocentre Finland
universities, Turku Polytechnic, VTT - Molecular Biotechnology.
CoE’s in: Translational Genome-Scale Biology; Evolutionary
Genetics and Physiology; Integrative Photosynthesis and Bioactive
Compound Research at Systems Biology Level; and Åbo Akademi
CoE in Cell Stress. The Systems Biology Research Program,
national research groups, Turku Hospitals, the Finnish Red Cross
and the National Animal Research Centre.
From left to right: Garry Corthals, Anne Rokka, Arttu Heinonen, Susumu Imanishi
and Dorota Muth
32
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PROTEIN CRYSTALLOGRAPHY
CORE FACILITY
BIOINFORMATICS CORE
http://www.btk.fi/crystallography/
Head:
Anastassios C. Papageorgiou, Ph.D., Adjunct Professor in
Biochemistry and Structural Biology Turku Centre for Biotechnology,
BioCity, Tykistökatu 6A, FI-20521 Turku, Finland.
Tel. +358-2-3338012, Fax +358-2-3338000.
E-mail: tassos.papageorgiou@btk.fi
Personnel:
Bhanupratap Singh Chouhan, Sini Junttila, Asta Laiho, Leena
Kytömäki, Bishwa Ghimire, Janne Isojärvi
Technical Team:
Technical support: Juha Strandén, Pasi Viljakainen.
Computational support: Petri Vahakoski, Mårten Hedman
Steering committee:
Jyrki Heino, Professor, Department of Biochemistry and Food
Chemistry, University of Turku; Reijo Lahti, Professor, Department
of Biochemistry and Food Chemistry, University of Turku; Tiina
Salminen, Senior lecturer, Department of Biochemistry, Åbo
Akademi; BioXlabs-Turku
Description of the Facility:
X-ray crystallography is a proven technique for detailed structurefunction studies of biological macromolecules. The Protein
Crystallography Core Facility at CBT uses state-of-the-art equipment
to determine the crystal structures of various proteins and their
complexes. The Facility consists of an X-ray generator (Rigaku
MicroMax 007 HF), Mar345 imaging plate detector, Varimax optics,
a Cryostream Cooler (Oxford Cryosystems) and several computers
running under Linux operating systems for heavy duty calculations.
The Facility has several workstations to run a variety of molecular
graphics software (O, XtalView, Grasp, COOT, CCP4mg, PyMol,
Chimera), modeling and docking programs (MODELLER, Hex,
Discovery Studio, ROSETTA), and various crystallographic packages
(HKL, XDS, CNS, CCP4, SHELX, SOLVE, SHARP, PHENIX) for data
processing, analysis, phasing and refinement. The Facility has long
expertise in all steps of a crystal structure determination: protein
purification, crystallization, data collection (both in-house and in
synchrotron radiation sources), data processing, phase determination,
refinement and detailed analysis of the final structure. Incubators at
different temperatures (4° C, 16 °C and 23 °C) for crystallization
set-ups and a number of commercial screens for establishing initial
crystallization conditions are available. In addition, we can provide
homology modeling services and design of mutants for functional
studies as well as ab initio predictions of protein structures. Since
protein crystallography requires highly pure protein preparations,
we can offer full support and consultation on protein purification
strategies apart from the services in structure determination and
modeling. The Facility is able to undertake research projects for
academic groups and companies, either in the form of collaborative
efforts or as services. Protein Crystallography requires a multidisciplinary approach and we are especially interested in bringing
together expertise from various groups in order to better understand
the structure-function relationship of biological macromolecules in
key biological processes.
Funding:
Systems Biology research program, Biocenter Finland, University
of Turku
34
Group leaders:
Konstantin Denessiouk, Ph.D., Docent in Biochemistry.
Bioinformatics Group leader. Centre for Biotechnology,
Tykistökatu 6, BioCity 5th floor, Turku, 20520 Turku.
E-mail: kdenessi@btk.fi
Attila Gyenesei, Ph.D., Turku Centre for Biotechnology,
BioCity, Tykistökatu 6A, P.O. Box 123, FIN-2050 Turku, Finland.
Tel. +3582-333 8634 Fax +358-2-333 8000.
E-mail: attila.gyenesei@btk.fi
33
Description of the Facility:
The bioinformatics core at the Turku Centre for Biotechnology
is divided into Structural Bioinformatics and High-throughput
Bioinformatics facilities.
The main goal of the Structural Bioinformatics Core is to apply
methods and techniques of bioinformatics to study biological
macromolecules, their interactions and function. We work in close
collaboration with experimental groups and are able to provide
structure-related analysis and prediction in different biological
systems. The core works closely with the CSC Finnish IT Center
for Science, the Finnish national supercomputing centre and the
Structural Bioinformatics Laboratory at the Åbo Akademi University.
High-throughput bioinformatics complements experimental
genomics and transcriptomics by storing, analysing and integrating
data and generating hypotheses to guide the design of new
experiments to further elucidate gene function. The core provides
services in the analysis of microarray and deep sequencing data.
In addition to providing data analysis and data integration services
we have robust methods for the design of experiments and novel
microarrays for both diagnostics and biological marker selection.
Our analysts are supported by robust super-computing facilities
and state-of-the-art software. Team members are engaged in the
ongoing development of advanced analysis tools and research on
generating novel approaches for the analysis of high-throughput
data sets.
The main services of our core are:
•· Experimental design consultation
•· Data analysis of various microarray and deep sequencing
data types
•· Data analysis education and training
•· Computer-based analysis of protein-protein and proteinligand interactions
•· Computer-aided prediction and intelligent molecular
modeling and design
•· Computer-based ligand docking
•· Analysis and prediction of effects of molecular recognition
and mutations on protein function
Major achievements in 2011:
·
• Two new computational clusters were acquired, one
dedicated to genome sequencing efforts (supporting BF
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Genomics), funded by the Center for Biotechnology (CBT),
and a second cluster partly funded by Åbo Akademi
• · IT support has integrated dedicated disks and software
tools into the high-capacity server to support BF Biological
Imaging.
• · Workstations and software (modeling, computational
chemistry, chemical structure databases, etc.) supporting
•
BF Structural Biology and BF Translational Activities
(DDCB) have been set up.
• · Structural bioinformatics projects (funded from research
funds) and using BF-funded infrastructure supports
researchers in Bergen (1 project), Heidelberg (2),
Stockholm (1), Tampere (1) and Turku (10).
• · High-throughput bioinformatics group analyzed 23 Next
Generation Sequences and 11 microarray projects (20
local; 13 domestic; 1 international).
Funding:
Grants from the Sigrid Jusélius Foundation, and the Borg
Foundation (Åbo Akademi University); Grant from the National
Graduate School in Informational and Structural Biology (ISB).
Biocenter Finland Infrastructure fund.
Users:
The Bioinformatics core has users from Finnish universities,
biocenters and research institutes in the field of biosciences.
VIRUS VECTOR FACILITY
http://virusvec.btk.fi/
Coordination
Eleanor Coffey, Ph.D., Adjunct Professor in Cellular and
Molecular Biology, Turku Center for Biotechnology,
BioCity, 5th floor, Tykistokatu 6, FI-20521, Finland.
Advisors and collaborators at Turku Center for Biotechnology:
Jukka Westermarck, M.D., Ph.D., Professor, Mikko Savantaus,
M.D., Ph.D. and Anna Cvrljevic, Ph.D.
Technical Team Ketlin Adel, Laboratory Technician, Email: kadel@btk.fi
The Virus Vector Facility produces viral vectors for local and
national research groups. Since 2010, the Virus Vector Facility has
participated in the national infrastructure network on Viral Gene
Transfer, funded by the Biocenter Finland organisation. Our primary
function is to facilitate the use of viral vectors by local researchers
and researchers in other parts of Finland. To this end, the virus
vector facility
·
• produces adenoviruses and lenti vectors expressing genes
of interest, as a research service
·
• maintains a fully equipped bio-safety level-2 lab for
researchers wishing to produce their own vectors
·
• supplies working protocols and technical advice on
production and safe handling of adeno and lenti vectors
·
• coordinates a network of local experts from whom
consultation on design of viral vectors can be sought
The virus vector facility has a national user base with customers from
the universities of Turku, Oulu and Helsinki as well as from biotech
companies. In addition to customer service, our infrastructure is
used by 50 local researchers producing adenoviruses, adenoassociated virus, retroviruses and lentiviral vectors for their
research. These viruses are used to obtain high efficiency gene
transfer in difficult to transfect cells such as primary cultures of T
lymphocytes and neurons and for in vivo cancer studies. Use of
viral gene transfer for gene knockdown including stable knockdown
studies is also popular.
To build on local expertise in gene transfer technologies, the Virus
Vector Facility networks with experts in viral vector design. Thus a
number of local experts on retroviruses and alpha-viruses are available
for consultation on vector design, production and concentration.
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From left to right: Ketlin Adel, Jukka Westermarck, Eleanor Coffey, Mikko
Savontaus and Anna Cvrljevic
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COORDINATION OF EUROPEAN
BIOBANKING
www.bbmri.eu, www.bbmri.se/en/About-BBMRIse/BBMRI-Nordic
Head:
Eero Vuorio, Professor, Director, Biocenter Finland,
P.O. Box 56, University of Helsinki, FI-00014 Helsinki, Finland
Mobile phone +358-50-415 6595, E-mail: eero.vuorio@helsinki.fi
Project Manager:
Heli Salminen-Mankonen, Ph.D., Docent, University of Turku,
Centre for Biotechnology, Tykistökatu 6, FI-20520 Turku, Finland,
Tel: +358-2-333 8566, E-mail: heli.salminen@utu.fi
with data from clinical phenotyping and health-related registries.
The new European legal entity (ERIC) developed by the European
Commission to support the needs and operation of research
infrastructures, foresees the establishment of operational sites
(National Nodes) in different Member States under one legislation.
The BBMRI Management Office in Turku has also played an active
part in establishing the clinical biobanking network in Finland, and
in organizing the collaboration of Nordic biobanks where many
of the operational concepts and principles of BBMRI have been
tested.
Funding:
The preparatory phase (1.2.2008-31.1.2011) of BBMRI has
been financially supported by the European Commission (grant
agreement 212111).
Description of project:
Human biological samples, such as blood, tissues or DNA, plus
associated clinical and research data, as well as biomolecular
research tools are key resources in unravelling genetic and
environmental factors underlying diseases and influencing
their outcome. Biological samples are used in high-throughput
techniques which allow examination of changes in the genome,
transcriptome, proteome, or metabolome. Insights derived
from these are expected to assist with the development of new
diagnostic, prognostic, and therapeutic tools. Consequently,
biological resources are considered as the essential raw material
for the advancement of biotechnology, human health and research
and development in life sciences. This is the landscape where
the pan-European Biobanking and Biomolecular Resources
Research Infrastructure (BBMRI) is expected and prepared to
integrate the existing quality controlled biobanks, biomolecular
resources and enabling technologies into a novel pan-European
biomedical research infrastructure, and to guide the way towards
establishment of high quality de novo European biobanks adhering
to the guidelines drafted by BBMRI.
The European Commission has granted 5 Mio € funding (20082011) to the Preparatory Phase of BBMRI to conceptualise and
secure funding for the construction of the European research
infrastructure for biobanking and biomolecular resources.
Management of BBMRI during the Preparatory Phase is divided
between Universities of Turku and Graz. Eero Vuorio has served as
a part-time Executive Manager and Heli Salminen as the Scientific
Manager of BBMRI. This has been a sizeable task as BBMRI
comprises 53 partners and nearly 250 associated organizations
from 33 countries.
The objectives addressed by the BBMRI consortium during the
Preparatory Phase were to develop a plan to integrate existing
quality controlled biobanks, biomolecular resources and enabling
technologies into a novel pan-European biomedical research
infrastructure (BBMRI-ERIC). BBMRI will not only provide a
comprehensive source of information about existing biological
sample collections and biomolecular resources, but will also
provide an operational concept for a sustainable infrastructure,
deliver standard operational procedures for future biobanking and
codes of conduct for European biobanks. A particular challenge
is the generation of an IT infrastructure capable of linking the
existing biobank-derived genetic and molecular phenotyping data
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39
MECHANISMS AND BIOSENSORS
OF GTPASES
Principal investigator:
Daniel Abankwa, PhD, Docent (Adjunct Professor) at
Åbo Akademi University, Academy of Finland Research Fellow.
Tel. +358-2-3336969, Fax. +358-2-3338000.
Email: daniel.abankwa@btk.fi
Biography:
Daniel Abankwa (b. 1972) graduated in Chemistry (Dipl. Chem.)
from the Georg-August University in Göttingen in 1997 and
received his PhD in Molecular Neurobiology from the HeinrichHeine University Düsseldorf (2001). In 2002, he joined Prof. Horst
Vogel at the EPFL in Lausanne as a Postdoc to become proficient
in quantitative fluorescence techniques. In 2006, he went to the
Institute for Molecular Biosciences in Brisbane, Australia with a
Fellowship from the Swiss National Science Foundation. With
Prof. John Hancock he worked as a senior postdoctoral fellow
on Ras nanoclusters and discovered a novel orientation-switch III
mechanism in Ras on the membrane. In 2008 he joined Prof. Kirill
Alexandrov as a senior scientist/ junior group leader at the same
institute, to work on Rab nanoclustering and a chemical screening
project to identify lipid transferase inhibitors. In July 2011, Daniel
joined the Turku Centre for Biotechnology. In June 2011 he became
Docent at Åbo Akademi University and since September 2011 he
is on an Academy of Finland Research Fellowship.
Personnel:
Postdoc: Camilo Guzman; Graduate students: Arafath Kaja
Najumudeen, MSc; Maja Solman, MSc, Rebecca Lo, MSc;
Reihaneh Kouhi Esfahani, MSc.
Description of the project:
Despite 30 years of intensive research, it is still not possible to
block small GTPases, in particular Ras, specifically to treat cancer
and other diseases. The major problem is to find a structural
‘pocket’ or mechanism that is characteristic for one out of the over
150 structurally highly related small GTPases. Crystal structures
provided detailed insight into the soluble G domain, revealing that
two parts of the molecule change their conformation upon GTPmediated activation. These structural elements, switch I and II, are
conserved in all GTPases and therefore not suitable for specific
drug-targeting. However, in the last few years novel structural
insight emerged that takes the organisation of Ras in the membrane
into account.
For almost two decades, the lipid modified C-terminal
HyperVariable Region (HVR) of small GTPases was recognized as
the primary structural determinant for isoform specificity. However,
a mechanistic explanation as to how the HVR realizes this was
missing. For Ras, we now have mechanistic insight how the HVR
is actually involved in this. Distinct HVRs of H-, N- and K-ras4B
guide the lateral segregation into distinct nanoscopic proteo-lipid
domains (nanoclusters) in the plasma membrane. From these
distinct nanoclusters, isoform specific signalling emerges.
vivo biophysical measurements, we have recently described a
novel switch III. This is formed by the b2-b3 loop and helix a5,
and is associated with the orientation of the G domain on the
membrane. Thus the Ras orientation is stabilized by the HVR and
helix a4 (Figure). We also showed that this orientation-switch is
specific for different Ras isoforms, regulates GTPase signalling and
combines with lateral segregation of Ras.
Research Questions:
•· We are interested in understanding the molecular and
structural determinants of GTPase isoform specificity.
•· Building on our novel mechanistic insight, we are
constructing specific biosensors to detect GTPase activity
•· Finally, we are applying our insight into the design of novel
screening assays, which will allow to identify novel isoform
specific drugs.
The novel orientation-switch III – the coding mechanism for
small GTPase isoform specificity. Membrane anchored H-ras
exists in two orientation-conformers. Reorientation (blue
curved arrow) was associated with a novel switch III region (red
arrows) and is stabilized by membrane contacts of either the
HVR (green; left) or helix a4 (blue; right).
This mechanism also applies to other Ras isoforms (Figure 2).
Funding:
The Academy of Finland, EU 7th framework (Marie-Curie grant),
Cancer Society Finland, Biocenter Finland, Sigrid-Juselius
Foundation
Collaborators:
Prof. Alemayehu Gorfe and Prof. John Hancock (UT Medical School,
Houston, USA), Prof. Kirill Alexandrov (Institute for Molecular
Bioscience, Brisbane, Australia), Dr. Christian Eggeling (Max-Planck
Institute Göttingen, Germany), Prof. Johanna Ivaska (VTT, Turku
Centre for Biotechnology), Dr. Harri Härmä (University of Turku),
Prof. Dimitrios Stamou (University of Copenhagen, Denmark),
Prof. Jukka Westermarck (Turku Centre for Biotechnology), Prof.
Parton (Institute for Molecular Bioscience, Brisbane, Australia), Dr.
Krishnaraj Rajalingam (University of Frankfurt, Germany), Prof. Mike
Waters (Institute for Molecular Bioscience, Brisbane, Australia)
In the last three years, we have described an additional mechanism,
which provides the missing structure-function link for small GTPase
specificity. Using a combination of computational biology and ex
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41
Selected Publications:
Sinha, B., Koster, D., Ruez, R., Gonnord, P., Bastiani, M., Abankwa,
D., Stan, R. V., Butler-Browne, G., Vedie, B., Johannes, L., Morone,
N., Parton, R. G., Raposo, G., Sens, P., Lamaze, C., and Nassoy,
P. (2011) Cells respond to mechanical stress by rapid disassembly
of caveolae Cell 144, 402-413.
Nguyen, U. T., Goodall, A., Alexandrov, K., and Abankwa, D. (2011)
Isoprenoid Modifications. in Post-Translational Modifications in
Health and Disease (Vidal, C. J. ed.), 1st Ed., Springer. pp 486
Crouthamel, M., Abankwa, D., Zhang, L., Dilizio, C., Manning, D.
R., Hancock, J. F., and Wedegaertner, P. B. (2010) An N-terminal
polybasic motif of G{alpha}q is required for signaling and influences
membrane nanodomain distribution Mol. Pharmacol. 78: 767-777.
Abankwa, D., Gorfe, A. A., Inder, K., and Hancock, J. F. (2010)
Ras membrane orientation and nanodomain localization generate
isoform diversity Proc. Natl. Acad. Sci. U S A 107, 1130-1135.
Bastiani, M., Liu, L., Hill, M. M., Jedrychowski, M. P., Nixon, S.
J., Lo, H. P., Abankwa, D., Luetterforst, R., Fernandez-Rojo, M.,
Breen, M. R., Gygi, S. P., Vinten, J., Walser, P. J., North,
K. N., Hancock, J. F., Pilch, P. F., and Parton, R. G. (2009) MURC/
Cavin-4 and cavin family members form tissue-specific caveolar
complexes J. Cell Biol. 185: 1259-1273.
Hill, M. M., Bastiani, M., Luetterforst, R., Kirkham, M., Kirkham, A.,
Nixon, S. J., Walser, P., Abankwa, D., Oorschot, V. M., Martin, S.,
Hancock, J. F., and Parton, R. G. (2008) PTRF-Cavin, a conserved
cytoplasmic protein required for caveola formation and function
Cell 132: 113-124.
Abankwa, D., Hanzal-Bayer, M., Ariotti, N., Plowman, S. J., Gorfe,
A. A., Parton, R. G., McCammon, J. A., and Hancock, J. F. (2008)
A novel switch region regulates H-ras membrane orientation and
signal output Embo J. 27: 727-735.
Abankwa, D., Gorfe, A. A., and Hancock, J. F. (2008) Mechanisms
of Ras membrane organization and signalling: Ras on a rocker Cell
Cycle 7: 2667-2673.
Gorfe, A. A., Bayer, M.-H., Abankwa, D., Hancock, J. F., and
McCammon, J. A. (2007) Structure and dynamics of the fulllength lipid-modified H-Ras protein in a 1,2-dimyristoylglycero-3phosphocholine bilayer J. Med. Chem. 50: 674-684.
Abankwa, D., and Vogel, H. (2007) A FRET map of membrane
anchors suggests distinct microdomains of heterotrimeric G
proteins J. Cell Sci. 120: 2953-2962.
From left to right: Camilo Guzman, Zuhair Iftikhar, Daniel Abankwa, Maja Solman
and Arafath Najumudeen
Abankwa, D., Gorfe, A. A., and Hancock, J. F. (2007) Ras
nanoclusters: molecular structure and assembly Seminars in cell &
developmental biology 18: 599-607.
Perez, J. B., Segura, J. M., Abankwa, D., Piguet, J., Martinez,
K. L., and Vogel, H. (2006) Monitoring the Diffusion of Single
Heterotrimeric G Proteins in Supported Cell-membrane Sheets
Reveals their Partitioning into Microdomains J. Mol. Biol. 363: 918930.
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PROTEIN KINASE REGULATION
OF BRAIN DEVELOPMENT AND
DISEASE
Eleanor Coffey, Ph.D., Academy Research Fellow,
Turku Centre for Biotechnology, Åbo Akademi and Turku University,
BioCity, Tykistokatu 6B, FI-20521 Turku, Finland.
Tel. +358-2-3338605, Fax. +358-2-3338000.
Email: ecoffey@btk.fi
Homepage: http://www.btk.fi/research/research-groups/coffeyeleanor-kinase-function-in-brain/
Biography:
Eleanor Coffey (b. 1967) graduated from Trinity College Dublin in
1990 and received her Ph.D. from the University of Dundee in 1994.
She received a Wellcome Trust fellowship to carry out postdoctoral
research in Prof. Karl Åkerman’s laboratory from 1994-1997. In
1997 she founded the Neuronal Signalling group at Åbo Akademi
and in 2000 joined Turku Centre for Biotechnology as a group
leader in molecular and cellular biology. In addition to running a
research group, she is vice director of the Centre, and heads the
Cell Imaging Core and Viral Vector Dacility. She was appointed to
an Academy of Finland Research Fellow post from 2008 to 2013.
Personnel:
Graduate students: Artur Padzik, M.Sc., Justyna Zdrojewska,
M.Sc., Emilia Komulainen, M.Sc., Raghu Mysore, M.Sc., Hasan
Mohammed, M.Sc., Prasanna Deshpande, M.Sc.
Undergraduate students: Dani Flinkman, Patrik Hollos, Ravi
Adusumalli
Description of the project
Neurodegenerative disorders such as Alzheimer’s and Parkinson’s
disease as well as stroke are characterised by the irreversible loss
of nerve cell function. These diseases for which no cure is known
are among the most costly to society. The protein kinase JNK is
recognised as a critical player in stroke and neurodegeneration.
However exactly how this family of kinases mediates cell death in
the brain remains largely unknown. Although targeting of JNK for
drug-based therapy is already underway, our understanding of the
physiological function of JNK in the brain is in its infancy.
A major challenge for signal transduction therapy is to selectively
target the pathological function of signalling molecules without
interfering with important physiological roles. To achieve this, our
lab established a proteomics-based screen to identify protein
kinase substrates and thereby broaden our understanding
of kinase function. While we have used this methodology to
successfully identify both novel and known substrates for JNK,
p38 and PIM kinases (collaboration with Päivi Koskinen), among
others (collaboration Erwin Wagner), the main focus of our
research is to elucidate the molecular mechanism of JNK and JNK
targets in the brain. Identification of novel JNK targets such as
SCG10 and MAP2, as well as others under study, has highlighted
a critical role for JNK in maintaining microtubule homeostasis
and subsequently regulating axodendritic architecture and nerve
cell movement. Identification of the JNK phosphorylation site on
kinesin-1 helped characterize a role for JNK in regulation of fast
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axonal transport in neurons. We combine biochemical, proteomic,
cell biology and imaging methods with neuronal and organotypic
cultures as well as transgenic mice to validate kinase targets and
elucidate their function. In collaboration with Laurent Nyguen, we
have established methods to track radial migration of neurons in
the developing telencephalon using 4D imaging. In addition, we
are examining dendrite and spine morphology in JNK1-/- brains
using lucifer yellow iontophoretic loading followed by quantitative
3D image analysis.
An important finding from our lab is the compartmentalization of
JNK function in neurons into physiological and pathological pools
residing in the cytoplasm and nucleus respectively. By using
compartment-targeted peptide inhibitors of JNK, we have shown
that nuclear JNK activity is critical for neuronal death in response
to trophic deprivation (neuronal death that occurs during brain
development) and excitotoxic stimuli (neuronal death that occurs
during epilepsy, stroke and is contributory in neurodegenerative
disorders). To explore the therapeutic potential of compartmental
targeted JNK inhibitors, we are collaborating with Peter Clarke
(University of Lausanne). This study investigates the value of
nuclear-targeted peptide inhibitors of JNK as protectants from
brain damage that occurs following stroke.
Interestingly, although JNK is highly localised to the cytoplasm in
neurons, we find that cytosolic JNK does not to these particular
death mechanisms in neurons of the central nervous system.
Instead, JNK plays a critical role in corticogenesis, being required
to control the duration of two critical steps during formation of the
cortex, i.e. multipolar stage transition and radial migration. This
function of JNK is mediated by SCG10 and is independent of
nuclear JNK activity.
An important new study in our lab is a proteomic screen for LRRK2
substrates. LRRK2 is a kinase that is the most frequently mutated
protein in Parkinson’s disease, both familial and sporadic. Mutations
in LRRK2 lead to a gain of function in kinase activity which is believed
to underlie Parkinson’s pathology. Yet, substrates for LRRK2 have
remained elusive and therefore the disease mechanism is unknown.
In collaboration with European partners, we are searching for
LRRK2 targets in brain using a shot-gun approach. We then
examine the function of these targets in neurotoxicity and assess
their potential as biomarkers for earlier detection of Parkinson’s.
We hope that in the long run this will contribute helpful information
for therapeutic treatment of Parkinson’s and in the shorter term,
contribute tools that can be used for earlier clinical diagnosis.
Funding:
The Academy of Finland, Biocenter Finland, Turku University
Biomedical Sciences Graduate School, Sitra.
Collaborators: Michael Courtney (University of Kuopio), Peter
James (University of Lund), Aoife Boyd (National University of
Ireland Galway), Tuula Kallunki (Danish Cancer Society), Thomas
Herdegen (University of Kiel), Peter Clarke (University of Lausanne),
Erwin Wagner (Research Institute of Molecular Pathology), Scott
Brady (Univeristy of Illinois at Chicago), Laurent Nguyen (University
of Liege), Päivi Koskinen (University of Turku), Aideen Long (Trinity
College, Dublin).
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Westerlund N., Zdrojewska J., Padzik A., Komulainen E., Björkblom
B., Rannikko E., Tararuk T., Garcia-Frigola C., Sandholm J., Nguyen
L., Kallunki T., Courtney M.J., Coffey E.T. (2011) Phosphorylation of
SCG10/stathmin-2 determines multipolar stage exit and neuronal
migration rate. Nat Neurosci. 14: 305-313.
From left to right: Raghavendra Mysore, Dani Flinkman, Artur Padzik, Eleanor Coffey, Justyna Zdrojewska, Emilia Komulainen, Hasan Mohammad and Prasannakumar Deshpande
Mai A., Veltel S., Pellinen T., Padzik A., Coffey E., Marjomäki V.,
Ivaska J. (2011) Competitive binding of Rab21 and p120RasGAP
to integrins regulates receptor traffic and migration. J. Cell Biol.
194: 291-306.
Matlawska-Wasowska K., Finn R., Mustel A., O’Byrne C.P., Baird
A.W., Coffey E.T., Boyd A. (2010) The Vibrio parahaemolyticus
Type III Secretion Systems manipulate host cell MAPK for critical
steps in pathogenesis. BMC Microbiol. 10: 329.
Uusi-Oukari M., Kontturi L.S., Coffey E.T., Kallinen S.A. (2010)
AMPAR signaling mediating GABA(A)R delta subunit up-regulation
in cultured mouse cerebellar granule cells. Neurochem Int. 57: 136-42.
Filén S., Ylikoski E., Tripathi S., West A., Björkman M., Nyström
J., Ahlfors H., Coffey E., Rao K.V., Rasool O., Lahesmaa R. (2010)
Activating transcription factor 3 is a positive regulator of human
IFNG gene expression. J. Immunol. 184: 4990-4999.
Podkowa M., Zhao X., Chow C.W., Coffey E.T., Davis R.J., Attisano
L. (2010) Microtubule stabilization by bone morphogenetic protein
receptor-mediated scaffolding of c-Jun N-terminal kinase promotes
dendrite formation. Mol. Cell Biol. 30: 2241-2250.
Morfini G., You Y., Pollema S., Kaminska A., Pigino G., Liu K.,
Yoshioka K., Björkblom B., Coffey E.T., Bagnato C., Han D.,
Huang C., Banker G. and Brady S.T. (2009) Inhibition of fast axonal
transport by pathogenic Huntingtin involves activation of JNK3 and
phosphorylation of kinesin-1. Nature Neuroscience 12: 864-871.
Waetzig V., Wacker U., Haeusgen, Björkblom B., Courtney M.J.,
Coffey E.T., Herdegen, T. (2009) Concurrent protective and
destructive signalling of JNK2 in neuroblastoma cells. Cellular
Signalling 21: 873-880.
Naumanen T., Johansen L.D., Coffey E.T., Kallunki T. (2008) Loss
of function of IKAP/ELP1: Could neuronal migration defect underlie
familial disautonomia? Cell Adhesion and Migration 2: 236-239.
Björkblom B., Vainio J.C., Hongisto V., Herdegen T., Courtney
M.J., Coffey E.T. (2008) All JNKs can kill, but nuclear localization
is critical for neuronal death. Journal of Biological Chemistry 283:
19704-19713.
Hongisto V., Vainio J.C., Thompson R., Courtney M.J., Coffey E.T.
(2008) The Wnt pool of GSK-3-beta is critical for trophic deprivation
induced neuronal death. Molecular and Cellular Biology 285: 15151527.
Dan Johansen L., Naumanen T., Knudsen A., Westerlund N.,
Gromova I., Junttila M., Nielsen C., Bottzauw T., Tolkovsky A.,
Westermarck J., Coffey E.T., Jäättelä M., Kallunki T. (2008) IKAP
localizes to membrane ruffles with filamin A and regulates actin
cytoskeleton organization and cell migration. Journal of Cell
Science 121: 854-64.
Westerlund N., Zdrojewska J., Courtney M., Coffey E. (2008)
SCG10 as a molecular effector of JNK1: Implications for the
therapeutic targeting of JNK in nerve regeneration. Expert Opinion
on Therapeutic Targets 12: 31-43. Review.
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Westerlund N., Zdrojewska J., Courtney M., Coffey E. (2008)
SCG10 as a molecular effector of JNK1: Implications for the
therapeutic targeting of JNK in nerve regeneration. Expert Opinion
on Therapeutic Targets 12: 31-43. Review.
Semanova M.M., Mäki-Hokkanen A.M.J., Cao C., Komarovski
V., Forsberg K.M., Koistinaho M., Coffey E.T., Courtney M.J.
(2007) Rho mediates calcium-dependent activation of p38a and
subsequent excitotoxic cell death. Nature Neuroscience 10: 436443.
Tararuk R., Östman N., Li W., Björkblom B., Padzik A., Zdrojewska
J., Hongisto V., Herdegen T., Konopka W., Courtney M.J.,
Coffey E.T. (2006) JNK1 phosphorylation of SCG10 determines
microtubule dynamics and axodendritic length. Journal of Cell
Biology 173: 265-277.
Björkblom B., Östman N., Hongisto V., Komarovski V., Filen J.,
Nyman T., Kallunki T., Courtney M., Coffey E. (2005) Constitutively
active cytoplasmic JNK1 is a dominant regulator of dendritic
architecture; role of MAP2 as an effector. Journal of Neuroscience
25: 6350-6361.
Yang J., Lindahl M., Lindholm P., Virtanen H., Coffey E., RunebergRoos P., Saarma M. (2004) PSPN/GFRalpha4 has a significantly
weaker capacity than GDNF/GFRalpha1 to recruit RET to rafts, but
promotes neuronal survival and neurite outgrowth. FEBS Letters
569: 267-271.
Cao J., Semenova M.M., Solovyan V.T., Han J., Coffey E.T.,
Courtney M.J. (2004) Distinct requirements for p38alpha and c-Jun
N-terminal kinase stress-activated protein kinase s in different
forms of apoptotic neuronal death. Journal of Biological Chemistry
279: 35903-35913.
Hongisto, V., Smeds, N., Brecht, S., Herdegen, T., Courtney, M.J.,
Coffey, E.T. (2003) Lithium blocks the c-Jun stress response and
protects neurons via its action on glycogen synthase kinase 3.
Molecular and Cellular Biology 23: 6027-6036.
Coffey E.T., Smiciene G., Hongisto V., Cao J., Brecht S., Herdegen
T., Courtney M.J. (2002) c-Jun N-terminal protein kinase (JNK) 2/3
is specifically activated by stress, mediating c-Jun activation, in
the presence of constitutive JNK1 activity in cerebellar neurons.
Journal of Neuroscience 22: 4335-4345.
Hietakangas V., Elo I., Rosenstrom H., Coffey E.T., Kyriakis J.M.,
Eriksson J.E., Sistonen L. (2001) Activation of the MKK4-JNK
pathway during erythroid differentiation of K562 cells is inhibited by
the heat shock factor 2-beta isoform. FEBS Letters 505: 168-172.
Coffey E.T., Hongisto V., Dickens M., Davis R.J. and Courtney M.J.
(2000) Dual roles for c-Jun N-terminal kinase in developmental
and stress responses in cerebellar granule neurons. Journal of
Neuroscience 20: 7602-7613.
Courtney M.J. and Coffey E.T. (1999) The mechanisms of ARA-C
induced apoptosis of differentiating cerebellar granule neurons.
European Journal of Neuroscience 11: 1073-1084.
Coffey E.T. and Courtney M.J. (1997) Regulation of SAPKs in CNS
neurons. Biochem. Soc. Trans. 25: S568.
TRANSLATIONAL PROTEOMICS
Garry Corthals, Ph.D. Address: Turku Centre for Biotechnology,
BioCity, Tykistökatu 6, FI-20521 Turku, Finland.
Tel. +358-2-333 8889, Fax. +358-2-333 8000.
E-mail: garry.corthals@btk.fi, Homepage: http://www.btk.fi/?id=109
Biography:
Garry Corthals completed his Ph.D. in 1997 at Macquarie University
in Sydney; and has since worked in the field of biomedical proteomics
oriented mass spectrometry. After completing his post-doctoral
studies with Ruedi Aebersold at the Department of Molecular
Biotechnology, University of Washington, Seattle, he moved to the
Garvan Institute for Medical Research in Sydney where he started
a research group and was head of the Proteomics Facility. In 2001
he was recruited to Geneva University Hospital where his research
continued to focus on technological aspects of biomedical mass
spectrometry and to coordinate and develop the Mass spectrometry
facility at Medical Faculty. Now at the Centre for Biotechnology his
group focuses on translational aspects of proteomics based mass
spectrometry. Additionally he is head of the Turku Proteomics
Facility and coordinates the ProtMet.net, the Finnish Proteomics and
Metabolomics infrastructure of Biocenter Finland. Further activities
include the coordination of several Nordic networks including Nordic
Quantitative Proteomics research schools, the Nordic Signals
research network and the Nordic MS imaging network. He is
chair of the new developments of the EuPA, serves on the HUPO
education committee and the ASMS committee. He is also an editor
of SciTopics Biochemistry, Genetics and Molecular Biology section.
Personnel:
Seniors scientists: Anne Rokka, Ph.D., Dorota Muth, Ph.D.
Graduate students: Anni Vehmas, Olli Kannaste, Veronika Suni,
Hugo de Santos, Darshana Kottahachchi
Technical personnel: Arttu Heinonen, Sini Eerola, Emmi Hakanen,
Pekka Haapaniemi
Undergraduate students: Ahmed BulBul, Thaman Chand, Noora
Jaakkola, Firouz Saeidi, Avinash Yadav, T. Santosh Kumar
Our group’s focus is to develop and apply powerful proteomics
tools to be used in translational and systems biology based
projects, where technological developments are driven by biological
questions. Of particular interest to our group are endometriosis,
epilepsy and prostate cancer, as well as several others biomedical
projects including the development of methods for quantitative
proteomics and phosphorylation analysis driven by our group or
through collaborative research.
The group of researchers involved in our work has a diverse set
of skills, ranging from chemistry and biochemistry, to clinical
backgrounds, to computational scientists and mathematicians,
reflecting a multidisciplinary environment. All of our research
essentially evolves around applications in mass spectrometry
(MS), which, over the past two decades MS, has emerged as the
method of choice to discover, measure and characterise proteins
and protein networks in biological systems.
For the analysis of tissues we are interested in defining and
measuring changes of proteins and peptides, which of these
48
49
have an impact on their microenvironment, which enter body fluids
such as the blood system, and ultimately which impact on disease
progression or reflect a disease state. We therefore require methods
that enable highly sensitive identification and quantitation of proteins
in tissues and body fluids. Measurement of proteins in tissues and
tissue-substructures is pursued analysis of minute amounts of
cryosectioned tissues, that ultimately enable exquisite detailing of the
molecular components of cellular substructures, adding important
molecular detail for regions of interest. The quantitative aspect of
these measurements focuses on measuring protein change in tissues.
To this end we are investigating novel computational methods that
enable quantitative measurements of proteins in tissues.
Leivonen S.K., Rokka A., Ostling P., Kohonen P., Corthals G.L.,
Kallioniemi O., Perälä M. (2011) Identification of miR-193b targets
in breast cancer cells and systems biological analysis of their
functional impact. Mol. Cell Proteomics 10: M110.005322.
Rokka A., Aro E.M., Vener A.V. (2011) Thylakoid phosphoproteins:
identification of phosphorylation sites. Methods Mol. Biol. 684:
171-186.
Kouvonen P., Rainio E.M., Suni V., Koskinen P., Corthals G.L.
(2011) Enrichment and sequencing of phosphopeptides on indium
tin oxide coated glass slides. Mol. Biosyst. 7: 1828-1837.
We are also pursuing the use of MALDI imaging MS, which now
allows the simultaneous analysis of the distributions of up to
hundreds of peptides and proteins directly from a tissue section or
tissue array. The technique uses the masses of the peptides and
proteins to distinguish between different species and thus does
not require any form of labeling. These profiles can be used to
obtain biomolecular signatures associated with specific histological
features, adding a further handle in our quest to distinguish different
regions within a tissue and to differentiate and classify tissues.
Another of interest for the group is the identification and quantitation
of phosphopeptides and proteins. Again we have a two-tiered
approach where we are developing both laboratory procedures
as well as computational methods. Our recent observations
have focused the on the use of planar surfaces that act as an
enrichment and analytical platform for phosphopeptide analysis,
paving the way for array based analyses. Our computational
methods in phosphorylation analysis focus on increasing the speed
and validation of phosphorylation analysis – nowadays seen as a
bottleneck delaying true HTP phosphorylation analysis. Additionally
we are developing several bioinformatics tools that allow the
efficient investigation of proteomics workflows in the laboratory.
Funding:
The Academy of Finland, TEKES, Finnish Cancer Foundations,
Nordforsk, the Systems Biology Research Program, Turku Centre
for Computer Science Graduate Programme (TUCS), The National
Graduate School in Informational and Structural Biology (ISB), the
University of Turku, Bruker Daltonics.
Santos H., Kouvonen P., Capelo J.L., Corthals G.L. (2012) Isotopic
labelling of peptides in tissues enhances mass spectrometric
profiling. Rapid Commun. Mass Spectrom. 26: 1–9 [in press]
Grouneva I., Rokka A., Aro E.M. (2011) The thylakoid membrane
proteome of two marine diatoms outlines both diatom-specific
and species-specific features of the photosynthetic machinery. J.
Proteome Res. 10: 5338-53.
Corthals G.L., Dunn M., James P., Gil C., Penque D., Albar J.P.,
Andrén P., Rabilloud T., Marko-Varga G. (2011) The transition of the
European Proteomics Association into the future. J. Proteomics
75: 18-22.
Legrain P., Aebersold R., Archakov A., Bairoch A., Bala K., Beretta
L., Bergeron J., Borchers C., Corthals G.L. et al. (2011) The human
proteome project: Current state and future direction. Mol. Cell
Proteomics 10: M111.009993.
50
From left to right: First row: Thaman Chand, Thatikonda Santhosh , Darshana
Kottahachchi, Sini Eerola, Susumu Imanishi, Susanne Nees and Anne Rokka
Second row: Firouz Saeidi, Arttu Heinonen, Dorota Muth, Garry Corthals, Olli Kannaste,
Veronika Suni and Anni Vehmas
51
ORGANISATION OF NEURONAL
SIGNALING PATHWAYS
Principal Investigator:
Michael Courtney, Ph.D., Affiliated Group Leader at CBT,
Professor of Cell Signaling at UEF. Contact information:
Molecular Signaling Laboratory, Department of Neurobiology, A.I.
Virtanen Institute, University of Eastern Finland, P.O. Box1627,
Neulaniementie 2, FIN-70211 Kuopio, Finland.
Tel. +358 40 355 3663.
Email: mjczmjc@gmail.com
Homepage: www.uef.fi/aivi/neuro/signalling Facility page: www.uef.fi/
aivi/muic
Biography:
Michael Courtney (b. 1967) graduated from University of Cambridge
in 1988 (B.A.), and the University of Dundee in 1991 (Ph.D).
Postdoctoral fellowships from the Royal Society, Wellcome Trust,
Academy of Finland and Sigrid Jusélius Foundation supported his
quantitative imaging development and application activities from
1992 in Prof. Karl Åkerman’s laboratory in Åbo Akademi, Turku.
After group leader positions at CBT from 1998, he was appointed
from 2000 to a position at the A.I. Virtanen Institute, Kuopio and
from 2006 to CBT. He has been affiliated with the Cell Imaging Core
since its inception, and established and is running the Multimodal
Imaging Unit at Kuopio University, now the University of Eastern
Finland. He was appointed to an Academy of Finland Researcher
post from 2003-2008, and Professor of Cell Signaling at the
University of Eastern Finland from 2008.
Personnel:
Post-doctoral researchers and Senior Scientists: Franz Ho Ph.D.,
Andrea Holme Ph.D., Peter Martinsson Ph.D., Jungah Min Ph.D.,
Ph.D, Olga Vergun Ph.D.; Graduate students: Lili Li, B.Sc.,
Xiaonan Liu, M.Sc., Xijun Wang, M.Sc., Laboratory Technician Aila
Seppänen; Undergraduate students: Surya Rai, Esther Gascogne
Neuronal cells possess a complex architecture consisting of
multiple subcellular compartments. Disease states place cells
under stressful conditions. The p38 and JNK stress-activated
protein kinase pathways are widely accepted to play a significant
role in cell death in and outside the nervous system, and drugs
directly targeting stress activated protein kinases have been under
development for many years. However, these pathways also
contribute to development, differentiation, and even survival and
proliferation. This suggests that direct stress-activated protein
kinase inhibitors may be of only limited use. In order to exploit the
pathways for the development of novel neuroprotective drugs,
it will be necessary to elucidate the mechanisms that organise
these pathways into pools with neurodegenerative or physiological
functions within the complex structure of neuronal cells. Only then
can the neurodegenerative activities of the pathways be selectively
eliminated. It has been suggested that this may help reduce the
neuronal death that contributes to neurodegenerative conditions
such as Alzheimer’s and Parkinson’s diseases, increasingly major
causes of death, disability and socioeconomic impact in society.
Previous studies of the mammalian stress-activated MAPK pathway
have revealed the existence of a plethora of upstream regulators
competent to recruit this pathway. In particular, proteins with
52
putative scaffolding actions have been found. Such components
could in principle have a number of effects on the associated
upstream regulator, including (i) to potentiate their ability to activate
the pathway, (ii) to restrict accessibility to activators, (iii) to channel
the downstream consequence to select targets and (iv) to localise
these properties to specific compartments within a cell.
Our lab’s aim is to elucidate how neuronal cells compartmentalise
the endogenous components of the stress-activated protein kinase
pathway and how specific stimuli recruit only select components
of these pathways. To achieve this, we focus mainly on 3 areas:
i) Signalling between post-synaptic density proteins and neuronal
stress-activated protein kinase pathways; ii) Small G-protein
signaling pathways regulating stress-activated protein kinases in
neurons; iii) Development and implementation of approaches to
imaging of intracellular signaling pathways. The mechanisms which
maintain selective responsiveness to upstream stimuli and restricted
downstream consequences are anticipated to be a fruitful source of
potential targets for future neuroprotective strategies. Thus we also
utilise the information gleaned from studies of neuronal signaling
mechanisms to develop and evaluate novel neuroprotective
molecules in cooperation with collaborating partners from both the
pharmaceutical industry and from academia.
While pursuing these scientific goals, we also implement imaging
methodologies. We adapt and establish the use of a wide range of
FRET-based probes of cell signaling and multiparameter imaging
methods, and have recently begun to combine these with targeted
RNAi screens. The probes allow spatiotemporal measurement of
several pathways simultaneously in the same cells. We established
facilities (physically located within Biocentre Kuopio, www.uef.fi/
aivi/muic) to make available to all researchers both live cell HighContent Analysis (HCA) and High-Throughput Microscopy (HTM)
and also TIR-FRET and TIR-FRAP techniques.
•· Total Internal Reflection methods exploit the spatially
restricted evanescent wave formed at the interface
between media of different refractive indices, thereby
surpassing the classical diffraction limits. These methods
are ideally suited to measure signaling events and protein
turnover at protein complexes in the plasma-membrane
proximal zones of living cells, such as the neuronal
postsynaptic density.
•· The live-cell HCA unit is now interfaced with automated
storage either at ambient, cooled or from humidified CO2regulated cell incubator as well as liquid handling facilities
and is suitable for high-throughput imaging studies (up
to ~1000 samples/hr, ~200000 sample capacity). This is
a nationally unique Biocentre Finland (BF) infrastructure
platform supported by two BF networks. Our group
continues to establish assays permitting application of
HCA methods to primary cultured neurons and recently,
an in vivo model. More details can be found via the links at
www.uef.fi/aivi/muic.
Funding:
The Academy of Finland, thThe EU 6th framework STREP
“STRESSPROTECT”, the EU 7 framework project “MEMOLOAD”,
The University of Eastern Finland, The Drug Discovery Graduate
School, The Informational and Structural Biology Graduate School
and The Doctoral Programme in Molecular Medicine.
53
Collaborators:
Eleanor Coffey and Tassos Papageorgiou (CBT, Åbo Akademi and
University of Turku), Christophe Bonny (University of Lausanne
and Xigen Pharma AG), Denise Manahan-Vaughan (University
of Bochum), Mark Spaller (Brown University, Providence, RI), Olli
Pentikäinen (University of Jyväskylä), Antti Poso (University of
Eastern Finland) and Anita Truttman (CHUV, Lausanne University
Hospital).
D’Orsi B., Bonner H., Tuffy L.P., Düssmann H., Woods I., Courtney
M.J., Ward M.W., Prehn J.H. (2012) Calpains Are Downstream
Effectors of bax-Dependent Excitotoxic Apoptosis. J. Neurosci.
32: 1847-1858.
Westerlund N., Zdrojewska J., Padzik A. Komulainen E., Björkblom
B., Rannikko E., Tararuk T., Garcia-Frigola C., Sandholm J. Nguyen
L., Kallunki T. Courtney M.J., Coffey E.T. (2011) Phosphorylation of
SCG10/stathmin-2 determines multipolar stage exit and neuronal
migration rate. Nat. Neurosci. 14: 305-313.
Yang H., Courtney M.J., Martinsson P. and Manahan-Vaughan
D. (2011) LTD is enhanced, depotentiation is inhibited and LTP is
unaffected by the application of a selective JNK inhibitor to the
hippocampus of freely behaving rats. Eur. J. Neurosci. 33: 16471655.
Waetzig V., Wacker U., Haeusgen W., Björkblom B., Courtney
M.J., Coffey E.T. and Herdegen T. (2009) Concurrent protective
and destructive signaling of JNK2 in neuroblastoma cells. Cell
Signal. 21: 873-880.
Hellwig C.T., Kohler B.F., Lehtivarjo A.-K., Dussmann H., Courtney
M.J., Prehn J.H. and Rehm M. (2008) Real-time analysis of TRAIL/
CHX-induced caspase activities during apoptosis initiation. J. Biol.
Chem. 283: 21676-21685.
Björkblom B., Östman N., Hongisto V., Komarovski V., Filén J.,
Nyman T.A., Kallunki T., Courtney M.J. and Coffey E.T. (2005)
Constitutively active cytoplasmic JNK1 is a dominant regulator of
dendritic architecture; role of MAP2 as an effector. J. Neurosci. 25:
6350-6361.
Cao J., Viholainen J.I., Dart C., Warwick H.K., Leyland M.L. and
Courtney M.J. (2005) The nNOS-PSD95 interface - a target for
inhibition of excitotoxic p38 stress-activated protein kinase
activation and cell death. J. Cell Biol. 168: 117-126.
Cao J., Semenova M.M., Solovyan V.T., Han J., Coffey E.T and
Courtney M.J. (2004) Distinct requirements for p38a and JNK
stress-activated protein kinases in different forms of apoptotic
neuronal death. J. Biol. Chem. 279: 35903-35913.
Solovyan V.T., Bezvenyuk Z., Salminen A., Austin C.A. and Courtney
M.J. (2002) The role of topoisomerase II beta in the excision of DNA
loop domains during apoptosis. J. Biol. Chem. 277: 21458-21467.
Coffey E.T., Smiciene G., Hongisto V., Cao J., Brecht S., Herdegen
T. and Courtney M.J. (2002) JNK2/3 is specifically activated by
stress, mediating c-Jun activation, in the presence of constitutive
JNK1 activity in cerebellar neurons. J. Neurosci. 22: 4335-4345.
Coffey E.T., Hongisto V., Davis R.J., Dickens M. and Courtney M.J.
(2000) Dual Roles for c-Jun N-terminal kinase in developmental
and stress responses in cerebellar granule neurons. J. Neurosci.
20: 7602-7613.
Courtney M.J., Åkerman K.E.O. and Coffey E.T. (1997)
Neurotrophins protect cultured cerebellar granule neurons against
the early phase of cell death by a two-component mechanism. J.
Neurosci. 17: 4201-4211.
Björkblom B., Vainio J.C., Hongisto V., Herdegen T., Courtney M.J.
and Coffey E.T. (2008) All JNKs can kill but nuclear localization is
critical for neuronal death. J. Biol. Chem. 283: 19704-19713.
Hongisto V., Vainio J.C., Thompson R., Courtney M.J. and Coffey
E.T. (2008) The Wnt pool of GSK-3b is critical for trophic deprivation
induced neuronal death. Mol. Cell. Biol. 28: 1515-1527.
Westerlund N., Zdrojewska J., Courtney M.J. and Coffey E.T.
(2008) SCG10 as a molecular effector of JNK1: Implications for the
therapeutic targeting of JNK in nerve regeneration. Expert Opin.
Ther. Targets 12: 1-13.
Semenova M.M., Mäki-Hokkonen A.M.J., Cao J., Komarovski
V., Forsberg K.M., Koistinaho M. Coffey E.T. and Courtney M.J.
(2007) Rho mediates calcium-dependent activation of p38a and
subsequent excitotoxic cell death. Nat. Neurosci. 10: 436-443.
Tararuk T., Östman N., Li W., Björkblom B., Padzik A., Zdrojewska
J., Hongisto V., Herdegen T., Konopka W., Courtney M.J. and
Coffey E.T. (2006) JNK1 phosphorylation of SCG10 determines
microtubule dynamics and axodendritic length. J. Cell Biol. 173:
265-277.
54
55
STRUCTURAL BIOINFORMATICS
Konstantin Denessiouk, Ph.D., Docent in Biochemistry.
Bioinformatics Group leader. Centre for Biotechnology,
Tykistökatu 6, BioCity 5th floor, Turku, 20520 Turku.
E-mail: kdenessi@btk.fi
Personnel:
Bhanupratap Singh Chouhan, MSc (Bioinformatics), Graduate
Student; Mari Heininen-Brown, BSc (Bioinformatics).
Areas of Expertise:
Our research involves studies of protein structure and function,
protein ligand interactions and protein evolution by means of
molecular modeling and computational biology. The group
provides large spectrum of services in computational analysis of
protein/nucleic acid sequences and structures. The Structural
Bioinformatics group provides support for Structural Bioinformatics
and Chemical Informatics (in conjunction with the Structural
Bioinformatics Laboratory, lead by Prof. Mark S. Johnson at the
Åbo Akademi University); and separately, support for projects
and development of high-throughput screening (HTS) of natural
molecules (in conjunction with Prof. Pia Vuorela, Department of
Biosciences, Åbo Akademi University). The Structural Bioinformatics
Group has its main expertise in:
(a) computer-based analysis of protein-protein and protein-ligand
interactions
(b) computer-aided prediction, molecular modeling and design
(c) computer-based ligand docking and analysis
(d) molecular dynamics
(d) analysis of effects of molecular recognition and mutations on
protein function
Research Projects:
In collaboration with laboratories of Prof. Mark S. Johnson (Åbo
Akademi University) and Prof. Jyrki Heino (University of Turku) we
continue our study on Structural Evolution of Integrins and Integrin
Domains (Johnson et al., 2009; Chouhan et al., 2011). Within the
project, we (1) identified several matching sequences in bacteria
that aligned surprisingly well with portions of the integrin subunits
(Johnson et al., 2009); and, separately, described a structurederived motif, which is specific only for the metazoan integrin
domains, and searched for the metazoan integrin type b-propeller
domains among all available sequences from bacteria and
unicellular eukaryotic organisms (Chouhan et al., 2011).
In collaboration with the laboratory of Prof. Riitta Lahesmaa (Turku
Centre for Biotechnology, University of Turku and Åbo akademi
University), we are characterizing a novel stem cell specific protein
(Närvä et al., 2011).
In collaboration with the laboratory of Dr. Klaus Elenius (University
of Turku), we study effects of molecular recognition and mutations
on protein function in macromolecular receptor ErbB4 complexes,
where we aim to construct the model of the ErbB4 dimer in its
active form and structurally analyze possible effects of naturally
occurring mutations on the ErbB4 conformational change and the
protein function.
56
Additionally, our on-going research is focused on molecular
dynamics of S100 proteins in collaboration with Prof. S. Permyakov,
Russian Academy of Sciences.
Separately, the group guides individual training of MSc students,
in collaboration with the Structural Bioinformatics Laboratory (Åbo
Akademi University), and leads a Ph.D. student in Bioinformatics
and Computational Biology within the National Graduate School
of Informational and Structural Biology (Åbo Akademi University).
Funding:
Grants from the Sigrid Jusélius Foundation, and the Borg
Foundation (Åbo Akademi University); Grant from the National
Graduate School in Informational and Structural Biology (ISB).
Collaborators:
Prof. Riitta Lahesmaa (Turku Centre for Biotechnology), Prof. Mark
S. Johnson (Åbo Akademi University), Dr. Klaus Elenius (University
of Turku); Prof. Jyrki Heino (University of Turku); Prof. S. Permyakov,
Russian Academy of Sciences.
Chouhan B., Denesyuk A.I., Heino J., Johnson M.S., Denessiouk K.
(2012) Evolutionary origin of the aC helix in integrins. International
Journal of Biological and Life Sciences. Submitted.
Närvä E., Rahkonen N., Emani M.R., Lund R., Pursiheimo J.P.,
Nästi J., Autio R., Rasool O., Denessiouk K., Lähdesmäki H., Rao
A., Lahesmaa R. (2011) RNA Binding Protein L1TD1 Interacts with
LIN28 via RNA and is Required for Human Embryonic Stem Cell
Self-Renewal and Cancer Cell Proliferation. Stem Cells 30: 452460.
Chouhan B., Denesyuk A., Heino J., Johnson M.S., Denessiouk
K. (2011) Conservation of the human integrin-type beta-propeller
domain in bacteria. PLoS One. 6: e25069.
Johnson M.S., Lu N., Denessiouk K., Heino J., Gullberg D. (2009)
Integrins during evolution: evolutionary trees and model organisms.
Biochim. Biophys Acta 1788: 779-789.
Xhaard H., Backström V., Denessiouk K., Johnson M.S. (2008)
Coordination of Na(+) by monoamine ligands in dopamine,
norepinephrine, and serotonin transporters. J. Chem. Inf. Model.
48: 1423-1437.
Denessiouk K.A., Denesyuk A.I., Johnson M.S. (2008) Negative
modulation of signal transduction via interleukin splice variation.
Proteins 71: 751-770.
Denessiouk K.A., Johnson M.S., Denesyuk A.I. (2005) Novel
CalphaNN structural motif for protein recognition of phosphate
ions. J. Mol. Biol. 345: 611-629.
Denessiouk K.A., Johnson M.S. (2003) “Acceptor-donor-acceptor”
motifs recognize the Watson-Crick, Hoogsteen and Sugar “donoracceptor-donor” edges of adenine and adenosine-containing
ligands. J. Mol. Biol. 333: 1025-1043.
57
DATA MINING AND MODELLING
Principal investigators:
Laura Elo, Ph.D., Affiliated Group Leader at CBT,
Adjunct Professor in Biomathematics, Department of Mathematics,
University of Turku, FI-20014 Turku, Finland.
Tel. +358-2-3336027, Fax. +358-2-2310311.
E-mail: laura.elo@utu.fi
Homepage: http://users.utu.fi/laliel/
Tero Aittokallio, Ph.D., Adjunct Professor in Biomathematics,
Department of Mathematics, University of Turku, FI-20014 Turku,
and FIMM-EMBL Group Leader, Institute for Molecular Medicine
Finland (FIMM), University of Helsinki, Finland.
Tel. +358-50-3182426. E-mail: tero.aittokallio@fimm.fi.
Homepage: http://users.utu.fi/teanai/
Olli Nevalainen, Ph.D., Professor of Computer Science, Turku
Centre for Computer Science, University of Turku, FI-20014 Turku,
Finland. Tel. +358-2-3338631. E-mail: olli.nevalainen@utu.fi
Biographies:
Laura Elo received her Ph.D. in Applied Mathematics from the
University of Turku in 2007. In 2008 she received a Postdoctoral
Fellowship from the Academy of Finland. Currently she is an
Adjunct Professor in the Biomathematics Research Group at the
Department of Mathematics, University of Turku.
Tero Aittokallio received his Ph.D. in Applied Mathematics from the
University of Turku in 2001. In 2006-2007, he was a postdoctoral
research fellow in the Systems Biology Group at Institut Pasteur,
Paris. Currently he is an Academy Research Fellow at FIMM and
Department of Mathematics, University of Turku.
Olli Nevalainen received his Ph.D. in 1976. From 1972 to 1976, he
was a lecturer with the Department of Computer Science, University
of Turku. From 1976 to 1999, he was an Associate Professor, and
since 1999 a Professor in the same department.
Personnel:
Post-doctoral researchers: Jussi Salmi, Ph.D.
Graduate students: Bin Gao, M.Sc., Marja Heiskanen, M.Sc.,
Jukka Hiissa, M.Sc., Ville Koskinen, M.Sc., Rolf Linden, M.Sc.,
Sebastian Okser, M.Sc., Tomi Suomi, M.Sc., Johannes Tuikkala,
M.Sc., Heidi Vähämaa, M.Sc.
Undergraduate students: Ville-Pekka Eronen, Aki Järvinen, Essi
Laajala, Teemu Daniel Laajala, Harri Santa
We develop mathematical modelling methods and implement
computational data analysis tools for biological and biomedical
research. A specific focus is on mining and interpreting data
generated by modern high-throughput biotechnologies, such as
microarrays, deep sequencing, and mass-spectrometry-based
proteomic assays.
The large number of molecular components together with high
technical and biological variability can make it difficult to extract
pertinent biological information from the background noise.
Therefore, computational models and tools are needed that can
58
efficiently integrate, visualise and analyse the experimental data so
that meaningful interpretations can be made. A specific computational
challenge is to take full advantage of all the accumulated data,
both from own laboratory and from public repositories, to obtain a
comprehensive view of the system under study.
We have developed data integration and data-driven optimization
approaches to improve the identification of reliable molecular
markers and their interaction partners in global cellular networks.
The eventual goal of the research is to model and explain the
observations as dynamic interaction networks of the key molecular
components and mechanisms controlling the underlying systems.
An integrative network-based modelling approach can provide
robust and unbiased means to reveal the key molecular mechanisms
behind the systems behaviour and to predict its response to
various perturbations. In clinically-oriented research, the modelling
approach has the potential to improve our understanding of the
disease pathogenesis and help us to identify novel molecular
markers for pharmaceutical or diagnostics applications.
Funding:
The Academy of Finland, Turku Systems Biology Research
Programme, The Finnish Funding Agency for Technology and
Innovation (Tekes), Finnish Doctoral Programme in Computational
Sciences (FICS), and Turku Centre for Computer Science (TUCS).
Collaborators:
Riitta Lahesmaa (Turku Centre for Biotechnology), Tuula Nyman
(University of Helsinki), Matej Orešic (VTT Biotechnology), Benno
Schwikowski (Pasteur Institute, Paris), Mats Gyllenberg (University
of Helsinki), Esa Uusipaikka (University of Turku), Samuel Kaski
(Helsinki University of Technology), Timo Koski (Royal Institute of
Technology, Stockholm), Eija Korpelainen (CSC – IT Center for
Science), Jan Westerholm (Åbo Akademi University), Esa Tyystjärvi
(University of Turku), and Mauno Vihinen (University of Tampere).
Elo L.L. and Schwikowski B. (2012) Mining proteomic data for
biomedical research. Invited review in WIREs Data Mining Knowl.
Discov. 2: 1-13.
Elo L.L., Kallio A., Laajala T.D., Hawkins R.D., Korpelainen E. and
Aittokallio T. (2012) Optimized detection of transcription factor
binding sites in ChIP-seq experiments. Nucleic Acids Res 40: e1.
Lietzén N., Öhman T., Rintahaka J., Julkunen I., Aittokallio T.,
Matikainen S. and Nyman T.A. (2011) Quantitative subcellular
proteome and secretome profiling of influenza A virus-infected
human primary macrophages. PLoS Pathog. 7: e1001340.
Vähämaa H., Koskinen V.R., Hosia W., Moulder R., Nevalainen
O.S., Lahesmaa R., Aittokallio T. and Salmi J. (2011) PolyAlign - A
versatile LC-MS data alignment tool for landmark-selected and
automated use. Int. J. Proteomics 2011: 450290.
Lindén R. O., Eronen V.P. and Aittokallio T. (2011) Quantitative
maps of genetic interactions in yeast - Comparative evaluation and
integrative analysis, BMC Systems Biology 5: 45.
59
Lahti L., Elo L.L., Aittokallio T. and Kaski S. (2011) Probabilistic
analysis of probe reliability in differential gene expression studies
with short oligonucleotide arrays, IEEE/ACM Trans Comput Biol
Bioinform 8: 217-225.
Lietzén N., Natri L., Nevalainen O.S., Salmi J. and Nyman T.A.
(2010) Compid: a new software tool to integrate and compare MS/
MS based protein identification results from Mascot and Paragon.
J. Proteome Res. 9: 6795-800.
Okser S., Lehtimäki T., Elo L.L., Mononen N., Peltonen N., Kähönen
M., Juonala M., Fan Y.M., Hernesniemi J.A., Laitinen T., Lyytikäinen
L.P., Rontu R., Eklund C., Hutri-Kähönen N., Taittonen L., Hurme
M., Viikari J.S.A., Raitakari O.T. and Aittokallio T. (2010) Genetic
variants and their interactions in the prediction of increased preclinical carotid atherosclerosis --The Cardiovascular Risk in Young
Finns Study, PLoS Genet 6: e1001146.
Ahlfors H., Limaye A., Elo L.L., Tuomela S., Burute M., Gottimukkala
K.V., Notani D., Rasool O., Galande S. and Lahesmaa R. (2010)
SATB1 dictates expression of multiple genes including IL-5 involved
in human T helper cell differentiation. Blood 116: 1443-1453.
Moulder R., Lönnberg T., Elo L.L., Filén J.J., Rainio E., Corthals
G., Orešic M., Nyman T.A., Aittokallio T. and Lahesmaa R. (2010)
Quantitative proteomics analysis of the nuclear fraction of human
CD4+ cells in the early phases of IL-4 induced Th2 differentiation,
Mol. Cell Proteomics 9: 1937-1953.
Codrea M.C., Hakala-Yatkin M., Kårlund-Marttila M., Nedbal L.,
Aittokallio T., Nevalainen O.S. and Tyystjärvi E. (2010) Mahalanobis
distance screening of Arabidopsis mutants with chlorophyll
fluorescence, Photosynth. Res. 205: 273-283.
Talvinen K., Tuikkala J., Nykänen M., Nieminen A., Anttinen J.,
Nevalainen O.S., Hurme S., Kuopio T. and Kronqvist P. (2010)
Altered expression of p120catenin predicts poor outcome in
invasive breast cancer. J. Cancer. Res. Clin. Oncol. 136: 13771387.
Elo L.L., Mykkänen J., Järvenpää H., Nikula T., Simell S., Aittokallio
T., Hyöty H., Ilonen J., Veijola J., Simell T., Knip M., Simell O.
and Lahesmaa R. (2010) Early suppression of immune response
pathways characterizes children with pre-diabetes in genome-wide
gene expression profiling, J. Autoimmun. 35: 70-76.
From left to right: Olli Nevalainen, Laura Elo, Marja Heiskanen, Sebastian Okser,
Tero Aittokallio and Teemu Laajala
Eronen V.P., Lindén R.O., Lindroos A., Kanerva M. and Aittokallio
T. (2010) Genome-wide scoring of positive and negative epistasis
through decomposition of quantitative genetic interaction fitness
matrices, PLoS ONE 5: e11611.
Elo L.L., Järvenpää H., Tuomela S., Raghav S., Ahlfors H., Laurila
K., Gupta B., Lund R.J., Tahvanainen J., Hawkins R.D., Orešic M.,
Lähdesmäki H., Rasool O., Rao K.V.S., Aittokallio T. and Lahesmaa
R. (2010) Genome-wide profiling of interleukin-4 and STAT6
transcription factor regulation of human Th2 cell programming,
Immunity 32: 852-862.
Piippo M., Lietzén N., Nevalainen O.S., Salmi J. and Nyman T.A.
(2010) Pripper: prediction of caspase cleavage sites from whole
proteomes. BMC Bioinformatics 11: 320.
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61
Aittokallio T. (2010) Dealing with missing values in large-scale
studies - microarray data imputation and beyond, Invited Review,
Brief. Bioinform. 11: 253-264.
Korolainen M.A., Nyman T.A., Aittokallio T. and Pirttilä T. (2010)
An update on clinical proteomics in Alzheimer’s research, J.
Neurochem 112: 1386-1414.
Laajala T.D., Raghav S., Tuomela S., Lahesmaa R., Aittokallio T. and
Elo L.L. (2009) A practical comparison of methods for detecting
transcription factor binding sites in ChIP-seq experiments. BMC
Genomics 10: 618.
Clément-Ziza M., Malabat C., Weber C., Moszer I., Aittokallio T.,
Letondal C. and Rousseau S. (2009) Genoscape: a Cytoscape
plug-in to automate the retrieval and integration of gene expression
data and molecular networks. Bioinformatics 25: 2617-2618.
Hiissa J., Elo L.L., Huhtinen K., Perheentupa A., Poutanen M. and
Aittokallio T. (2009) Resampling reveals sample-level differential
expression in clinical genome-wide studies. OMICS 13: 381-396.
Elo L.L., Hiissa J., Tuimala J., Kallio A., Korpelainen E. and Aittokallio
T. (2009) Optimized detection of differential expression in global
profiling experiments: case studies in clinical transcriptomic and
quantitative proteomic datasets. Brief. Bioinform. 10: 547-555.
Merisaari H., Parkkola R., Alhoniemi E., Teräs M., Lehtonen L.,
Haataja L., Lapinleimu H. and Nevalainen O.S. (2009) Gaussian
mixture model-based segmentation of MR images taken from
premature infant brains. J. Neurosci. Methods 182: 110-122.
Salmi J., Nyman T.A., Nevalainen O.S. and Aittokallio T. (2009)
Filtering strategies for improving protein identification in highthroughput MS/MS studies. Proteomics 9: 848-860.
Laajala E., Aittokallio T., Lahesmaa R. and Elo L.L. (2009) Probelevel estimation improves the detection of differential splicing in
Affymetrix exon array studies. Genome Biol. 10: R77.
Huhtinen K., Suvitie P., Hiissa J., Junnila J., Huvila J., Kujari H.,
Setälä M., Härkki P., Jalkanen J., Fraser J., Mäkinen J., Auranen A.,
Poutanen M. and Perheentupa A. (2009) Serum HE4 concentration
differentiates malignant ovarian tumours from ovarian endometriotic
cysts. Br J Cancer 100: 1315-1319.
CYTOSKELETAL AND SURVIVAL
SIGNALING
John E. Eriksson, Ph.D., Professor. Address: Dept. of Biology, Åbo
Akademi University, FI-20520 Turku, Finland. Tel. int. + 358–2–215 3313.
Laboratory address: Turku Centre for Biotechnology, BioCity,
Tykistökatu 6B, P.O. Box 123, FIN-20521 Turku, Finland.
Tel. int. + 358–2–333 8036, Fax int. +358–2–333 8000.
E-mail: john.eriksson@abo.fi
Biography:
John E. Eriksson (b. 1957) received his Ph.D. at the Åbo Akademi
University in 1990. He was a post-doctoral fellow at Northwestern
University in the laboratory of Prof. Robert D. Goldman during 19901993 (Fogarty International Fellowship from the National Institutes
of Health 1991-1993). In November 1993 he joined the Centre for
Biotechnology as a Senior Research Fellow in Cell Biology. In 1999
he was appointed as Professor of Zoology at the Department of
Biology, University of Turku. In 2006 he was appointed as Professor
of Cell Biology at the Department of Biology, Åbo Akademi University
and became Head of Cell Biology at the department in 2007. He is
also the Chair of Turku BioImaging, Chair of the Biocenter Finland
Imaging Infrastructure Network, and Chair of the Workpackage 12
(User access) in the Eurobioimaging ESFRI network.
Personnel:
Post-doctoral fellows: Fang Cheng, MD-Ph.D., Senthil Kumar,
Ph.D., Hanna-Mari Pallari, Ph.D., Emilia Peuhu, Ph.D., Praseet
Poduval, Ph.D.
Graduate students: Tomoko Asaoka, MSc, Saima Ferraris, MSc,
Claire Hyder, MSc, Kimmo Isoniemi, MSc, Julia Lindqvist, MSc,
Ponnuswamy Mohanasundaram, MSc, Preethy Paul, MSc, Mika
Remes, MSc, Elin Torvaldson, MSc
Undegraduate students: Josef Gullmets, Jolanta Lundgren, Max
Roberts, John Russell, Joanna Pylvänäinen. Laboratory Technician:
Helena Saarento. Secretary: Beata Paziewska
Description of the Project:
Post-translational modifications (PTMs) modulate the activity
of most eukaryotic proteins and are responsible for producing
highly complex proteomes from relatively simple genomes. We
use a selection of signaling networks that represent the core of
our expertise to identify PTM targets and interactions when a
cell is embarking upon fate-determining responses, such as
activating transcriptional or post-translational defense and survival
mechanisms or triggering death machineries. Our main models
are apoptotic, stress-mediated, and cytoskeletal signaling and
we are also interested in their interrelationship. By exploring the
interactions between these completely different signaling modes,
we hope to advance our understanding how critical intracellular
signals are processed and integrated.
We are especially interested in the interaction between death
receptor, stress, and survival signaling. Early on, we observed that
growth signaling through the mitogen-activated kinase (MAPK/
ERK) pathway has a dominant inhibiting effect on apoptosis
induced by death receptors (Fas, TRAIL, and TNF receptors) and
have shown that this mode of regulation has ramifications both in
regulating death receptor responses of recently activated T-cells
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63
From left to right: First row: Josef Gulmets, Claire Hyder, Saima Ferraris, Rajendran Senthil, Tomoko Asaoka and Emilia Peuhu Second row: John Eriksson, John Russell, Kimmo Isoniemi, Erik Niemelä,
Ponnuswamy Mohana Sundaram, Elin Torvaldsson, Julia Lindqvist, Helena Saarento and Beata Paziewska
and in the resistance of certain tumor cell lines to death receptor
stimulation. On the other hand death receptors are also able to
activate survival signals, both MAPK/ERK and NF-kB and stress
signaling facilitates
death receptor-mediated apoptosis in a independently of heat
shock protein expression. The survival of cells is, therefore,
determined by a continuum between these signaling modalities.
An example of a signaling hub protein that affects the survival
in all of the above signaling modes is c-FLIP, which is a specific
inhibitor of death receptor signaling. Targeted FLIP degradation by
ubiquitylation is responsible for the sensitization to death receptor
signals following heat stress and during differentiation erythroid
cells. We have found a PKCalpha/beta-mediated signaling module
that regulates the turnover FLIP by an isoform and phosphorylation
site-specific mechanism. These findings help understanding the
regulation of death receptor responses during stress, fever, or
inflammation, as well as during cell growth and differentiationrelated processes.
Intermediate filaments (IFs) are major cytoskeletal proteins important
for ultrastructural organization and protection against various
mechanical and other types of stresses. We have established that
intermediate filaments are important signaling determinants, a
question that relates to how the organization of the cytoskeleton
will affect different signaling modules. By employing the interactions
of different IFs (keratin 8/18, vimentin, nestin) with their signaling
partners as models, we have elucidated the relationship between
the cytoskeletal structure and the signaling state of the cell, and
how this relationship will affect cell differentiation, growth, and
survival. We observed that IFs act as general scaffolds for signaling
proteins, and have focused on the association of IFs with JNKs,
Cdk5, PKC isoforms, 14-3-3, and surface adhesion molecules are
all involved in key regulatory processes in the cell. Recently, we
determined that vimentin is a regulator of lymphocyte adhesion
and transcellular migration, showing that the vimentin IFs form a
highly dynamic anchoring structure, which is involved in organizing
the surface molecules crucial for the migration. Another topical
highlight includes the discovery of nestin as regulator of Cdk5
signaling. We have shown that nestin forms a scaffold and rheostat
for the Cdk5/p35 signaling complex and shown that this function
is important both during the differentiation of muscle cells and in
apoptosis of neuronal cells.
Collaborators:
The studies on apoptosis-related signaling are done in collaboration
with Birgit Lane and David Lane (Institute of Medical Biology, A*Star,
Singapore), Roger Johnson and Deirdre Meldrum (Biodesign
Institute, Phoenix, USA), Henning Walczak (Imperial College,
London, UK), and Lea Sistonen (Turku Centre for Biotechnology).
The studies on IF-related signaling functions are carried out as
a collaboration with Teng-Leong Chew and Robert Goldman
(Northwestern Univ., Chicago, USA), Johanna Ivaska (Univ. of
Turku), Sirpa Jalkanen (Univ. of Turku), Hannu Kalimo (Univ. of
Turku), Andras Nagy (Univ. of Toronto, Canada), Kuo-Fen Lee (Salk
Institute, CA, USA).
Funding:
The Academy of Finland, TEKES, the European Union, the Finnish
Cancer Organizations, the Sigrid Jusélius Foundation, and the Åbo
Akademi Foundation.
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65
Mohseni P., Sung H.K., Murphy A.J., Laliberte C.L., Pallari H-M.,
Henkelman M., Georgiou J., Xie G., Quaggin S.E., Thorner
P.S., Eriksson J.E. & Nagy A. (2011). Nestin is not essential for
development of the CNS but required for dispersion of acetylcholine
receptor clusters at the area of neuromuscular junctions. J.
Neurosci. 31: 11547-11552.
Pallari H.M., Lindqvist J., Torvaldson E., Ferraris S.E., He T.,
Sahlgren C. & Eriksson J.E. (2011). Nestin as a regulator of Cdk5
in differentiating myoblasts. Mol. Biol. Cell 22: 1539-1549.
Toivonen H.T., Meinander A., Asaoka T., Westerlund M., Pettersson
F., Mikhailov A., Eriksson J.E. & Saxen H. (2011) Modeling reveals
that dynamic regulation of c-FLIP levels determines cell-to-cell
distribution of CD95-mediated apoptosis. J. Biol. Chem. 286:
18375-18382.
Yang J., Dominguez B., de Winter F., Gould T.W., Eriksson J.E.
& Lee K.F. (2011). Nestin negatively regulates postsynaptic
differentiation of the neuromuscular synapse. Nat. Neurosci. 14:
324-330.
Asaoka T., Kaunisto A. & Eriksson J.E. (2011). Regulation of cell death
by c-FLIP phosphorylation. Adv. Exp. Med. Biol. 691: 625-630.
Peuhu E., Kaunisto A., Laihia J.K., Leino L. & Eriksson J.E. (2010).
Molecular targets for the protodynamic action of cis-urocanic acid
in human bladder carcinoma cells. BMC Cancer. 10: 521.
Blom T., Bergelin N., Meinander A., Löf C., Slotte J.P., Eriksson
J.E., Törnquist K. (2010). An autocrine sphingosine-1-phosphate
signaling loop enhances NF-kappaB-activation and survival. BMC
Cell Biol. 11: 45.
Rosenholm J.M., Peuhu E., Bate-Eya L.T., Eriksson J.E., Sahlgren
C. & Lindén M. (2010). Cancer-cell-specific induction of apoptosis
using mesoporous silica nanoparticles as drug-delivery vectors.
Small 6: 1234-1241.
Blomster H.A., Imanishi S.Y., Siimes J., Kastu J., Morrice N.A.,
Eriksson J.E. & Sistonen L. (2010). In vivo identification of
sumoylation sites by a signature tag and cysteine-targeted affinity
purification. J. Biol. Chem. 285: 19324-19329.
de Thonel A., Ferraris S.E., Pallari H.M., Imanishi S.Y., Kochin V.,
Hosokawa T., Hisanaga S., Sahlgren C. & Eriksson J.E. (2010).
Protein kinase Czeta regulates Cdk5/p25 signaling during
myogenesis. Mol. Biol. Cell 21: 1423-1434.
Shen W.J., Patel S., Eriksson J.E., Kraemer F.B. (2010). Vimentin
is a functional partner of hormone sensitive lipase and facilitates
lipolysis. J. Proteome Res. 9: 1786-1794.
Peuhu E., Rivero-Müller A., Stykki H., Torvaldson E., Holmbom T.,
Eklund P., Unkila M., Sjöholm R. & Eriksson J.E. (2010). Inhibition of
Akt signaling by the lignan matairesinol sensitizes prostate cancer
cells to TRAIL-induced apoptosis. Oncogene 29: 898-908.
Imanishi S.Y., Kouvonen P., Smått J.H., Heikkilä M., Peuhu E.,
Mikhailov A., Ritala M., Lindén M., Corthals G.L. & Eriksson J.E.
66
(2009). Phosphopeptide enrichment with stable spatial coordination
on a titanium dioxide coated glass slide. Rapid Commun. Mass
Spectrom. 23: 3661-3667.
Rosenholm J.M., Peuhu E., Eriksson J.E., Sahlgren C. & Lindén M.
(2009). Targeted intracellular delivery of hydrophobic agents using
mesoporous hybrid silica nanoparticles as carrier systems. Nano
Lett. 9: 3308-3311.
Eriksson J.E., Dechat T., Grin B., Helfand B., Mendez M., Pallari
H.M., Goldman R.D. (2009). Introducing intermediate filaments:
from discovery to disease. J. Clin. Invest. 119: 1763-1771. Review.
Rosenholm J., Meinander A. Peuhu E., Niemi R., Eriksson J.E.,
Sahlgren C. & Lindén M. (2009). Selective uptake of porous silica
nanoparticles by cancer cells. Amer. Chem. Soc. 27: 197-206.
Kaunisto A, Kochin V, Asaoka T, Mikhailov A, Poukkula M, Meinander
A. & Eriksson JE. (2009). PKC-mediated phosphorylation regulates
c-FLIP ubiquitylation and stability. Cell Death Differ.16: 1215-1226.
Mikhailov A., Sokolovskaya A., Yegutkin G.G., Amdahl H., West A.,
Yagita H., Lahesmaa R., Thompson L.F., Jalkanen S., Blokhin D. &
Eriksson J.E. (2008). CD73 participates in cellular multiresistance
program and protects against TRAIL-induced apoptosis. J.
Immunol. 181: 464-475.
Meinander, A., Söderström, T.S., Kaunisto, A., Poukkula, M.,
Sistonen, L. and Eriksson, J.E. (2007) Fever-like hyperthermia
controls T-lymphocyte persistence by inducing degradation of
c-FLIPshort. J. Immunol. 178: 3944-3953.
Imanishi S.Y., Kochin V., Ferraris S.E., deThonel A., Pallari H-M.,
Corthals G.L. & Eriksson J.E. (2007). Reference-facilitated
phosphoproteomics: fast and reliable phosphopeptide validation
by mikro-LC-ESI-Q-TOF MS/MS. Mol. Cell. Proteomics 6: 13801391.
Nieminen, M., Henttinen, T., Merinen, M., Marttila-Ichihara,
F., Eriksson, J.E. and Jalkanen S. (2006) Vimentin function in
lymphocyte adhesion and transcellular migration. Nat. Cell Biol. 8:
156-162.
Kochin, V., Imanishi S.Y. and Eriksson, J.E. (2006) Fast track
to a phosphoprotein sketch – MALDI-TOF characterization of
TLCbased tryptic phosphopeptide maps at femtomolar detection
sensitivity. Proteomics 6: 5676-82.
Sahlgren, C.M., Pallari, H-P., He, T., Chou, Y-H., Goldman, R.D.
and Eriksson, J.E. (2006) An essential role of a nestin scaffold
for regulation of Cdk5/p35 signaling in oxidant-induced death of
neuronal progenitor cells. EMBO J. 25: 4808-4819.
Imanishi, S.Y., Kochin, V. and Eriksson, J.E. (2006) Optimization
of phosphopeptide elution conditions in immobilized Fe(III) affinity
chromatography. Proteomics 7: 174-176.
Pallari, H.M. and Eriksson, J.E. (2006) Intermediate filaments as
signaling platforms. Science STKE. 19: pe53. Review.
Söderström, T.S., Nyberg, S., Nieminen, M.I. and Eriksson, J.E.
67
(2005) CD95 capping is ROCK-dependent and dispensable for
apoptosis. J. Cell Sci. 118: 2211-2223.
EPIGENOMICS
Poukkula, M., Kaunisto, A., Hietakangas, V., Denessiouk, K.,
Katajamäki, T., Johnson, M.J., Sistonen, L. and Eriksson, J.E.
(2005) Rapid turnover of c-FLIPshort is determined by its unique
C-terminal tail. J. Biol. Chem. 280: 27345-27355.
David Hawkins, Ph.D., Turku Centre for Biotechnology, Biocity,
5th floor, Tykistökatu 6A, FI-20520, Finland. Tel. +358-2-3338094,
Fax. +358-2-3338000. Email: dhawkins@btk.fi
Home page: http://www.btk.fi/research/research-groups/hawkins/
Goswami, A., Burikhanov, R., de Thonel, A., Fujita, N., Goswami,
M., Zhao, Y., Eriksson, J.E., Tsuruo, T. and Rangnekar, V.M. (2005).
Binding and phosphorylation of Par-4 by Akt is essential for cancer
cell survival. Mol. Cell. 20: 33-44.
Personnel:
Post-doctoral researchers: Kalyan Kumar Pasumarthy, Ph.D.,
Cristina Valensisi, Ph.D.
Eriksson, J.E., He, T., Trejo-Skalli, A.V., Härmälä-Brasken, A.S.,
Hellman, J., Chou, Y.H. and Goldman, R.D. (2004) Specific in
vivo phosphorylation sites determine the assembly dynamics of
vimentin intermediate filaments. J. Cell Sci. 117: 919-932.
Hietakangas, V., Poukkula, M., Heiskanen, K.M., Karvinen, J.T.,
Courtney, M.J., Sistonen, L. and Eriksson, J.E. (2003) Erythroid
differentiation in K562 leukemia cells leads to sensitization to
TRAIL-induced apoptosis by downregulation of FLIP. Mol. Cell.
Biol. 23: 1278-1291.
Hietakangas, V., Poukkula, M., Heiskanen, K.M., Karvinen, J.T.,
Sistonen, L. and Eriksson, J.E. (2003) Erythroid differentiation in
K562 leukemia cells leads to sensitization to TRAIL-induced
apoptosis by downregulation of FLIP. Mol. Cell. Biol. 23: 12781291.
Sahlgren, C.M., Mikhailov, A., Vaittinen, S., Pallari, H.M., Kalimo,
H., Pant, H.C. and Eriksson, J.E. (2003) Cdk5 regulates the
organization of Nestin and its association with p35. Mol. Cell. Biol.
23: 5090-5106.
Tran, S.E.F., Meinander, A., Holmström, T.H., Rivero-Muller, A.,
Heiskanen, K.M., Linnau, E.K., Courtney, M.J., Mosser, D.D.,
Sistonen, L. and Eriksson, J.E. (2003) Heat stress downregulates
FLIP and sensitizes to Fas receptor-mediated apoptosis. Cell Death
Differ. 10: 1137-1147.
Epigenomics includes histone tail modifications, DNA methylation
and noncoding RNAs. These factors are closely linked to
transcriptional regulation, and provide unique signatures of cellular
identity. The epigenome exhibits remarkable cellular specificities
and is likely critical in defining unique cell populations such stem cells.
Using
next-generation
sequencing
and
computational
technologies, we are investigating how the epigenome plays a role
in pluri- and multi-potency of stem cells. We are also investigating
the transcriptional regulation and unique signatures of cellular
differentiation.
Funding:
BioCenter Finland
Collaborators:
Riitta Lahesmaa, Turku Centre for Biotechnology
Harri Lähdesmäki, Tampere University of Technology and Aalto
University
Riikka Lund, Turku Centre for Biotechnology
Saara Laitinen, Finnish Red Cross Blood Service
Hon G., Hawkins, R.D., Caballero O.L., Lo C., Lister R.,
Pelizzola M., Valsesia A., Ye Z., Kuan S., Edsall L.E., Camargo
A.A., Stevenson B.J., Ecker J.R., Bafna V., Strausberg R.L.,
Simpson A.J. And Ren B. (2012) Global DNA hypomethylation
coupled to repressive chromatin domain formation and
gene silencing in breast cancer. Genome Res. 22: 246-258.
Elo L.L., Kallio A., Laajala T.D., Hawkins R.D., Korpelainen E. and
Aittokallio T. (2012) Optimized detection of transcription factor
binding sites in ChIP-seq experiments. Nucl. Acids Res. 40: e1.
Hawkins R.D†., Hon G.C†., Yang C., Antosiewicz J.E., Lee L.K., Ngo
Q.M., Klugman S., Ching K.A., Edsall L.E., Kuan S., Yu P., Liu H.,
Zhang X., Green R.D., Lobanenkov V.V., Stewart R., Thomson J.A.
and Ren B. (2011) Dynamic chromatin states in human ES cells reveal
potential regulatory sequences and genes involved in pluripotency.
Cell Research 21: 1393-1409. †Equal contribution of work.
Alvarado D.M., Hawkins R.D., Bashiardes S., Veile R.A., Powder
K.E., Speck J., Warchol M.E. and Lovett M. (2011) An RNAi-Based
Screen of Transcription Factor Gene Pathways During Sensory
Regeneration in the Avian Inner Ear. J. Neurosci. 31: 4535-4543.
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69
Lister R†., Pelizzola M†., Kida Y.S., Hawkins R.D., Nery J.R.,
Hon G., Antosiewicz-Bourget J., O’Malley R., Castanon R.,
Klugman S., Downes M., Yu R., Stewart R., Ren B., Thomas
J.A., Evans R.M. and Ecker JR. (2011) Hotspots of aberrant
epigenomic reprogramming in human induced pluripotent
stem cells. Nature 471: 68-73. †Equal contribution of work.
Egelhofer T.A†., Minoda A†., Klugman S., Kolasinska-Zwierz P.,
Alekseyenko A.A., Gadel S., Gorchakov A.A., Gu T., Kharchenko
P.V., Kuan S., Latorre I., Linder-Basso D., Luu Y., Ngo Q.,
Rechtsteiner A., Riddle N.C., Schwartz Y.B., Vielle A., Elgin S.C.R.,
Kuroda M.I., Park P.J., Pirrotta V., Ren B., Ahringer J., Strome S.,
Karpen G^., Hawkins R.D^. and Lieb J.D^. (2011) Assessment
of histone-modification antibody quality. Nat. Struct. Mol. Biol. 18:
91-93. †Equal contribution of work; ^Co-corresponding Authors.
Harris R.A., Wang T., Coarfa C., Nagarajan R.P., Hong C., Downey
S.L., Johnson B.E., Fouse S.D., Delaney A., Zhao Y., Olshen A.,
Ballinger T., Zhou X., Forsberg K.J., Gu J., Echipare L., O’Geen H.,
Lister R., Pelizzola M., Xi Y., Epstein C.B., Bernstein B.E., Hawkins
R.D., Ren B., Chung W.Y., Gu H., Bock C., Gnirke A., Zhang M.Q.,
Haussler D., Ecker J.R., Li W., Farnham P.J., Waterland R.A.,
Meissner A., Marra M.A., Hirst M., Milosavljevic A. and Costello
J.F. (2010) Comparison of sequencing-based methods to profile
DNA methylation and identification of monoallelic epigenetic
modifications. Nat. Biotechnology 28(10), 852-862.
Elo L.L†.., Järvenpää H†., Tuomela S†., Raghav S†., Ahlfors H.,
Laurila K., Gupta B., Lund R,J., Tahvanainen J., Hawkins R,D.,
Oresic M., Lähdesmäki H., Rasool O., Rao K,V., Aittokallio T.
and Lahesmaa R. (2010) Genome-wide profiling of interleukin-4
and STAT6 transcription factor regulation of human Th2 cell
programming. Immunity 32: 852-862.
Hawkins R.D†., Hon G.C†. and Ren B. (2010) Next-Generation
Genomics: An Integrative Approach. Nat. Rev. Genetics. 11: 476486.
Hawkins R.,D†., Hon G.C†., Lee L.K., Ngo Q., Lister R., Pelizzola
M., Kuan S., Edsall L.E., Ye Z., Espinoza C., Antosiewicz-Bourget
J., Agarwahl S., Shen L., Ruotti V., Wang W., Stewart R., Thomson
J.A., Ecker J.R. and Ren B. (2010) Distinct epigenomic landscapes
of pluripotent and lineage-committed human cells. Cell Stem Cell
6: 279-491.
Lister R†., Pelizzola M†., Dowen R.H., Hawkins R.D., Hon G.C.,
Tonti-Filippini J., Nery J.R., Lee L.K., Edsall L.E., AntosiewiczBourget J., Ruotti V., Elwell A., Hernandez A., Stewart R., Millar
A.H., Thomson J.A., Ren B. and Ecker J.R. (2009) Human DNA
methylomes at single-base resolution reveal widespread cellspecific epigenetic signatures. Nature 462: 315-322.
From left to right: Kalyan Pasumarthy, David Hawkins and Cristina Valensisi
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Heintzman N.D†., Hon G†., Hawkins R.D†., Kheradpour P.,
Ching K.A., Stuart R.K., Harp L.F., Ching C.W., Liu H., Zhang X.,
Green R.D., Crawford G.E., Kellis M. and Ren B. (2009) Histone
modifications at human enhancers reflect global cell-type-specific
gene expression. Nature 459: 108-112.
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CELL ADHESION AND CANCER
Johanna Ivaska, Professor, Ph.D., VTT Medical Biotechnology,
Itäinen Pitkäkatu 4C, FI-20520 Turku, Finland.
Phone: + 358 40 7203971. FAX: + 358 20 722 2840,
E-mail: johanna.ivaska@vtt.fi
Home page: http://www.btk.fi/research/research-groups/ivaska/
Biography:
Johanna Ivaska (b. 1972) received her MSc in Biochemistry in
1995 and Ph.D. in 2000 from the University of Turku. In 2000 she
received a Post-doctoral Fellowship from the Academy of Finland.
In 2001 she received the EMBO Long Term Fellowship. She was a
post-doctoral fellow at Cancer Research UK in Prof. Peter Parker’s
laboratory during 2000-2003. She returned to Finland in 2003
and joined VTT Medical Biotechnology and University of Turku
Centre for Biotechnology as senior research fellow of the Academy
of Finland and established her own research group. She was
selected as a member of the EMBO Young Investigator program
for 2007-2009. She was nominated professor of Molecular Cell
Biology at University of Turku for 2008-2014 and her research
group received ERC Starting Grant funding for 2008-2013 in their
Cancer Signalosome project.
integrin endo/exocytic traffic, a process critical for cell migration.
Taken together, we aim to understand adhesion regulated signaling
and the biological function of integrin membrane traffic in human
malignancies.
Rantala, J.K., Pouwels, J., Pellinen, T., Veltel, S., Laasola, P.,
Potter, C., Duffy, T., Sundberg, J.P., Askari, J.A.-. Humphries,
M., Kallioniemi, O., Parsons, M., Salmi, M. and Ivaska, J. (2011)
Sharpin is an endogenous inhibitor of beta1-integrin activation.
Nat. Cell Biol. 13: 1315-1324.
Högnäs, G., Tuomi, S., Veltel, S., Mattila, E., Murumägi, A.,
Edgren, H., Kallioniemi, O. and Ivaska, J. (2011) Cytokinesis failure
due to derailed integrin traffic induces aneuploidy and oncogenic
transformation in vitro and in vivo. Oncogene. e-pub 2011 Nov 28.
Personnel:
Post-doctoral researchers: Elina Mattila, Ph.D.; Jeroen Pouwels,
Ph.D.; Stefan Veltel, Ph.D.; Ghaffar Muharram, Ph.D., Saara
Tuomi, Ph.D., Emilia Peuhu, Ph.D. Graduate students: Antti
Arjonen, M.Sc; Reetta Virtakoivu, M.Sc; Gunilla Högnäs;
M.Sc., Riina Kaukonen, M.Sc, Jonna Alanko, M.Sc, Nicola De
Franceschi, M.Sc. Laboratory Technicians: Jenni Siivonen and
Laura Lahtinen.
We investigate the relationship between cell adhesion and cancer.
Cancer is a disease where cells grow out of control and invade,
erode and destroy normal tissue. Invasive and metastatic behavior
of malignant cells is the major cause of mortality in all cancer
patients. Migration and cell proliferation are critically regulated by
physical adhesion of cells to each other and to their non-cellular
surroundings (i.e. extracellular matrix) mediated by a family of
adhesion receptors called integrins. Adhesion dependency of
signaling pathways is well established but incompletely understood.
In normal cells permissive signaling from integrins are prerequisite
for receptor tyrosine kinase (RTKs) induced proliferation. This
regulation is lost upon transformation. In the past few years, we
have performed genome-wide screens to identify integrin-binding
intracellular proteins to gain novel insight into integrin signaling
and traffic in cancer cells. Our results demonstrate that integrins
can also convey negative regulation on RTKs via a mechanism
that is often lost in epithelial carcinomas. Our aim is to extend our
studies on identifying integrin binding proteins to understand the
diverse and sometimes unexpected biological roles of integrins.
In addition to defining cytoplasmic integrin triggered pathways,
we are also actively investigating regulation of integrin activity
and traffic by cytosolic proteins. Using high-throughput siRNA
screening we have recently identified and important novel inhibitor
of integrin activity called SHARPIN. In addition, we have extended
these siRNA screens to identify previously unknown regulators of
72
From left to right: : Antti Arjonen, Jeroen Pouwels, Stefan Veltel, Nicola De
Franceschi, Gunilla Högnäs, Johanna Ivaska, Anja Mai, Jenni Siivonen, Laura
Lahtinen, Riina Kaukonen, Jonna Alanko and Ghaffar Muharram
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Mai, A., Veltel, S., Pellinen, T., Padzik, A., Coffey, E., Marjomäki,
V. and Ivaska, J. (2011) Competitive binding of Rab21 and
p120RasGAP to integrins regulates receptor trafficking in migrating
cancer cells. J. Cell Biol. 194: 291-306.
Vuoriluoto, K., Haugen, H., Kiviluoto, S., Mpindi, J-P, Nevo, J.,
Gjerdrum, C., Lorens, J.B. and Ivaska, J. (2011) Vimentin regulates
EMT induction and migration by governing Axl expression in breast
cancer. Oncogene. 30: 1436-1448.
Ivaska J. and Heino J (2011) Cooperation Between Integrins and
Growth Factor Receptors in Signaling and Endocytosis. Annu. Rev.
Cell Dev. Biol. Annu. Rev. Cell. Dev. Biol. 27: 291-320. Review.
Arjonen A, Kaukonen R and Ivaska J. (2011) Filopodia and adhesion
in cancer cell motility. Cell Adh Migr. 5:421-430. (Review)
Nevo, J., Mai, A., Tuomi, S., Pellinen, T., Pentikäinen, O.T., Heikkilä,
P., Lundin, J., Joensuu, H., Bono, P. and Ivaska, J. (2010) Mammary
derived growth inhibitor (MDGI) interacts with integrin a-subunits
and suppresses integrin activity and invasion. Oncogene. 29:
6452-6463.
Plantard, L. Arjonen, A., Lock, J.G., Nurani, G., Ivaska, J. and
Strömblad S. (2010) PtdIns(3,4,5)P3 is a regulator of Myosin-X
localization and filopodia formation. J. Cell Sci. 123: 3525-3534.
Tuomi, S., Mai, A., Nevo, J., Laine, JO, Vilkki, V., Öhman, TJ.,
Gahmberg, CG., Parker, PJ. and Ivaska, J. (2009) PKCe Regulation
of an a5 Integrin-ZO-1 Complex Controls Lamellae Formation in
Migrating Cancer Cells. Sci. Sign., 2 (77): ra32.
Nevo, J., Mattila, E., Pellinen, T., Yamamoto, D.L., Sara, H., Iljin,
K., Kallioniemi, O., Bono, P., Joensuu, H., Wärri, A. and Ivaska, J.
(2009) Mammary Derived growth inhibitor facilitates escape from
EGFR inhibitory therapy. Clin. Cancer Res. 15: 6570-6578.
Pellinen T., Tuomi, S., Arjonen, A., Wolf, M., Edgren, H., Meyer,
H., Grosse, R., Kitzing, T., Rantala, JK., Kallioniemi O., Fässler, R.,
Kallio, M., and Ivaska, J. (2008) Integrin traffic regulated by Rab21
is necessary for cytokinesis. Dev. Cell, 15: 371-385.
Pellinen T, Arjonen A, Vuoriluoto K, Kallio K, Fransen JA, Ivaska J.
(2006) Small GTPase Rab21 regulates cell adhesion and controls
endosomal traffic of beta1-integrins. J. Cell Biol. 2006 173: 76780.
Mattila E., Pellinen, T., Nevo, J., Vuoriluoto, K. Arjonen, A. and
Ivaska, J (2005) Negative regulation of EGFR signalling via integrin
a1b1-mediated activation of protein tyrosine phosphatase TCPTP.
Nat. Cell Biol. 7: 78-85.
HYPOXIA IN CELL SURVIVAL
Panu Jaakkola, M.D., Ph.D., Address: Turku Centre for Biotechnology,
Biocity, Tykistökatu 6B, P.O. Box 123, FIN-20521, Turku, Finland,
Tel. +358 2 3338030, Fax. +358 2 3338000
E-mail: pjaakkol@btk.fi
Biography:
Panu Jaakkola (b. 1965) received his M.D. in 1992 and Ph.D.
in 1998 at the University of Turku. In 1999 he received a Junior
Fellowship from the Academy of Finland. He was a postdoctoral
fellow at the University of Oxford in Prof. Peter Ratcliffe’s laboratory
during 1999-2001. He joined the Turku Centre for Biotechnology
in the fall 2001. In 2002 he was appointed as a senior fellow of the
Academy of Finland.
Personnel:
Graduate students: Terhi Jokilehto, (M.Sc.), Pekka Heikkinen,
(M.Sc.), Heidi Högel, (M.Sc.), Krista Rantanen, (M.Sc.) Laboratory
Technician: Taina Kalevo-Mattila Undergraduate students: Maiju
Nuutila, Petra Miikkulainen
Hypoxia (reduced O tension) is the main tissue damaging factor
2
in normal tissue. In contrast, tumours use hypoxia as a growthpromoting factor. During ischemic assaults such as strokes, hypoxia
activates apoptosis and leads to severe tissue damage. During
cancer progression hypoxia causes inhibition of apoptosis and
enhances tumour aggressiveness and metastasis. In keeping with
this, it has been known for much of the past century that hypoxia
causes resistance cancer treatments -both to chemotherapy
and radiotherapy -and leads to poor prognosis. The aim of the
project is to reveal mechanisms by which hypoxia regulates survival
decisions in ischemic diseases and cancer progression.
Our group has undertaken two major avenues to tackle the issue.
The reduced oxygen is sensed by a family of enzymes called the
HIF prolyl hydroxylases (PHD1-3). Under normoxia the hypoxiainducible factor (HIF) is hydroxylated by PHDs at critical proline
residues. This leads to ubiquitylation and proteosomal destruction
of HIF. Under hypoxic conditions the hydroxylation ceases and
HIF is stabilised. HIF then exerts its effects by activation of at least
80 genes. These have key functions in glucose homeostasis,
angiogenesis, as well as cell survival and metastasis formation.
Our studies have revealed novel and separate functions for two
PHD isoforms (PHD2 and -3) in regulating cell growth, survival
and regulation of apoptosis. Besides studying several aspects of
molecular and cellular biology of the hydroxylases, we study the
clinical importance of these factors.
Transforming growth factor-b (TGF-b) is one of the best characterised
tumour growth regulating factors. It restricts the growth of early
stage tumours, but at later stages of tumour progression cancer
cells begin to exploit it as a malignancy, invasion and metastasis
promoting cytokine. This paradox of TGF-b was originally described
in skin cancer models over ten years ago and since then the
paradox has been recapitulated in several other cancer models.
Our group has recently identified a putative mechanism by which
this may occur. We have found that hypoxia is an environmental
74
75
factor in tumours that can convert the TGF-b response into
supporting tumorigenesis. Mechanistically, this involves hypoxic
dephosphorylation of a TGF-b effector Smad3. Moreover, we have
recently discovered that hypoxia converts Smad7, an inhibitor of the
TGF-b signaling, from an inhibitor into a promoter of cell invasion.
Dhanda, A., Tian, Y.-M., Masson, N., Hamilton, D.L., Jaakkola, P.,
Barstead, R., Hodgkin, J., Maxwell, P.H., Pugh, C.W., Schofield,
C.J., Ratcliffe, P.J. C.elegans EGL-9 and mammalian homologues
define a family of dioxygenases that regulate HIF through prolyl
hydroxylation. (2001) Cell 107: 43-54.
Funding:
The Academy of Finland, Sigrid Juselius Foundation, Emil Aaltonen
Foundation, Finnish Cancer Unions. Turku University Hospital
Pursiheimo, J., Taskén, K., Jalkanen, M. and Jaakkola, P. (2000)
Involvement of Protein Kinase A in FGF-2 Activated Transcription.
Proc. Natl. Acad. Sci. USA 97: 168–173.
Collaborators:
Peter Ratcliffe and Chris Pugh (Oxford University, UK), Eric Metzen
(Luebeck University, Germany), Reidar Grenman (Turku University),
Veli-Matti Kähäri (Turku University), Heikki Minn (PET Centre, Turku
University Hospital)
Cockman, M.E., Masson, N, Mole, D.R., Jaakkola, P, Chang, G.W.,
Clifford, S.C, Maher, E.R, Pugh, C.W., Ratcliffe, P.J., Maxwell, P.H.
(2000) Hypoxia inducible factor-alpha binding and ubiquitylation
by the von hippel-lindau tumor suppressor protein. J. Biol. Chem.
275: 25733-25741.
Högel H., Rantanen K., Jokilehto T., Grenman R. and, Jaakkola P.M.
(2011). Prolyl hydroxylase PHD3 enhances the hypoxic survival and
G1 to S transition of carcinoma cells. PloS One 6: e27112.
Heikkinen P., Nummela M., Kähäri V.M. and Jaakkola P.M. (2010).
Hypoxia converts Smad7 from tumor suppressor into tumor
promoter. Cancer Res. 70: 5984-5993.
Heikkinen P.T., Nummela M., Leivonen S.K., Westermarck J.,
Hill C.S., Kähäri V.-M., Jaakkola P.M. (2010). Hypoxia activated
Smad3-specific dephosphorylation by PP2A. (2010). J Biol.Chem.,
285: 3740-9.
Jokilehto T., Högel H., Heikkinen, P., Rantanen K., Elenius, K.,
Sundström J., Jaakkola P.M. (2010). Retention of prolyl hydroxylase
PHD2 in the cytoplasm prevents PHD2-induced anchorageindependent carcinoma cell growth. Exp. Cell Res. 316: 1169-1178.
Pursiheimo J., Rantanen K., Heikkinen P.T., Johansen T., Jaakkola
P.M. (2009). Hypoxia-activated autophagy accelerates degradation
of SQSTM1/p62. Oncogene, 28: 334-344.
Rantanen K., Pursiheimo J., Högel H., Himanen V., Metzen E.,
Jaakkola P.M. (2008) Prolyl Hydroxylase PHD3 Activates Oxygendependent Protein Aggregation. Mol. Biol. Cell 19: 2231-2240.
Jokilehto, T., Rantanen, K., Luukkaa, M., Grenman, R., Minn, H.,
Kronqvist, P., Jaakkola P.M. (2006). Overexpression and nuclear
translocation of HIF prolyl hydroxylase PHD2 in head and neck
squamous cell carcinoma associates with tumor aggressiveness.
Clin. Cancer Res. 12: 1080-1087.
Marxsen, J. H., Stengel, P., Doege, K., Heikkinen, P., Jokilehto,
T., Wagner, T., Jelkmann, W., Jaakkola, P., and Metzen, E. (2004)
Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by
induction of HIF-alpha-prolyl-4-hydroxylases. Biochem J. 381: 761-767.
Jaakkola, P., Mole, D. R., Tian, Y. M., Wilson, M.I., Gielbert, J., Gaskell,
S.J., Kriegsheim, Av, Hebestreit, H.F., Mukherji, M., Schofield,
C.J., Maxwell, P.H., Pugh, C.W., Ratcliffe, P.J. (2001) Targeting of
HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2regulated prolyl hydroxylation. Science 292; 468-472.
Epstein, A.C.R., Gleadle, J.M., McNeill, L.A., Hewitson, K.S.,
O’Rourke, J., Mole, D.R., Mukherji, M., Metzen, E., Wilson, M.I.,
From left to right: Heidi Högel and Krista Rantanen
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77
BIOENERGY
Patrik R. Jones, Ph.D., Affiliated Group Leader at CBT,
University of Turku, Centre for Biotechnology, Turku BioCity,
Tykistökatu 6B, 4krs, 20520, Turku. Tel.:+358-2-333-7913.
E-mail: patrik.jones@utu.fi
Home page: http://www.btk.fi/research/affiliated-groups/jonespatrik-bioenergy-group/
Biography:
Patrik Jones (b. 1968) completed his undergraduate degree in
Agricultural Sciences (Oenology, Honours) at the University of
Adelaide and obtained his Ph.D. (2001) from the University of
Adelaide, Australia, and the Royal Veterinary and Agricultural
University of Copenhagen, Denmark, on the topic of plant natural
product metabolism. Before commencing his current position in
Turku in 2008, he held a position as JSPS-funded post-doctoral
fellow (2001-2002, plant natural product metabolism) at Chiba
University, Japan; Research Chemist (2003-2004, wine chemistry
and sensory perception) at the Australian Wine Research Institute
in Adelaide, Australia; Research Director (2005-2008, microbial
metabolic engineering and renewable fuel production) at Fujirebio
Inc. (100% for-profit), Tokyo, Japan.
Personnel:
Undergraduate students: Danilo Corredu, Artur Tallihärm, Hariharan
Dapandani, Melak Weldengodguad
Graduate students: Sanna Peltonen, Linda Vuorijoki, Jari
Kämäräinen, Veronica Carbonell, Andras Pasztor, Francy El Souki
Researchers: Fernando Guerrero, M. Kalim Akhtar
Coordinator: Yumi Otani
We target the interface between fundamental and applied sciences
by studying fundamental questions of applied importance. In most
cases, we wish to answer or obtain insight about outstanding
questions and issues which are important for current and theoretical
biological energy conversion processes. The laboratory currently
has two main lines of research:
(1) Fermentative and photobiological H2-production. Topics
include H2-pathway engineering, iron sulfur cluster metabolism
and NADP(H)-homeostasis. The subjects are studied with a
combination of computational and experimental methodologies,
with a focus on key reactions and/or the entire metabolism of the
cell (systems biology).
(2) Synthesis of hydrocarbon transport fuels. We engineer a tiny
fraction of the metabolism of model hosts in order to (a) introduce
biofuel-pathways that do not exist in nature and (b) modify host
metabolism to favor those pathways. The engineering is aided
by computational flux balance analysis and development of
engineering tools.
Funding:
European Research Council, EU FP7, Tekes, Academy of Finland,
Nordic Energy Research
Selected publications:
Akhtar, M.K. and Jones, P.R. (2009) Construction of a synthetic
YdbK-dependent pyruvate:H2 pathway in Escherichia coli
BL21(DE3). Metabolic Engineering 11: 139-147.
Veit, A., Akhtar, K.M., Mizutani, T., Jones P.R. (2008) Constructing
and testing the thermodynamic limits of synthetic NAD(P)H:H2
Pathways. Microbial Biotechnology 1: 382-394.
Akhtar, K.M., and Jones P.R. (2008) Deletion of iscR stimulates
recombinant clostridial Fe-Fe hydrogenase activity and H2
accumulation in Escherichia coli BL21(DE3). Applied Microbiology
and Biotechnology 78: 853-862.
From left to right, first row: Patrik Jones, Fernando Guerrero, Danilo Correddu,
second row: Linda Vuorijoki, Francy El Souki, Eva Fredriksson-Lidsele, Sanna
Peltonen, Veronica Carbonell, Hariharan Dapandani, Melak Weldenegodguad,
András Pásztor, Jari Kämäräinen
78
79
MITOSIS AND DRUG DISCOVERY
Marko Kallio, Ph.D. Docent, Affiliated group leader at CBT,
Principal Scientist and Team Leader, VTT Biotechnology for Health
and Wellbeing, Itäinen Pitkäkatu 4C, FI-20521,
Turku, Finland and Turku Centre for Biotechnology,
BioCity, Tykistökatu 6B, FI-20521 Turku, Finland.
Tel. +358-(0)2-4788614, Fax.+358(0)20-7222840
E-mail: marko.kallio@vtt.fi
Biography:
Marko Kallio (b. 1967) graduated in Genetics from University of
Turku in 1992 and received his Ph.D. degree from Department
of Human Genetics at University of Turku 1996 with an honorary
mention. In 1996-1998 Dr. Kallio was in the laboratory of Prof.
Gary Gorbsky (Univ. Virginia, USA) as a Post-doctoral Fellow and in
1998-2000 in the laboratories of Prof. John Eriksson and Prof. Lea
Sistonen (Univ. Turku, Finland) as a Senior Post-doctoral Fellow. In
2000-2003 Dr. Kallio worked as an Assistant Research Professor
at University of Oklahoma HSC, USA. His research group received
Marie Curie Excellence grant for 2004-2008. In early 2004, Dr.
Kallio moved back to Finland and has since been a group leader
at VTT Biotechnology for Health and Wellbeing, a research institute
affiliated with the University of Turku.
Personnel:
Post-doctoral researchers: Anu Kukkonen-Macchi, Ph.D., Leena
Laine, Ph.D., Elli Narvi, Ph.D., Sebastian Winsel, Ph.D.
Graduate students: Jenni Mäki-Jouppila, M.Sc., Anna-Leena
Salmela, M.Sc., Mahesh Tambe, M.Sc.
Undergraduate students: Adel Asghar
Laboratory Technician: Pauliina Toivonen
Alumni: Tim Holmström, Kimmo Jaakkola, M.D., Ph.D., Jeroen
Pouwels, Ph.D., Oana Sicora, Ph.D., Christina Oetken-Lindholm,
Ph.D., Asta Varis, Ph.D., Chang-Dong Zhang, Ph.D.
Description of the projects:
The Mitosis and Drug Discovery Team investigates mechanisms of
cell division in somatic cells and in meiotic systems. Understanding
cell division errors may help to explain origin of genomic instability
and is expected to identify novel therapeutic possibilities for
treatment of cancer. We are especially interested of conditions that
suppress cancer cells’ viability as a consequence of premature
inactivation of the spindle assembly checkpoint (SAC), a conserved
signalling pathway monitoring fidelity of mitosis. To this end, we
have performed a number of high-throughput screens (HTS) for
anti-mitotic small molecules, siRNAs, and miRNAs. These activities
have led to the identification of (i) novel pharmacophores targeting
key mitotic proteins such as Hec1, Aurora B and Plk1, (ii) new
mitotic gene functions and (iii) mitosis regulating miRNAs. Finally,
we are investigating the mechanisms of acquired resistance to
microtubule (mt)-drugs, a growing clinical problem in the treatment
of cancer. Resistance to mt-drugs has links to malfunction of
tubulin and mitotic checkpoint proteins but these mechanisms are
poorly understood.
80
Errors during cell division may result in unequal distribution of
DNA between the daughter cells. Gain or loss in the number of
chromosomes of the genome is a known cause for miscarriages and
birth defects in human, and a hallmark of cancer. Mitotic processes
are also clinically relevant drug targets in cancer treatment as
demonstrated by the great anti-cancer efficacy of microtubuletargeting drugs. In our main projects, we are working to validate
the mechanism of action of putative anti-Hec1 compounds and
several SAC targeting miRNAs that perturb normal mitosis and
trigger cancer cell killing in cell culture assays. Moreover, we
are characterizing the phenotypes of a handful of new mitosis
targeting siRNAs that we have recently discovered. In our work
we use various cell-based and biochemical assays in vitro as well
as VTT biochip technologies. The results from these activities are
expected to catalyze cancer drug discovery by identification of new
possibilities for inhibition of Hec1, and SAC in general.
Funding:
VTT Technical Research Centre of Finland, The Academy of Finland,
TuBS and DDGS Graduate Schools, Bayer HealthCare AG
Collaborators:
Gary Gorbsky (OMRF, Oklahoma USA), Todd Stukenberg (Univ.
Virginia, USA), Olli Kallioniemi (FIMM). Lauri Aaltonen (Biomedicum
Helsinki), Lea Sistonen (Turku Centre for Biotechnology).
Kukkonen-Macchi A., Sicora O., Kaczynska K., Oetken-Lindholm
C., Pouwels J., Laine L., and Kallio M.J. (2011) Loss of p38gamma
MAPK induces pleiotropic mitotic defects and massive cell death.
J. Cell Sci., 124: 216-227.
Niittymäki I., Gylfe A., Laine L., Laakso M., Lehtonen H.J., Kondelin
J., Tolvanen J., Nousiainen K., Pouwels J., Järvinen H., Nuorva
K., Mecklin J.P., Mäkinen M., Ristimäki A., Ørntoft T.F., Hautaniemi
S., Karhu A., Kallio M.J., Aaltonen L.A. (2011) High frequency
of TTK mutations in microsatellite-unstable colorectal cancer
and evaluation of their effect on spindle assembly checkpoint.
Carcinogenesis 32: 305-311.
Vuoriluoto M., Laine L.J., Saviranta P., Pouwels J., Kallio M.J.
(2011) Spatio-temporal composition of the mitotic Chromosomal
Passenger Complex detected using in situ proximity ligation assay.
Mol. Oncol. 5: 105-111.
Salmela A.L., Pouwels J., Varis A., Kukkonen A.M., Toivonen P.,
Halonen P.K., Perälä M., Kallioniemi O., Gorbsky G.J., and Kallio
M.J. (2009) Dietary flavonoid fisetin induces a forced exit from
mitosis by targeting the mitotic spindle checkpoint. Carcinogenesis
30: 1032-1040.
Pellinen T., Tuomi S., Arjonen A., Wolf M., Edgren H., Meyer H.,
Grosse R., Kilzing T., Rantala J.K., Kallioniemi O., Fässler R., Kallio
M., and lvaska J. (2008). Integrin trafficking regulated by Rab21 is
necessary for cytokinesis. Dev. Cell 15: 371-385.
Pouwels J., Kukkonen A.M., Lan W., Daum J.R., Gorbsky G.J.,
Stukenberg T. and Kallio M.J. (2007) Shugoshin 1 plays a central
role in kinetochore assembly and is required for kinetochore
targeting of Plk1. Cell Cycle 6: 1579-1585.
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Wang V.Y., Parvinen M., Toppari J., and Kallio M.J. (2006) Inhibition
of Aurora kinases perturbs chromosome alignment and spindle
checkpoint signaling in rat spermatocytes. Exp. CelI Res. 312:
3459-3470.
Ahonen L.J., Kallio M.J., Daum J.R., Bolton M., Manke I.A., Yaffe
M.B., Stukenberg P.T. and Gorbsky G.J. (2005) Polo-like kinase 1
creates the tension-sensing 3F3/2 phosphoepitope and modulates
the association of spindle-checkpoint proteins at kinetochores.
Curr Biol. 15: 1078-1089.
McCleland M.L., Kallio M.J., Barrett-Wilt G.A., Kestner C.A.,
Shabanowitz J., Hunt D.F., Gorbsky G.J. and Stukenberg P.T.
(2004) The vertebrate Ndc80 complex contains functional homologs
of Spc24 and Spc25 and is required to establish and maintain
kinetochore-microtubule attachment. Curr Biol. 14: 131-137.
McCleland M.L., Gardner R.D., Kallio M.J., Daum J.R., Gorbsky
G.J., Burke D.J. and Stukenberg P.T. (2003) The highly conserved
Ndc80 complex is required for kinetochore assembly, chromosome
congression, and spindle checkpoint activity. Genes. Dev. 17:
101-114.
CANCEROMICS RESEARCH
PROGRAMME
Olli Kallioniemi, M.D., Ph.D., Director, Institute for Molecular
Medicine Finland (FIMM), University of Helsinki, Tukholmankatu 8,
00140 University of Helsinki, Finland. Director of the Academy
of Finland Centre of Excellence on Translational Genome-scale
Biology (2006-2011), Medical Biotechnology,
VTT Technical Research Centre of Finland and University of Turku.
Laboratory address: Medical Biotechnology, PharmaCity,
Itäinen Pitkäkatu 4C, FI-20521 Turku, Finland.
Tel. +358-20-722 2800. Fax +358-20-722 2840.
E-mail: olli.kallioniemi@helsinki.fi.
Biography:
Dr. Olli Kallioniemi received his M.D. in 1984 and Ph.D. in 1988 at
the University of Tampere in Finland. Olli Kallioniemi held several
positions in the US over a 10-year period, such as Head of
Translational Genomics Section at the Cancer Genetics Branch,
National Human Genome Research Institute, at the NIH, Bethesda,
Maryland during 1995-2002. In 2003, he was appointed as
Professor of Medical Biotechnology at the VTT Technical Research
Centre of Finland with a joint appointment at the University of
Turku. Academy of Finland Professor in 2004-2007. In 2007, he
was nominated as a director of the Institute for Molecular Medicine
Finland (FIMM), a Nordic EMBL Partnership in Molecular Medicine.
He continues to direct the ongoing projects in Turku until the end
of 2011. He is an author of 263 publications and editor or member
of the editorial board of six journals. Inventor of 18 issued patents,
with a focus on technology development, such as Comparative
Genomic Hybridization (CGH) in 1992, tissue microarrays in 1998
and cell-based RNAi microarrays in 2003. EACR young investigator
award in 1994, Anders Jahre Prize in 1998, NIH Director’s lecture
in 2000, Medal of the Swedish Medical Society in 2003, National
Academy of Sciences (Finland) in 2005, EMBO Membership in
2006, and the Abbot-IFCC award in Molecular Diagnostics 2009.
Personnel:
Ph.D-students and postdocs at the University of Turku: Anna
Aakula, M.Sc., Santosh Gupta, M.Sc., Kirsi Ketola, M.Sc., Pekka
Kohonen, Ph.D. Paula Vainio, M.D., Sirkku Pollari, M.Sc., Laboratory
Technician: Pirjo Käpylä, Coordinator: Terhi Jokilehto, M.Sc.
From left to right: Pauliina Toivonen, Jenni Mäki-Jouppila, Leena Laine, Adel
Ashgar, Anna-Leena Salmela, Elli Narvi, Mahesh Tambe, Lila Kallio and
Sebastian Winsel. Standing: Marko Kallio
The overall purpose of this research program is to develop and
apply high-throughput technologies to understand mechanisms of
progression of breast and prostate cancers as well as to identify
mechanisms of drug response.
We use systems biology and chemical biology approaches to
characterize the deregulation of cancer cell functions. The research
is carried out in collaboration between the Institute for Molecular
Medicine Finland (FIMM), the Medical Biotechnology Centre of the
VTT Technical Research Centre of Finland and the Turku Centre
for Biotechnology. Our group coordinates Academy of Finland
Centre of Excellence in Translational Genome-Scale Cell Biology.
We have developed and are applying biochip technologies, next-
82
83
generation RNA sequencing, bioinformatics, systems biology,
drug development technologies, cell microarrays, protein lysate
microarrays, in silico profiling of gene expression in clinical samples
and many others.
Collaborators:
Tomi Mäkelä, Lauri Aaltonen, Jussi Taipale, Päivi Ojala, Sampsa
Hautaniemi, Heli Nevanlionna, Heikki Joensuu, Kari Alitalo,
Jonathan Knowles, Emmy Verschuren, Sergey Kuznetshov, Samuli
Ripatti, Krister Wennerberg (FIMM and Biomedicum Helsinki), Antti
Poso, Samuel Kaski, Tapio Visakorpi, Jukka Westermarck and
many others in other Universities in Finland. We have over 100
partners in EU-FP7 collaborative projects such as Epitron, Genica,
APO-SYS, Prosper, Meta-Cancer and Systems Microscopy.
Funding:
The Academy of Finland, Tekes, Finnish Cancer Organizations and
Sigrid Juselius Foundation. Our biggest source of funding comes
from the EU framework projects.
Selected recent publications:
Mpindi J.P., Sara H., Haapa-Paananen S., Kilpinen S., Pisto T.,
Bucher E., Ojala K., Iljin K., Vainio P., Björkman M., Gupta S.,
Kohonen P., Nees M. and Kallioniemi O. (2011) GTI: A Novel
Algorithm for Identifying Outlier Gene Expression Profiles from
Integrated Microarray Datasets. PLoS One 16: e17259.
Hanash S.M., Baik C.S. and Kallioniemi O. (2011) Emerging
molecular biomarkers-blood-based strategies to detect and
monitor cancer. Nat. Rev. Clin. Oncol. 8: 142-150.
Ostling P., Leivonen S.K., Aakula A., Kohonen P., Mäkelä R., Hagman
Z., Edsjö A., Kangaspeska S., Edgren H., Nicorici D., Bjartell A.,
Ceder Y., Perälä M. and Kallioniemi O. (2011) Systematic Analysis
of MicroRNAs Targeting the Androgen Receptor in Prostate Cancer
Cells. Cancer Res. 71: 1956-1967.
Vainio P., Gupta S., Ketola K., Mirtti T., Mpindi J.P., Kohonen P.,
Fey V., Perälä M., Smit F., Verhaegh G., Schalken J., Alanen K.A.,
Kallioniemi O. and Iljin K. (2011) Arachidonic acid pathway members
PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel
therapeutic targets in prostate cancer. Am. J. Pathol. 178: 525-536.
Edgren H., Murumagi A., Kangaspeska S., Nicorici D., Hongisto
V., Kleivi K., Rye I.H., Nyberg S., Wolf M., Borresen-Dale A.L. and
Kallioniemi O (2011) Identification of fusion genes in breast cancer
by paired-end RNA-sequencing. Genome Biol.12: R6.
Kilpinen S., Ojala K., Kallioniemi O. (2010) Analysis of kinase gene
expression patterns across 5681 human tissue samples reveals
functional genomic taxonomy of the kinome. PLoS One. 5: e15068.
Rantala J.K., Edgren H., Lehtinen L., Wolf M., Kleivi K., Vollan
H.K., Aaltola A.R., Laasola P., Kilpinen S., Saviranta P., Iljin K. and
Kallioniemi O. (2010) Integrative functional genomics analysis of
sustained polyploidy phenotypes in breast cancer cells identifies
an oncogenic profile for GINS2. Neoplasia 12: 877-888.
From left to right, first row: Paula Vainio, Mari Björkman, Riina Plosila, Pekka
Kohonen, Back row: Kirsi Ketola, Anna Aakula, Santosh Gupta, Olli Kallioniemi,
Sirkku Pollari, Elmar Bucher.
84
Gupta S., Iljin K., Sara H., Mpindi J.P., Mirtti T., Vainio P., Rantala J.,
Alanen K., Nees M. and Kallioniemi O. (2010) FZD4 as a mediator
85
of ERG oncogene-induced WNT signaling and epithelial-tomesenchymal transition in human prostate cancer cells. Cancer
Res. 70: 6735-45.
Härmä V., Virtanen J., Mäkelä R., Happonen A., Mpindi J.P.,
Knuuttila M., Kohonen P., Lötjönen J., Kallioniemi O. and Nees M.
(2010) A comprehensive panel of three-dimensional models for
studies of prostate cancer growth, invasion and drug responses.
PLoS One 5: e10431.
International Cancer Genome Consortium, Hudson T.J.,et al.
(2010) International network of cancer genome projects. Nature
464: 993-998.
Pollari S., Käkönen S.M., Edgren H., Wolf M., Kohonen P., Sara
H., Guise T., Nees M. and Kallioniemi O. (2011) Enhanced serine
production by bone metastatic breast cancer cells stimulates
osteoclastogenesis. Breast Cancer Res. Treat.125: 421-430.
Leivonen S.K., Mäkelä R., Ostling P., Kohonen P., Haapa-Paananen
S., Kleivi K., Enerly E., Aakula A., Hellström K., Sahlberg N.,
Kristensen V.N., Børresen-Dale A.L., Saviranta P., Perälä M. and
Kallioniemi O. (2009) Protein lysate microarray analysis to identify
microRNAs regulating estrogen receptor signaling in breast cancer
cell lines. Oncogene, 28: 3926-3936.
Iljin K., Ketola K., Vainio P., Halonen P., Kohonen P., Fey V.,
Grafström R.C., Perälä M. and Kallioniemi O. (2009) Highthroughput cell-based screening of 4910 known drugs and
drug-like small molecules identifies disulfiram as an inhibitor of
prostate cancer cell growth. Clin. Cancer Res., 15: 6070-6078.
Varjosalo M., Björklund M., Cheng F., Syvänen H., Kivioja T.,
Kilpinen S., Sun Z., Kallioniemi O., Stunnenberg H.G., He,
W-W., Ojala P. and Taipale J. (2008) Application of Active
and Kinase-Deficient Kinome Collection for Identification of
Kinases Regulating Hedgehog Signaling. Cell 133: 537-548.
Pellinen T., Tuomi S., Arjonen A., Wolf M., Edgren H., Meyer
H., Rantala J.K., Kallioniemi O., Fässler R., Kallio M. and Ivaska
J. (2008) Integrin traffic regulated by Rab21 is necessary for
cytokinesis. Dev. Cell., 15: 371-385.
Kilpinen S., Autio R., Ojala K., Iljin K., Bucher E., Sara H., Pisto
T., Saarela M., Skotheim R., Björkman M., Mpindi J. P., HaapaPaananen S., Vainio P., Edgren H., Wolf M., Astola J., Nees M.,
Hautaniemi S. annd Kallioniemi O. (2008) Systematic bioinformatic
analysis of expression levels of 17,330 human genes across 9,783
samples from 175 types of healthy and pathological tissues.
Genome Biol., 9: R139.
86
SIGNALING PATHWAYS REGULATED
BY ONCOGENIC PIM KINASES
Päivi J. Koskinen, Ph.D., Senior Assistant, Adjunct Professor in
Molecular and Cell Biology. Current laboratory address:
Section of Genetics and Physiology, Department of Biology,
University of Turku, FIN-20014 University of Turku, Finland.
Tel. + 358-2-3335936, Fax + 358-2-3336598.
E-mail: paivi.koskinen@utu.fi
Biography:
Päivi Koskinen (b. 1961) received her Ph.D. at the University of
Helsinki in 1992. During years 1993-1996 she worked as a
postdoctoral fellow in Dr. Robert Eisenman´s laboratory at the Fred
Hutchinson Cancer Research Center in Seattle, USA. In 1996 she
joined the Turku Centre for Biotechnology as a group leader and
a research fellow of the Academy of Finland. Since 2006 she has
been employed by the Department of Biology, University of Turku,
where her group also moved during autumn 2011.
Personnel:
Co-supervisor: Eeva Rainio, Ph.D. Graduate students: Jouko
Sandholm, M.Sc., Riitta Vahakoski, M.Sc., Niina Santio, M.Sc.
Undergraduate students: Heidi Ekman, Juho Virtanen, Sini Eerola.
The studies of our research group focus on the signaling pathways
regulated by the oncogenic Pim family of serine/threoninespecific protein kinases. We have shown that the three highly
homologous members of this family are expressed in partially
overlapping patterns, mainly in cells of the immune or the nervous
system. In hematopoietic cells, pim expression can be induced
by multiple cytokines and also by some hormones, suggesting a
role for Pim kinases in signal transduction initiated by cytokine or
hormone receptors. When overexpressed in lymphoid tissues of
transgenic mice, pim genes promote lymphomagenesis, especially
in cooperation with other oncogenes that either enhance cell
proliferation (myc) or cell survival (bcl-2). We and others have
observed that in human cancer patients, elevated levels of pim-1
mRNA and protein can be found in leukemias, lymphomas and
solid tumors such as prostate cancer. Recently we have noticed
that pim-1 overexpression also promotes radioresistance in
patients suffering from squamocellular head and neck carcinomas.
We have previously shown that Pim-1 stimulates activities of several
cellular or viral transcription factors such as Myb, NFATc, EBNA2
as well as RUNX family members. More recently also LANA, the
latency-associated nuclear antigen of Kaposi sarcoma-associated
herpesvirus has been identified as a direct Pim substrate. We have
also analysed expression of pim family genes during cytokine-
dependent T helper cell differentiation. Furthermore, we have
shown that Pim kinases promote cytokine-independent survival
and inhibit apoptosis by several mechanisms, including upregulated
expression of the anti-apoptotic Bcl-2 protein and phosphorylationinduced inactivation of the pro-apoptotic Bad protein. Altogether,
our studies based on domestic or international collaborations have
had a major impact to the understanding of Pim kinase activities
in both normal and transformed cells and have explained why Pim
87
kinases can so efficiently co-operate with Myc family transcription
factors in murine, and most likely also in human tumorigenesis.
Even though Myc-overexpressing cells proliferate faster, they are
more prone to apoptosis, so it is advantageous for them to cooverexpress also Pim kinases, which regulate the balance between
anti- and proapoptotic factors and boost activities of transcription
factors that are essential for production of cytokines and other
survival factors.
To further characterize the signaling pathways downstream of
Pim kinases, we have used phosphoproteomics to reveal novel
substrates for Pim kinases. These proteins have recently been
confirmed as true Pim substrates and their functional validation
is underway using both overexpression and RNA interferencebased approaches. Since we aim to identify the relevant
phosphorylation target sites in the novel Pim substrates, we have
participated in developing sensitivity of the methodology to identify
phosphopeptides. In addition, we have been collaborating with
three groups of chemists to identify and validate Pim-specific small
molecule inhibitors, which appear to be great tools for our research,
but may also have therapeutic value. Using these inhibitors, we
have recently revealed a novel role for Pim kinases in stimulation of
cancer cell migration and invasion.
Funding:
The Academy of Finland, TEKES, The Drug Discovery Graduate
School.
Key Collaborators:
Jari Yli-Kauhaluoma (Viikki Biocenter, Helsinki), Pascale Moreau
(CNRS, France), Asko Uri (University of Tartu, Estonia), Margarita
Glazova (Sechenov Institute, St. Petersburg, Russia), Michael
Nonet (Washington University, MO, USA), Päivi Ojala (Biomedicum
Helsinki), Garry Corthals (CBT), Eleanor Coffey (CBT), Pirkko
Härkönen (UTU), Sirpa Jalkanen (UTU).
Letribot, B., Akué-Gédu, R., Santio, N.M., El-Ghozzi, M., Avignant,
D., Cisnetti, F., Koskinen, P.J., Gautier, A., Anizon, F. and Moreau,
P. (2012) Use of Copper(I) Catalyzed Azide Alkyne Cycloaddition
(CuAAC) for the preparation of conjugated pyrrolo[2,3-a]carbazole
Pim kinase inhibitors. Eur. J. Med. Chem., in press.
Sarek, G., Ma, L., Enbäck, J., Järviluoma, A., Haas, J. Gessain,
A., Koskinen, P.J., Laakkonen, P. and Ojala, P.M. (2012) Kaposi’s
sarcoma herpesvirus lytic replication compromises apoptotic
response to p53 reactivation in virus-induced lymphomas.
Oncogene, in press.
Kouvonen, P., Rainio, E.M., Suni, V., Koskinen, P. and Corthals,
G. (2011) Enrichment and sequencing of phosphopeptides using
indium tin oxide coated glass slides. Mol. BioSyst. 7: 1828-1837.
Santio, N.M., Vahakoski, R.L., Rainio, E.M., Sandholm, J.A.,
Virtanen, S.S., Prudhomme, M., Anizon, F., Moreau, P. and
Koskinen, P.J. (2010) Pim-selective inhibitor DHPCC-9 reveals Pim
kinases as potent stimulators of cancer cell migration and invasion.
Mol. Cancer 19: 279.
Kouvonen, P., Rainio, E.M., Suni, V., Koskinen, P. and Corthals,
G.L. (2010) Data combination from multiple matrix-assisted
88
laser desorption/ionization (MALDI) matrices: opportunities and
limitations for MALDI analysis. Rapid Commun. Mass Spectrom.
15: 3493-3495.
Peltola, K.J., Hollmén, M., Maula, S.M., Rainio, E.M., Ristamäki,
R., Luukkaa, M., Sandholm, J., Sundvall, M., Elenius, K., Koskinen,
P.J., Grenman, R. and Jalkanen, S. (2009) Pim-1 kinase expression
predicts radiation response in squamocellular carcinoma of head
and neck and is under the control of epidermal growth factor
receptor. Neoplasia 11: 629-636.
Cheng, F., Weidner-Glunde, M., Varjosalo, M., Rainio, E.M.,
Lehtonen, A., Schulz, T.F., Koskinen, P.J., Taipale, J. and Ojala,
P.M. (2009) KSHV reactivation from latency requires Pim-1 and
Pim-3 kinases to inactivate the latency-associated nuclear antigen
LANA. PLoS Pathogens, 5: e1000324.
Aho, T.L.T., Peltola, K.J. and Koskinen, P.J. (2006) Pim-1 kinase
phosphorylates RUNX family transcription factors and enhances
their activity. BMC Cell Biol. 7: 1-9.
Aho, T.L.T., Lund, R., Ylikoski, E., Matikainen, S., Lahesmaa, R.
and Koskinen, P.J. (2005) Expression of human pim family genes
is selectively upregulated by cytokines promoting Th1, but not Th2
cell differentiation. Immunol. 116: 82-88.
Glazova, M., Aho, T.L.T., Palmetshofer, A., Murashov, A., Scheinin,
M. and Koskinen, P.J. (2005). Pim-1 kinase enhances NFATc
activity and neuroendocrine functions in PC12 cells. Mol. Brain
Res. 138: 116-123.
Rainio, E.M., Ahlfors, H., Carter, K., Ruuska, M., Matikainen, S.,
Kieff, E. and Koskinen, P.J. (2005) Pim kinases are upregulated
by Epstein-Barr virus infection and enhance EBNA2 activity. Virol.
333: 201-206.
Peltola, K.J., Paukku, K., Aho, T.L.T., Ruuska, M., Silvennoinen, O.
and Koskinen, P.J. (2004). Pim-1 kinase inhibits Stat5-dependent
transcription via its interactions with SOCS1 and SOCS3. Blood
103: 3744-3750.
Aho, T.L.T., Sandholm, J., Peltola, K.J., Mankonen, H.P., Lilly, M.
and Koskinen, P.J. (2004) Pim-1 kinase promotes inactivation 112
of
the pro-apoptotic Bad protein by phosphorylating it on the Ser
gatekeeper site. FEBS Lett. 571: 43-49.
Yan, B., Zemskova, M., Kraft, A., Koskinen, P.J. and Lilly, M. (2003).
The Pim-2 kinase phosphorylates Bad on serine-112 and reverses
Bad-induced cell death. J. Biol. Chem. 278: 45358-45367.
Rainio, E.M., Sandholm, J. and Koskinen, P.J. (2002).
Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase.
J. Immunol.168: 1524-1527.
Eichmann, A., Yuan, L., Bréant, C., Alitalo, K. and Koskinen,
P.J. (2000). Developmental expression of Pim kinases suggests
functions also outside of the hematopoietic system. Oncogene 19:
1215-1224.
89
MOLECULAR IMMUNOLOGY AND
SYSTEMS BIOLOGY OF CELL
DIFFERENTIATION
cell signaling, and transcriptional and epigenetic programs that
determine cell differentiation and fate. We want to understand
molecular mechanisms of human immune mediated diseases and
certain types of cancer to enable development of novel therapeutic
approaches to help patients suffering from these conditions.
Riitta Lahesmaa, M.D., Ph.D., Professor, Turku Centre for
Biotechnology, BioCity, Tykistökatu 6A, FI-20521 Turku, Finland.
Tel. +358-2-333 8601, Fax. +358-2-333 8000.
Email: riitta.lahesmaa@btk.fi
Home page: www.btk.fi
T helper cell activation and differentiation to functionally distinct
subsets. Selective activation of T helper (Th) cell subsets plays
an important role in the pathogenesis of human allergy and
inflammatory diseases. Dissecting pathways and regulatory
networks leading to the development of Th1, Th2, Th17 or
regulatory T cells (Treg) is essential to understand the pathogenesis
of allergy and inflammatory diseases. Th2 cytokines lead to a
series of inflammatory processes characteristic for asthma and
other atopic diseases whereas Th1 and Th17 cells play a role in
the pathogenesis of autoimmune diseases (e.g. type I diabetes).
Treg cells have an important role in inhibiting all these T effector
cell functions. Detailed analysis of upstream T cell Receptor (TCR)/
key cytokine receptor induced differentiation will increase our
understanding of these processes central for human health and
disease and provide novel insights into new therapeutic interventions.
STAT6 is known to be an essential upstream mediator of IL-4R
signaling and Th2 differentiation. We were the first to identify
STAT6 target genes on a genome wide scale in human CD4+ T
cells - only a small fraction of which were previously known to
be STAT-6 regulated. This study, published in Immunity, revealed
that in human a surprisingly high proportion, up to 80%, of IL-4
induced response is STAT6 regulated. We identified several new
candidates for therapeutic intevention (Elo L et al. 2010, O’Shea et
a.. 2011). Our studies on IL-4 R signaling in lymphocytes resulted
in identification of new IL4R/STAT-6 regulated proteins and their
molecular functions in human and mice (Aflakian N, et al. 2009,
Moulder R. et al. 2010, Tripathi et al. 2011, Tuomela S. et al. 2009,
Cho CH et al. 2009). Our results have led to novel hypotheses on
the key factors involved in human Th cell differentiation (Lund et al.,
2007, Rautajoki et al. 2007). We further discovered that ATF3 and
SATB1 are important regulators of human Th cell differentiation.
ATF3 promotes Th1 differentiation (Filen S et al. 2010) whereas
SATB1 regulates multiple genes during early Th cell differentiation
(Ahlfors et al. 2010).
Biography:
Biography: Riitta Lahesmaa received her M.D. in 1984 and Ph.D.
in 1987 from the University of Turku, and was appointed Docent in
Immunology in 1990. She was a postdoctoral fellow at Stanford
University Medical Center with Professor Lawrence Steinman
during the years 1990-1993 (NIH Fogarty Fellowship). In 1994
she moved to Syntex Research Institute (later Roche Bioscience)
in Palo Alto, California. As a Principal Scientist she focused on
lymphocyte signaling and drug discovery with state-of-the-art
functional genomics tools. In 1998 she was appointed Director of
Turku Centre for Biotechnology. In 2009 she carried out research
in Professor Anjana Rao’s laboratory in Immune Disease Institute,
Harvard Medical School, Boston. She also directs Turku Centre for
Systems Biology since 2000.
Personnel:
Senior scientists/ Post-doctoral researchers: Kanchan Bala, Jane
Zhi Chen, Ph.D., Sanna Edelman, Ph.D., Laura Elo-Uhlgren,
Ph.D.., Riikka Lund, Ph.D., Robert Moulder, Ph.D., Juha-Pekka
Pursiheimo, Ph.D., Omid Rasool, Ph.D., Emaheswa Reddy, Ph.D.,
Jussi Salmi, Ph.D., Johanna Tahvanainen, Ph.D., Viveka Öling, Ph.D.
Visiting Scientists: Kanury Rao, Ph.D., (Director, Immunology Group
at ICGEB, New Delhi, India); Anjana Rao, Ph.D. Professor, La Jolla
Institute for Allegy and Immunology, San Diego, CA, U.S., Brigitta
Stockinger, Ph.D. (Principal Investigator, Division of Molecular
Immunology, NIMR, London, UK)
Graduate students: Henna Kallionpää, M.Sc., Kartiek Kanduri,
M.Sc., Moin Khan, M.Sc., Juha Korhonen, M.D., Minna Kyläniemi,
M.Sc., Essi Laajala, M. Tech., Tapio Lönnberg, M.Sc., Elisa Närvä,
M.Sc., Mirkka Heinonen, M.Sc., Nelly Rahkonen, M.Sc., Verna
Salo, M.Sc., Alexey Sarapulov, M.Sc., Soile Tuomela, M.Sc.,
Subhash Tripathi, M.Tech, M.Sc.
Laboratory Technicians: Bogata Fezazi, Marjo Hakkarainen, Sarita
Heinonen, Päivi Junni, Elina Pietilä
Undergraduate students: Krista Maurinen, Johanna Myllyviita, Lotta
Oikari, Anna Rajavuori
Our research group is part of the “Centre of Excellence on Molecular
Systems Immunology and Physiology” Academy of Finland
nominated for years 2012-17. In this CoE we are responsible for
molecular systems immunology. In addition we focus on stem cell
biology. We use holistic genome and proteome wide methods and
systems biology to identify and study molecular mechanisms of
90
Human embryonic stem cells (hESC) have a unique capacity to
differentiate to any type of cell or tissue providing an enormous
potential for therapeutic applications. Our recent results based on
the use of high resolution microarray technology demonstrate the
necessity of monitoring stem cell lines carefully to minimize the
risk of malignancies in stem cell therapies. Our study published in
Nature Biotechnology and highlighted in Nature Methods revealed
that in prolonged culture human embryonic stem cells acquire
chromosomal abnormalities and changes in gene expression,
many of which are linked to cancer. (Närvä et al. 2010). This was
followed up by a study published in Nature, where the number
of copy number variations in both early and intermediate-stage
human induced pluripotent stem (iPS) cells was compared with
their respective parental, originating cells as well as embryonic
stem cells. The results suggest that whole genome analysis should
be included as quality control of iPS cell lines to verify that the cells
remain genetically normal after the reprogramming process, before
use for studies and/or clinical applications. (Hussein S, et al. 2011).
91
From left to right: Bogata Fezazi, Alexey Sarapulov, Tapio Lönnberg, Khan Mohd Moin, Emani Maheswara Reddy, Robert Moulder, Kanduri Kartiek, Essi Laajala, Chen Zhi Jane, Sarita Heinonen, Juha-Pekka
Pursiheimo, Iida Koho, Sanna Edelman, Terhi Jokilehto, Riitta Lahesmaa, Omid Rasool, Verna Salo, Marjo Hakkarainen, Henna Kallionpää, Minna Kyläniemi, Mirkka Heinonen, Lotta Oikari, Nelly Rahkonen,
Johanna Myllyviita, Subhash Tripathi, Riikka Lund, Elisa Närvä and Elina Pietilä
Our goal is to elucidate the molecular mechanisms regulating self
renewal and pluripotency of hESC and induced pluripotent stem
cells (iPS). We have identified novel genes and signaling pathways
characteristic for the pluripotent hESC and iPS cells based on a
genome wide transcriptome analyses of hESC. This resulted in the
discovery of a RNA binding protein L1TD1 selectively expressed in
stem cells and required for hESC renewal (Närvä et al. 2011).
Type 1 diabetes (T1D) is the most common metabolic-endocrine
disorder in children in western countries and the annual incidence
of T1D in Finland is record high. In almost all children, progression
to clinical T1D is associated with the presence of b cell specific
autoantibodies. Clinical T1D occurs when 80-90% of the b cells
have been destroyed. Today, a T1D patient is dependent on daily
insulin substitution for the rest of his/her life and there is a high risk
of developing acute and long-term complications. Development
of early diagnostics would enable early therapy and possibly
preventive treatments resulting in significant health benefits.
We are studying molecular mechanisms of T1D to discover molecular
markers that would indicate development of autoimmunity and
progression towards clinical T1D. Exploiting the unique biobank of
the Type 1 Diabetes Prediction and Prevention Project in Finland
(DIPP) we investigated transcriptomic profiles of prospective
whole-blood samples from children who have developed T1Dassociated autoantibodies and eventually clinical T1D. Gene-level
investigation showed systematic differential expression of 520
probesets. A network-based analysis revealed a highly significant
down-regulated network of genes involved in antigen presentation
as well as T-cell receptor and insulin signaling. (Elo et al. 2010).
Further studies include analysis of larger cohort of longitudinal
samples using transcriptomics, proteomics and integrating the
data with our previous metabolomics data (Oresic et al. 2008).
Funding:
The Academy of Finland, The National Technology Agency of
Finland (TEKES), EU 6th framework “ESTOOLS”, JDRF, The
Sigrid Jusélius Foundation, The Finnish Cancer Organizations,
Turku University Hospital Fund, Graduate Schools (TuBS, ISB),
University of Turku, Åbo Akademi University, European Research
Council, EU 7th framework projects “SYBILLA”, “DIABIMMUNE” ,
“NANOMMUNE”, “PEVNET”, EraSysBioPlus, European Research
Council
Collaborators:
Ruedi Aebersold & Matthias Gstaiger (ETZ, Zürich, Swizrland) and
the other 14 EU FP7 SYBILLA partners , Reija Autio (Tampere
University of Technology ), Christopher Burge (MIT, Cambridge,
MA, USA), Sanjeev Galande (IISER, Pune, India), Heikki Hyöty
(U. Tampere), Mikael Knip (U. Helsinki), Harri Lähdesmäki (Aalto
University), David Goodlett (University of Washington, Seattle, WA,
USA and a FiDiPro in CBT) , Matej Oresic (VTT Technical Research
Centre of Finland, Turku), Anjana Rao (La Jolla Institute for Allergy
and Immunology, San Diego, CA, USA and visiting professor
at CBT), Kanury V.S. Rao (ICGEB, New Delhi, India and visiting
professor at CBT), Bing Ren (Ludwig Institute for Cancer Research,
University of California, San Diego, USA), Olli Simell (U. Turku),
Brigitta Stockinger (NIMR, London, UK and visiting professor at
CBT), Thomas Tushl (Rockefeller University, New York, NY, USA)
92
93
Aflakian N., Ravichandran S., Sarwar Jamaal Md. S., Jarvenpää
H., Lahesmaa R., Rao K.V.S. (2009) Integration of signals from the
B-cell antigen receptor and the IL-4 receptor leads to a cooperative
shift in the cellular response axis. Mol. Biosyst. 5: 1661-1671.
Ahlfors H., Limaye A., Elo-Uhlgrén L., Notani D., Gottimukkala K.,
Burute M., Tuomela S., Rasool O., Galande S.* & Lahesmaa R.*.
(2010) SATB1 dictates expression of multiple genes including IL-5
involved in human T helper cell differentiation. *Equal contribution.
Blood 116: 1443-1453.
Cho S.H., Goenka S., Henttinen T., Gudapati P., Reinikainen A.,
Lahesmaa R., Boothby M. (2009) PARP-14, a member of the B
aggressive lymphoma (BAL) family, transduces survival signals in
primary B cells. Blood 113: 2416-2425.
Elo L.L.#, Järvenpää H.#, Tuomela S.#, Raghav S.#, Ahlfors H.,
Laurila K., Gupta B., Lund R.J., Tahvanainen J., Hawkins R.D.,
Orešic M., Lähdesmäki H., Rasool O., Rao K.V.S.*, Aittokallio T.*,
Lahesmaa R. (2010) IL-4- and STAT6-mediated transcriptional
regulation to initiate Th2 program in human T cells. Immunity, 32:
852-862. #, * Equal contribution.
Elo L.L.*, Mykkänen J.*, Nikula T., Järvenpää H., Aittokallio T., Hyöty
H., Ilonen J., Veijola R., Knip M., Simell O., Lahesmaa R. (2010)
Genome-wide gene expression profiling reveals early suppression
of immune response pathways in prediabetic children.. *Equal
contribution. J. Autoimmun. 35: 70-76.
Filén J.J., Filén S., Moulder R., Tuomela S., Ahlfors H., West A.,
Kouvonen P., Kantola S., Björkman M., Katajamaa M., Rasool O.,
Nyman T.A., Lahesmaa R. (2009) Quantitative Proteomics Reveals
GIMAP Family Proteins 1 and 4 to Be Differentially Regulated during
Human T Helper Cell Differentiation. Mol. Cell Proteomics 8: 32-44.
Filén S., Ylikoski E., Tripathi S., West A., Björkman M., Nyström
J., Ahlfors H., Rao K.V.S., Coffey E., Rasool O., and Lahesmaa
R. (2010) ATF3 is a Positive Regulator of Human IFNG Gene
Expression. J. Immunol. 184: 4990-4999.
Hussein S., Batada N., Vuoristo S., Autio R., Närvä E., Ng S.,
Hämäläinen R., Olsson C., Lundin K., Mikkola M., Trokovic R., Peitz
M., Brüstle O., Alitalo K., Lahesmaa R., Nagy A. #, Otonkoski T.#
(2011) Increased mutation load is associated with reprogramming
of human somatic cells. Nature 471: 58-62. #.Equal contribution.
Koh K.P., Yabuuchi A., Rao S., Huang Y., Cunniff K., Nardone J.,
Laiho A., Tahiliani M., Sommer C.A., Mostoslavsky G., Lahesmaa
R., Orkin S.H., Rodig S.J., Daley G.Q., Rao A. (2011) Tet1 and
tet2 regulate 5-hydroxymethylcytosine production and cell lineage
specification in mouse embryonic stem cells. Cell Stem Cell 8:
200-213.
Kumar D., Srikanth R., Ahlfors H., Lahesmaa R., Rao K. (2007)
Capturing cell-fate decisions from the molecular signatures of
a receptor-dependent signaling response. Molecular Systems
Biology, 3: 150.
Rasool O., Lahesmaa R. (2007) Genome wide identification of
Novel Genes Involved in Early Th1 and Th2 Cell Differentiation . J.
Immunol. 178: 3648-3660.
Moulder R.*, Lönnberg T.*, Filén J-J., Elo L., Rainio E., Corthals
G., Oresic M., Nyman T.A., Aittokallio T., Lahesmaa R. (*equal
contribution) (2010) Quantitative Proteomics Analysis of the Nuclear
Fraction of Human CD4+ Cells in the Early Phases of IL-4 Induced
Th2 Differentiation. Mol Cell Proteomics 9: 1937-1953.
Närvä E., Autio R., Rahkonen N., Kong L., Harrison N., Kitsberg
D., Borghese L., Itskovitz-Eldor J., Rasool O., Dvorak P., Hovatta
O., Otonkoski T., Tuuri T., Cui W., Brüstle O., Baker D., Maltby E.,
Moore H.D., Benvenisty N., Andrews P.W., Yli-Harja O. & Lahesmaa
R. (2010) High resolution genome wide DNA analysis on a large
panel of Human Embryonic Stem Cell lines reveals novel genomic
changes associated with culture and affecting gene expression.
Nat. Biotechnol. 28: 371-377.
Närvä E., Rahkonen N., Emani M.R., Lund R., Pursiheimo J.P.,
Nästi J., Autio R., Rasool O., Denessiouk K., Lähdesmäki H., Rao
A., Lahesmaa R. (2011) RNA Binding Protein L1TD1 Interacts with
LIN28 via RNA and is Required for Human Embryonic Stem Cell
Self-Renewal and Cancer Cell Proliferation. Stem Cells 30: 452460.
Oresic M., Simell S.*, Sysi-Aho M.*, Näntö-Salonen K.*, SeppänenLaakso T.*, Parikka V.*, Katajamaa M.*, Hekkala A., Mattila I.,
Keskinen P., Yetukuri L., Reinikainen A., Lähde J., Suortti T., Hakalax
J., Simell T., Hyöty H., Veijola R., Ilonen J., Lahesmaa R., Knip M.,
Simell O. (2008) Dysregulation of lipid and amino acid metabolism
precedes islet autoimmunity in children who later progress to type
1 diabetes. * Equal contribution. J. Exp. Med. 205: 2975-84.
O’Shea J.J., Lahesmaa R., Vahedi G., Laurence A., Kanno Y.
(2011) Genomic views of STAT function in CD4(+) T helper cell
differentiation. Nat. Rev. Immunol. 11: 239-50.
Rautajoki, K., Marttila, E., Nyman, T., Lahesmaa, R. (2007)
Interleukin-4 inhibits caspase-3 by regulating several proteins
in the Fas pathway during initial stages of human T helper 2 cell
differentiation. Mol. Cell Proteomics 6: 238-251.
Tahvanainen J., Kallonen T., Lähteenmäki H., Heiskanen K.M.,
Westermarck J., Rao K.V., Lahesmaa R. (2009) PRELI is a
mitochondrial regulator of human primary T helper cell apoptosis,
STAT6 and Th2 cell differentiation. Blood 113: 1268-77.
Tripathi P.*, Sahoo N.*, Ullah U.*, Järvenpää H., Suneja A.,
Lahesmaa R., Rao K.V.S. (2011) MAP kinase initiates digital
regimes of signal sensing to control specificity and amplitude of
human Th2 cell differentiation. Immunol. Cell Biol. doi: 10.1038/
icb.2011.87. [Epub ahead of print] *Equal contribution.
Tuomela S., Rautajoki K.J., Moulder R., Nyman T.A., Lahesmaa
R. (2009) Identification of novel Stat6 regulated proteins in IL-4treated mouse lymphocytes. Proteomics 9: 1087-98.
Lund R.*, Pykäläinen M.*, Naumanen T., Dixon C., Chen Z.,
Ahlfors H., Tuomela S., Tahvanainen J., Scheinin J., Henttinen T.,
94
95
COMPUTATIONAL SYSTEMS
BIOLOGY
Erkkilä T., Lehmusvaara S., Ruusuvuori P., Visakorpi T., Shmulevich I.
and Lähdesmäki H. (2010) Probabilistic analysis of gene expression
measurements from heterogeneous tissues, Bioinformatics 26:
2571-2577.
Harri Lähdesmäki, D.Sc. (Tech), Prof. (pro term), Affiliated Group
Leader at CBT. Contact information: Aalto University School of
Science, Department of Information and Computer Science,
PO Box 15400, FI-00076 Aalto, Finland.
E-mail: harri.lahdesmaki@aalto.fi
Home page: http://users.ics.tkk.fi/harrila/research/
Elo L. L., Järvenpää H., Tuomela S., Raghav S., Ahlfors H., Laurila
K., Gupta B., Lund R. J., Tahvanainen J., Hawkins D., Oresic M.,
Lähdesmäki H., Rasool O., Rao K. V., Aittokallio T. and Lahesmaa
R. (2010) Genome-wide Profiling of Interleukin-4 and STAT6
Transcription Factor Regulation of Human Th2 Cell Programming,
Immunity, 32: 727-862.
Personnel:
Post-doctoral researchers: Jukka Intosalmi
Graduate students: Timo Erkkilä, Kartiek Kanduri, Lingjia Kong,
Antti Larjo, Henrik Mannerström, Kari Nousiainen, Maria Osmala,
Tarmo Äijö
Undergraduate students: Kaur Alasoo, Juhani Kähärä, Maia
Malonzo, Sini Rautio, Janne Seppälä, Juhi Somani
Laurila K. and Lähdesmäki H. (2009) A protein-protein interaction
guided method for competitive transcription factor binding improves
target predictions, Nucleic Acids Research, 37: e146.
We use computational techniques to model and understand
molecular regulatory mechanisms and their role in health and
disease. We focus on developing statistical modeling and
machine learning methods to understand transcriptional, posttranscriptional and epigenetic regulatory mechanisms, protein
signaling pathways, and effects of mutations on regulatory
mechanisms. We also develop methods for biological sequence
analysis, combining heterogeneous biological information sources
and analyzing high-throughput measurement data, such as deepsequencing and microarray measurements. Research projects are
carried out in close collaboration with experimental groups, and we
collaborate on molecular immunology, stem cell, cancer and type 1
diabetes systems biology research projects.
Laurila K. and Lähdesmäki H. (2009) Systematic analysis of
disease-related regulatory mutation classes reveals distinct effects
on transcription factor binding, In Silico Biology 9: 0018.
Funding:
Academy of Finland, EU FP7, EraSysBio+, Emil Aaltonen
Foundation, FICS and TISE graduate schools.
Äijö T. and Lähdesmäki H. (2009) Learning gene regulatory
networks from gene expression measurements using nonparametric molecular kinetics. Bioinformatics 25: 2937-2944.
Lähdesmäki H., Rust A. G. and Shmulevich I. (2008) Probabilistic
inference of transcription factor binding from multiple data sources,
PLoS ONE, 3: e1820.
Lähdesmäki H. and Shmulevich I. (2008) Learning the structure
of dynamic Bayesian networks from time series and steady state
measurements. Machine Learning 71: 185-217.
Ahdesmäki M., Lähdesmäki H., Gracey A., Shmulevich I. and
Yli-Harja O. (2007) Robust regression for periodicity detection in
non-uniformly sampled time-course gene expression data, BMC
Bioinformatics, 8: 233.
Collaborators:
Prof. Riitta Lahesmaa (University of Turku), Prof. Matej Orešic (VTT
Technical Research Centre of Finland), Prof. Mikael Knip (University
of Helsinki), Prof. Olli Simell (Hospital District of Southwest Finland)
Närvä E., Rahkonen N., Emani M.R., Lund R., Pursiheimo J.-P.,
Nästi J., Autio R., Rasool O., Denessiouk K., Lähdesmäki H.,
Rao A. and Lahesmaa R., (in press) RNA binding protein L1TD1
interacts with LIN28 via RNA and is required for human embryonic
stem cell self-renewal and cancer cell proliferation, Stem Cells, in
press.
Urbanucci A., Sahu B., Seppälä J., Larjo A., Latonen L.M., Waltering
K.K., Tammela T.L.J., Vessella R.L., Lähdesmäki H., Jänne O.A.
and Visakorpi T., (in press) Overexpression of androgen receptor
enhances the binding of the receptor to the chromatin in prostate
cancer, Oncogene, in press.
Annala M., Laurila K., Lähdesmäki H., and Nykter M., (2011) A
linear model for transcription factor binding affinity prediction in
protein binding microarrays, PLoS ONE, 6: e20059.
96
97
COMPLEX BIOSYSTEMS MODELING
Matti Nykter, D. Sc., Affiliated Group Leader at CBT,
Department of Signal Processing, Tampere University of Technology,
Korkeakoulunkatu 1, FI-33720 Tampere, Finland.
Tel. +358-40-8490651.
Email: matti.nykter@tut.fi
Home page: www.cs.tut.fi/~nykter/
Biography:
Matti Nykter (b. 1978) received the degree of Master of Science
(Engineering) with Distinction in information technology in 2002 and
the degree of Doctor of Science (Technology) in signal processing
in 2006 from Tampere University of Technology, Tampere, Finland.
He has worked as a visiting researcher at The University of Texas
M. D. Anderson Cancer Center in Houston, Texas, USA in 20042005, and as a post-doctoral research at the Institute for Systems
Biology, Seattle, USA during 2007-2009. Since 2010, he has
been a group leader at the Department of Signal Processing at
Tampere University of Technology and affiliated group leader with
Turku Centre for Biotechnology. His research interests are focused
on development of computational methodologies to understand
the mechanisms of gene regulation in context of disease related
dysregulation.
Personnel:
Post-doctoral researchers: Kati Waltering, PhD, Kirsi Granberg,
PhD, Juha Kesseli, D.Sc.
Graduate students: Antti Ylipää, Virpi Kivinen, Matti Annala,
Septimia Sarbu
Undergraduate students: Kimmo Kartasalo, Simo-Pekka Leppänen,
Saija Sorsa, Thomas Liuksiala, Tero Soininen.
The Complex Biosystems Modeling laboratory uses systems
biology methodology to study biology. Our research is rooted in high
throughput measurement data from genomic and transcriptomic
levels. We develop and apply computational tools and mathematical
modelling to understand the biosystems. Research activities of
our laboratory range from theoretical biology to experimental
work. Theoretical work is focused on the fundamental principles
of biological systems, such as the information processing and the
effect of structural constrains to dynamics. Applied research is
focused on cancer research as well as on immunology and cellular
differentiation.
The Academy of Finland, Finnish Funding Agency for Technology
and Innovation (Tekes), Tampere University of Technology, Tampere
Doctoral Programme in Information Science and Engineering,
Graduate School in Electronics, Telecommunications and
Automation, Emil Aaltonen Foundation, Sigrid Juselius Foundation.
Collaborators:
Wei Zhang (University of Texas M.D. Anderson Cancer Center),
Ilya Shmulevich (Institute for Systems Biology), Tapio Visakorpi
(University of Tampere), Riitta Lahesmaa (Turku Centre for
Biotechnology), Johanna Schleutker (University of Turku), Hannu
Haapasalo (Tampere University Hospital), Harri Lähdesmäki (Aalto
University), Merja Heinäniemi (Luxemburg Center for Systems
Biomedicine).
Yang J., Ylipää A., Sun Y., Zheng H., Chen K., Nykter M., Trent J.,
Ratner N., Lev D.C. and Zhang W. (2011) Genomic and molecular
characterization of malignant peripheral nerve sheath tumor
identifies the IGF1R pathway as a primary target for treatment. Clin.
Cancer Res. 17: 7563-7573.
Annala M., Laurila K., Lähdesmäki H. and Nykter M. (2011) A linear
model for transcription factor binding affinity prediction in protein
binding microarrays. PLoS One. 6: e20059.
Ylipää A., Hunt K.K., Yang J., Lazar A.J., Torres K.E., Lev D.C.,
Nykter M., Pollock R.E., Trent J. and Zhang W. (2011) Integrative
genomic characterization and a genomic staging system for
gastrointestinal stromal tumors. Cancer 117: 380-389.
Galas D. J., Nykter M., Carter G.W., Price N. D. and Shmulevich
I. (2010) Biological information as set-based complexity, IEEE
Transactions on Information Theory 56: 667-677.
Litvak V., Ramsey S.A., Rust A.G., Zak D.E., Kennedy K.A.,
Lampano A.E., Nykter M., Shmulevich I. and Aderem A. (2009)
Function of C/EBPdelta in a regulatory circuit that discriminates
between transient and persistent TLR4-induced signals. Nat.
Immunol. 10: 437-43.
Nykter M., Price N. D. , Aldana M., Ramsey S., Kauffman S. A.,
Hood L., Yli-Harja O., and Shmulevich I. (2008) Gene Expression
Dynamics in the Macrophage Exhibit Criticality. PNAS 105: 18971900.
Main research directions are currently related to cancer research.
We are using deep sequencing the characterize the cancer genome
of prostate cancer and glioma. We have identified novel oncogenic
mechanisms that are currently ongoing functional validation.
Another key project is related to understanding cell differentiation.
We have integrated a collection of over three thousand gene
arrays, measured from 166 normal cell types. Based on novel
data integration and data analysis methodology, we are studying
the gene networks that give raise to different cell types and
apply computational approach to uncover recipes for cell type
reprogramming experiments.
Funding:
98
99
METABOLOME IN HEALTH
AND DISEASE
ˇ Ph.D., Prof., Affiliated Group Leader at CBT,
Matej Orešic,
VTT Technical Research Centre of Finland
Tietotie 2, P.O. Box 1000, FI-02044 VTT, Espoo, Finland
E-mail: matej.oresic@vtt.fi
Home page: http://sysbio.vtt.fi/
Biography:
Prof. Matej Orešicˇ holds a PhD in biophysics from Cornell University.
Since 2003 he leads the research in domains of quantitative
biology and bioinformatics at VTT Technical Research Centre of
Finland (Espoo, Finland), where he is a Research Professor in
Systems Biology and Bioinformatics. Prof. Orešicˇ is a director of
the newly established Finnish Centre of Excellence in Molecular
Systems Immunology and Physiology Research (2012-2017). He
is also a co-founder and board member of Zora Biosciences, Oy.
(Espoo, Finland) and current board member of the Metabolomics
Society. His main research areas are metabolomics applications in
biomedical research and computational systems biology. Recent
investigations include studies of longitudinal metabolic profiles
of children who progressed to type 1 diabetes, investigations of
lipidomic profiles associated with acquired obesity and lipotoxicity
induced insulin resistance and metabolomic studies of psychiatric
disorders. Prof. Orešicˇ has initiated the popular MZmine open
source project, leading to popular software for metabolomics
data processing. Prior to joining VTT, Prof. Orešicˇ was a head of
computational biology and modeling at Boston-based Beyond
Genomics, Inc. and bioinformatician at LION Bioscience Research
in Cambridge/MA.
Personnel:
Senior personnel: Tuulia Hyötyläinen, PhD, Team leader,
Metabolomics (analytical chemistry, metabolite analytics), Marko
Sysi-Aho, PhD, Team leader, Biosystems ModellingResearch scientists: sabel Bondia Pons, PhD (metabolomics,
nutritional systems biology), Sandra Castillo, MSc (bioinformatics,
MZmine development), Mika Hilvo, PhD (cancer metabolomics),
Sirkku Jäntti, PhD (analytical chemistry), Maarit Kivilompolo, PhD
(analytical chemistry), Artturi Koivuniemi, MSc (computational
biophysics), Erno Lindfors, PhD (bioinformatics, network biology),
Maria Lankinen, PhD (nutritional systems biology), Tapio Lönnberg
(MSc, molecular systems immunology), Tijana Marinković, PhD
(computational systems biology, theoretical physics), Ismo Mattila,
MSc (analytical chemistry), Heli Nygren, PhD (metabolite analytics),
Gopal Peddinti, PhD (bioinformatics), Vidya R.Velagapudi, PhD
(applied Biochemistry, metabolomics and systems biology),
Laxman Yetukuri, PhD (lipid bioinformatics)
Technicians: Ulla Lahtinen (technician, analytical chemistry), AnnaLiisa Ruskeepää (technician, analytical chemistry), Han Zhao,
MSc (information systems), Leena Öhrnberg (technician, analytical
chemistry)
Metabolome is sensitive to pathogenically relevant factors such as
genetic variation, diet, development, age, immune system status
or gut microbiota. Metabolomics has emerged as a powerful tool
100
for the characterization of complex phenotypes as well as for the
development of biomarkers for specific physiological responses.
We are investigating:
1. how are the genetic and environmental factors imprinted in
the metabolome;
2. the mechanisms by which alterations of metabolome lead
to (patho)physiological changes at the systems level;
3. discovery and functional characterization of metabolic
markers and targets for selected complex diseases.
We are relying on metabolomics techniques to characterize
the metabolome, combined with systems biology strategies to
investigate, e.g., how changes in gene expression, gut microbial
composition or immune/inflammatory status alter the metabolic
phenotypes. Current biomedical interests include metabolic and
autoimmune diseases.
Funding:
EU FP7, Juvenile Diabetes Research Foundation, Academy of
Finland, NordForsk
Collaborators:
Prof. Mikael Knip (University of Helsinki), Prof. Olli Simell (Hospital
District of Southwest Finland), Prof. Riitta Lahesmaa (University
of Turku), Prof. Harri Lähdesmäki (Aalto University), Prof. Sami
Kaski (Aalto University), Prof. Eytan Ruppin (Tel Aviv University),
Antonio Vidal-Puig (University of Cambridge), Hannele Yki-Järvinen
(University of Helsinki), Fredrik Bäckhed (Gothenburg University),
Hilkka Soininen (University of Eastern Finland)
Orešicˇ M., Seppänen-Laakso T., Sun D., Tang J., Therman
S., Viehman R., Mustonen U., van Erp T. G. M., Hyötyläinen T.,
Thompson P., Toga A. W., Huttunen M. O., Suvisaari J., Kaprio J.,
Lönnqvist J. and Cannon T. D. (2012) Phospholipids and insulin
resistance in psychosis: a lipidomics study of twin pairs discordant
for schizophrenia, Genome Med. 4: e1.
Orešicˇ M., Hyötyläinen T., Herukka S.-K., Sysi-Aho M., Mattila I.,
Seppänan-Laakso T., Julkunen V., Gopalacharyulu P. V., Hallikainen
M., Koikkalainen J., Kivipelto M., Helisalmi S., Lötjönen S. and
Soininen H., (2011) Metabolome in progression to Alzheimer’s
disease, Transl. Psychiatry 1: e57.
Sysi-Aho M., Ermolov A., Gopalacharyulu P. V., Tripathi A.,
Seppänen-Laakso T., MaukonenJ, Mattila I., Ruohonen S. T.,
Vähätalo L., Yetukuri L., Härkönen T., Lindfors E., Nikkilä J., Ilonen
J., Simell O., Saarela M., Knip M., Kaski S., Savontaus E. and
Orešicˇ M. (2011) Metabolic regulation in progression to autoimmune
diabetes, PLoS Comp. Biol. 7: e1002257.
Pietiläinen K., Róg T., Seppänen-Laakso T, Virtue S., Gopalacharyulu
P., Tang J., Rodriguez-Cuenca S., Maciejewski A., Naukkarinen J.,
Rissanen A., Ruskeepää A.-L., Niemelä P., Velagapudi V., Castillo
S., Nygren H., Hyötyläinen T., Kaprio J, Yki-Järvinen H, Vattulainen
I., Vidal-Puig A. and Orešicˇ M. (2011) Association of lipidome
remodeling in the adipocyte membrane with acquired obesity in
humans, PLoS Biol. 9: e1000623.
Orešicˇ M., Tang J., Seppänen-Laakso T., Mattila I., Saarni S. E.,
Saarni S. I., Lönnqvist J., Sysi-Aho M., Hyötyläinen T. , Perälä J.
and Suvisaari J. (2011) Metabolome in schizophrenia and other
psychotic disorders: a general population-based study, Genome
Med. 3: e19.
101
Hilvo M., Denkert C., Lehtinen L., Müller B., Brockmöller S.,
Seppänen-Laakso T., Budczies J, Bucher E., Yetukuri L., Castillo
S., Berg E., Nygren H., Sysi-Aho M., Griffin J. L., Fiehn O., Loibl
S., Richter-Ehrenstein C., Radke C., Hyötyläinen T., Kallioniemi O,
Iljin K. and Orešicˇ M. (2011) Novel theranostic opportunities offered
by characterization of altered membrane lipid metabolism in breast
cancer progression, Cancer Res. 71: 3236-3245.
Pluskal T., Castillo S., Villar-Briones A and Orešicˇ M. (2010) MZmine
2: Modular framework for processing, visualizing, and analyzing
mass spectrometry-based molecular profile data, BMC
Bioinformatics 11: 395.
Westerbacka J., Kotronen A., Fielding B. A., Wahren J., Hodson L.,
Perttilä J., Seppänen-Laakso T., Suortti T., Arola J., Hultcrantz R.,
Castillo S., Olkkonen V. M., Frayn K. N., Orešicˇ M. and Yki-Järvinen
H. (2010) Splanchnic balance of free fatty acids, endocannabinoids
and lipids in subjects with NAFLD, Gastroenterology 139: 19611971.
Yetukuri L., Söderlund S., Koivuniemi A., Seppänen-Laakso
T., Niemelä P. S., Hyvönen M., Taskinen M.-R., Vattulainen I.,
Jauhiainen M. and Orešiсˇ M. (2010) Composition and lipid spatial
distribution of High Density Lipoprotein particles in subjects with
low and high HDL-cholesterol, J. Lipid Res. 51: 2341-2351.
Velagapudi V. R., Hezaveh R., Reigstad C. S., Gopalacharyulu P. V.,
Yetukuri L., Islam S., Felin J., Perkins R., Borén J., Orešicˇ M., and
Backhed F. (2010) The gut microbiota modulates host energy and
lipid metabolism in mice, J. Lipid Res. 51: 1101-1112.
Kotronen A., Velagapudi V. R., Yetukuri L., Westerbacka J.,
Bergholm R., Ekroos K., Makkonen J., Taskinen M.-R., Orešicˇ
M. and Yki-Järvinen H. (2009) Saturated fatty acids containing
triacylglycerols are better markers of insulin resistance than total
serum triacylglycerol concentrations, Diabetologia 52: 684-690.
Gopalacharyulu P. V., Velagapudi V. R., Lindfors E., Halperin E. and
Orešicˇ M. (2009) Dynamic network topology changes in functional
modules predict responses to oxidative stress in yeast, Mol.
BioSyst. 5: 276-287.
Orešicˇ M., Simell S., Sysi-Aho M., Näntö-Salonen K., SeppänenLaakso T., Parikka V., Katajamaa M., Hekkala A., Mattila I., Keskinen
P., Yetukuri L., Reinikainen A., Lähde J., Suortti T., Hakalax J.,
Simell T., Hyöty H., Veijola R., Ilonen J., Lahesmaa RKnip., M. and
Simell O. (2008) Dysregulation of lipid and amino acid metabolism
precedes islet autoimmunity in children who later progress to type
1 diabetes, J. Exp. Med. 205: 2975-2984.
Nikkilä J., Sysi-Aho M., Ermolov A., Seppänen-Laakso T., Simell
O., Kaski S., Orešicˇ M. (2008) Gender dependent progression of
systemic metabolic states in early childhood, Mol. Syst. Biol. 4:
e197.
Yetukuri L., Katajamaa M., Medina-Gomez G., Seppänen-Laakso
T., Vidal Puig A. and Orešicˇ M. (2007) Bioinformatics strategies
for lipidomics analysis: characterization of obesity related hepatic
steatosis, BMC Systems Biology 1: e12.
Laaksonen R., Katajamaa M., Päivä H., Sysi-Aho M., Saarinen
L., Junni P., Lütjohann D., Smet J., Van Coster R., SeppänenLaakso T., Lehtimäki T., Soini J. and Orešicˇ M. (2006) A systems
biology strategy reveals biological pathways and plasma biomarker
candidates for potentially toxic statin induced changes in
muscle, PLoS ONE 1: e97.
102
PROTEIN CRYSTALLOGRAPHY
Anastassios C. Papageorgiou, Ph.D., Adjunct Professor in
Biochemistry and Structural Biology Turku Centre for Biotechnology,
BioCity, Tykistökatu 6A, FI-20521 Turku, Finland.
Tel. +358-2-3338012, Fax +358-2-3338000
E-mail: tassos.papageorgiou@btk.fi
Biography:
Tassos Papageorgiou obtained his Ph.D. from the University of
Athens in 1992. He was a postdoctoral fellow at the University of
Oxford and University of Bath (UK). In May 2000, he joined the Centre
for Biotechnology as senior scientist in protein crystallography.
Personnel:
Graduate students: Prathusha Dhavala, Teemu Haikarainen,
Sachin Wakadkar, Bishwa Subedi, Abdi Muleta
Undergraduate students: Morgane Bruneau, Jesse Mattsson,
David Hernandez, Pradeep Battula
We use X-crystallography, molecular biology, and biophysical
techniques to study the structure and function of biological
molecules. One of our major projects has been the Dps family of
proteins that are widely spread among procaryotes and responsible
for protection against oxidative stress due to their ability to oxidize and
store iron. Although Dps proteins are structurally similar to ferritins,
they form a spherical shell of 12 subunits instead of 24 and have
a different ferroxidase center compared to that of ferritins. Based
on our recent results, several mutants were generated to study the
iron core formation using X-ray crystallography, microcalorimetry
(with G. Nounesis, Athens), EXAFS (with Wolfram Meyer-Klaucke,
EMBL-Hamburg), magnetization (with Petriina Paturi, Wihuri
Laboratory, University of Turku) and Mössbauer spectroscopy (with
Johan Linden, Åbo Akademi University) techniques. The magnetic
properties of the iron core in the wild type protein and the mutants
were studied and EXAFS experiments were performed at Stanford
Synchrotron Radiation Lightsource, Menlo Park, CA, USA.
Studies on oxidative stress protection and detoxification
mechanisms have been extended by determining high-resolution
crystal structures of a tau family glutathione transferase (GST)
from Glycine max in free form and in the presence of a substrate
analogue. Importantly, the crystal structures revealed a novel site
on the surface of the protein that may be utilised for storage and/
or transport of dangerous compounds for detoxification. Docking
calculations were carried out to study the binding of diphenylether
herbicides in the active site. Work is currently underway on chimeric
GSTs or mutants created through directed evolution approaches
to produce new GSTs with altered specificity for new applications
in agriculture, biomedicine and environmental security. Crystals of
human GST-A1 have been grown in our lab for use in structureassisted drug design efforts. In addition, the structure of a novel
glutathione transferase was determined by the SAD method using
the anomalous signal of bromide. The overall fold and the geometry
of the active site suggest a new class (coined eta class) of the
glutathione transferase superfamily.
In the theme of enzyme function and stability, we continued
our work on PhaZ7, an extracellular depolymerase involved in
103
the degradation of poly(R)-hydroxyalkanoates (PHAs), a group
of thermoplastic polyesters considered as biodegradable
substitutes for non-degradable plastics. Several mutants were
generated by our collaborators and characterized for their ability
to bind PHAs. Crystal structure determination has revealed a
large conformational change that may play a role in the enzyme’s
function. Further analysis is currently underway and soaking with
substrate analogues is in progress . Work on the Atu (acyclic
terpene utilization) catabolic pathway found in P. Aeruginosa
has been initiated using a combination of X-ray crystallography,
biophysics, molecular biology, homology modelling, computational
and bioinformatics tools. Atu enzymes are involved in the
metabolisn of acyclic terpenes that possess a great potential in
biotechnology, for example in the food, drink and pharmaceutical
industry. A preliminary structure of AtuE has been obtained to 2.5
Å resolution and is currently in the final stages of refinement.
Funding:
Academy of Finland, University of Turku, Biocenter Finland,
Federation of European Microbiology Societies, EU FP7 (access
to synchrotrons).
Collaborators:
Jukka Finne (University of Helsinki), Sauli Haataja (University of
Turku), Dieter Jendrossek (University of Stuttgart), Nikos Labrou
(Agricultural University of Athens), Li Duochuan (Shandong
Agricultural University)
Li, D.-C., Li, A.-N. & Papageorgiou, A.C. (2011) Cellulases from
thermophilic fungi: Recent insights and biotechnological potential.
Enzyme Res. Vol 2011, Article ID 308730
Skopelitou, K., Muleta, A.W, Pavli, O., Skaracis, G.N, Flemetakis, E.,
Papageorgiou, A.C. & Labrou, N.E. (2011). Overlapping protective
roles for glutathione transferase gene family members in chemical
and oxidative stress response in Agrobacterium tumefaciens.
Funct. Integr. Genomics Sep 10. [Epub ahead of print]
Haikarainen, T., Paturi, P., Lindén, J., Haataja, S., Meyer-Klaucke,
W., Finne, J. & Papageorgiou, A.C. (2011). Magnetic properties and
structural characterization of iron oxide nanoparticles formed by
Streptococcus suis Dpr and four mutants. J. Biol. Inorg. Chem. 16:
799-807
Haikarainen, T., Thanassoulas, A., Stavros, P., Nounesis, G., Haataja,
S. & Papageorgiou, A.C. (2011) Structural and thermodynamic
characterization of metal ion binding in Streptococcus suis Dpr. J.
Mol. Biol 405: 448-460.
Wakadkar, S., Zhang,L.Q., Li, D.-C., Haikarainen, T., Dhavala,
P. & Papageorgiou, A.C. (2011) Expression, purification and
crystallization of Chetomium thermophilum Cu, Zn superoxide
dismutase. Acta Cryst F 66: 648-655.
Haikarainen, T., Tsou, C.C., Wu, J.J. & Papageorgiou, A.C. (2010)
Structural characterization and biological implications of di-zink
binding in the ferroxidase center of Strepococcus pyogenes Dpr.
Bichem. Biophys. Res. Comm. 398: 361-365.
104
Haikarainen, T. & Papageorgiou, A.C. (2010) Dps-like proteins:
Structural and functional insights into a versatile protein family. Cell.
Mol. Life Sci. 67: 341-351.
Axarli, I., Georgiadou, C., Dhavala, P., Papageorgiou, A.C. &
Labrou, N. (2010) Investigation of the role of conserved residues
Ser13, Asn48 and Pro49 in the catalytic mechanism of the tau
class glutathione transferase from Glycine max. Bioch. Biophys.
Acta 1804: 662-667.
Labrou, N., Papageorgiou, A.C. & Avramis, V.I. (2010) Structurefunction relationships and clinical applications of L-asparaginases.
Curr. Med. Chem. 17: 2183-2195.
Wakadkar, S., Hermawan, S., Jendrossek, D. & Papageorgiou, A.C.
(2010) The crystal structure of PhaZ7 at atomic (1.2 Å) resolution
reveals details of the active site and suggests a substrate-binding
mode. Acta Cryst. F 66: 648-654.
Melissis, S.C., Papageorgiou, A.C., Labrou, N.E & Clonis, Y.D. (2010)
Purification of moloney murine leukemia virus reverse transcriptase
lacking RNase activity (M-MLVH-RT) on a 9-aminoethyladenine
[1,6-diamine-hexane]-triazine selected from a combinatorial library
of dNTP-mimetic ligands. J. Chromatogr. Sci. 48: 496-502.
Haikarainen, T., Tsou, C.C., Wu, J.J. & Papageorgiou, A.C.
(2010) Crystal structures of Streptococcus pyogenes Dpr reveal
a dodecameric iron-binding protein with a ferroxidase site. J. Biol.
Inorg. Chem. 15: 183-194.
Axarli, I. Dhavala, P., Papageorgiou, A.C. & Labrou, N.E. (2009)
Crystallographic and functional characterization of the fluorodifen
inducible glutathione transferase from Glycine max reveals an
active site topography suited for diphenylether herbicides and a
novel L-site. J. Mol. Biol. 385: 984-1002.
Axarli, I. Dhavala, P., Papageorgiou, A.C. & Labrou, N.E. (2009)
Crystal structrure of Glycine max glutathione transferase in complex
with glutathione: investigation of the induced-fit mechanism
operating by the tau class glutathione transferases. Biochem. J.
422: 247-256.
Mitsiki, E., Papageorgiou, A. C., Iyer, S., Thiyagarajan, N., Prior, S.
H., Sleep, D., Finnis, C. & Acharya, K. R. (2009) Structures of native
human thymidine phosphorylase and in complex with 5-iodouracil.
Biochem. Biophys. Res. Commun. 386: 666-670.
Dhavala, P. & Papageorgiou, A.C. (2009) The crystal structure
of Helicobacter pylori L-asparaginase at 1.4 Å resolution. Acta
Crystallogr. D 65: 1253-1261.
Havukainen, H., Haataja, S., Kauko, A., Pulliainen, A.T., Salminen,
A., Haikarainen, T., Finne, J. & Papageorgiou, A.C. (2008) Structural
basis of zinc- and terbium-mediated inhibition of ferroxidase activity
in Dps ferritin-like proteins. Protein Sci. 17: 1513-1521
Papageorgiou, A.C., Posypanova, G.A., Andersson, C.A., Sokolov,
N.N & Krasotkina, J. (2008) Structural and functional insights into
Erwinia carotovora L-asparaginase. FEBS J. 275: 4306-4316.
105
Dhavala, P., Krasotkina, J., Dubreuil, C. & Papageorgiou, A.C.
(2008) Expression, purification and crystallization of Helicobacter
pylori L-asparaginase. Acta Crystallogr Sect F Struct Biol Cryst
Commun. 64: 740-742
Papageorgiou, A.C., Hermawan, S., Singh C.B. & Jendrossek, D.
(2008) Structural basis of poly(3-hydroxybutyrate) hydrolysis by
PhaZ7 depolymerase from Paucimonas lemoignei. J. Mol. Biol.
382: 1184-1194
Saarinen S., Kato, H., Uchiyama, T., Miyoshi-Akiyama, T. &
Papageorgiou, A.C. (2007) Crystal structure of Streptococcus
dysgalactiae-derived mitogen reveals a zinc-binding site and
alterations in TcR binding. J. Mol. Biol. 373: 1089-1097
Weckström, K. & Papageorgiou, A.C. (2007) Lower consolute
boundaries of the nonionic surfactant C(8)E(5) in aqueous alkali
halide solutions: An approach to reproduce the effects of alkali
halides on the cloud-point temperature. J Colloid Interface Sci.
310: 151-162
Zhao, J., Hayashi, T., Saarinen, S., Papageorgiou, A.C., Kato,
H., Imanishi, K., Kirikae, T., Abe, R., Uchiyama, T. & MiyoshiAkiyama, T. (2007) Cloning, expression and characterization
of the superantigen streptococcal pyrogenic exotoxin-G from
Streptococcus dysgalactiae. Inf. Immun. 75: 1721-1729
CELL FATE
Cecilia Sahlgren, PhD, Academy Research Fellow, + Turku Centre
for Biotechnology, BioCity, Tykistökatu 6B, FI-20521 Turku, Finland.
Tel. 358-2-3338611, Fax. +358-2-3338000
E-mail: cecilia.sahlgren@btk.fi
Biography:
Cecilia Sahlgren received her Ph.D. from Turku Centre of
Biotechnology, Åbo Akademi University December 2002. She
was appointed research fellow at the Department of Biology at
Åbo Akademi University from 2003-2005. 2005-2007 she was a
postdoctoral fellow in Prof. Urban Lendahls lab at the Department
of Cell and Molecular Biology at the Karolinska Institute. 2008 she
was appointed senior research fellow Åbo Akademi University.
In 2009 she founded the Cell fate group at the Turku Centre
for Biotechnology. She currently holds an Academy of Finland
Research Fellow position.
Personnel:
Post-doctoral researchers: Veronika Mamaeva, MD, PhD
Graduate students: Habib Baghinov, M.Sc, Marika Sjöqvist, M.Sc,
Sebastian Landor, M.Sc, Christian Antila, M.Sc,
Laboratory Technician: Helena Saarento
Undergraduate students: Daniel Antfolk, B.Sc, Habib Baghiro,
B.Sc. Neeraj Prabhakar, B.Sc, Santhosh Kumar, B.Sc, Sara
Sarinko, B.Sc
We aim at understanding the basic molecular principles of
signaling mechanisms regulating cell fate choices during stem
cell differentiation, and how disturbances in these mechanisms
link to cancer. Another important goal is to develop technology
to specifically monitor and tune these signals at will in specific cell
populations, in order to steer stem cell fate and curtail oncogenic
activities. We are particularly interested in the role and regulation of
the evolutionary conserved Notch signaling pathway, a key regulator
of stem cell function and tumorigenesis. The main objectives of our
research are to understand i) how the cellular microenvironment
influences Notch signaling activities and how this impinges on cell
identity, function and tumor progression, ii) how Notch signaling
interlinks with other signaling and cellular mechanisms to fine tune
and modulate the cellular response, iii) how intracellular temporal
and spatial control of Notch signaling activities are achieved and
to iv) develope technology platforms to regulate Notch signaling
in targeted cell populations and tools for bioimaging of cellular
functions in vivo.
Funding:
The Academy of Finland, Åbo Akademi University, Centre of
Excellence in Cell Stress and Molecular Aging, EU 7thNotchIT,
Turku Graduate school for Biomedical Sciences, Cancer Society of
Finland, Sigrid Juselius Foundation.
From left to right: Chamundeeswari Sivaraman, Bishwa Subedi, Abdi Muleta,
Teemu Haikarainen and Tassos Papageorgiou
106
Collaborators:
Prof. Milos Pekny (Sahlgrenska Academy at Göteborg University),
Prof. John Eriksson (Turku Centre for Biotechnology). Prof. Urban
Lendahl (Karolinska Institute), Ph.D Susumu Imanishi (Turku
Centre for Biotechnology), Prof. Lea Sistonen (Turku Centre for
107
Bio- technology). Dr.Tech Jessica Rosenholm (Laboratory for
Physical Chemistry, Åbo Akademi, Turku), Prof. Mika Linden (Dept
of Chemistry, Ulm University, Germany), Professor Lucio Miele
(The University of Mississippi Medical Centre), Professor Roberto
Sequeiras (University of Oulu).
Rosenholm J.M., Mamaeva, V., Sahlgren C. # and Lindén, M.#
(2011) Nanoparticles in targeted cancer therapy: Mesoporous
silica nanoparticles entering preclinical development stage.
Nanomedicine in press. # shared corresponding authorship
Landor S., Mamaeva V., Mutvei A., Jin S., Busk M., Borra R.,
Grönroos T., Kronqvist P., Lendahl U. and Sahlgren C.. (2011) Hypoand hyperactivated Notch signaling resets cellular metabolism
in breast tumor cells by distinct mechanisms. Proceedings of
National Academy of Sciences of the United States of America,
PNAS 108:18814-18819. Highlighted in Nature Chemical Biology:
Nat. Chem. Biol. 2011 8: 20. Metabolism: A Warburg shakeup.
Mamaeva V., Rosenholm J.M., Tabe Bate-Eya L., Bergman L.,
Peuhu E., Duchanoy A., Fortelius L.E., Landor S., Toivola D.M
Lindén M. and Sahlgren C. (2011) Mesoporous silica nanoparticles
as drug delivery systems for targeted inhibition of Notch signaling
in cancer. Molecular Therapy 19: 1538-1546.
Rosenholm J.M, Sahlgren C.,# and Linden M.# (2011) Multifunctional
mesoporous silica nanoparticles for combined therapeutic,
diagnostic and targeted action in cancer treatment Current Drug
Targets 12:1166-1186. # shared corresponding authorship
Pallari H.M., Lindqvist J., Torvaldson E., Ferraris S.E., He T.,
Sahlgren C. and Eriksson J.E. (2011). Nestin as a regulator of
Cdk5 in differentiating myoblasts. Molecular Biology of the Cell.
22: 1539-1549.
Das D., Lanner F., Main H., Andersson E.R., Bergmann O., Sahlgren
C., Heldring N., Hermanson O., Hansson E.M. and Lendahl U.
(2010) Notch induces cyclin-D1-dependent proliferation during
a specific temporal window of neural differentiation in ES cells.
Developmental Biology 348: 153-166.
Rosenholm J.M., Sahlgren C#., Linden M.# (2010) Cancer cellspecific targeting of and targeted delivery by mesoporous silica
nanoparticles. Highlight to Journal of Material Chemistry 14: 2707-2713.
Rosenholm J.M., Peuhu E., Eriksson J.E., Sahlgren C#. and Linden
M#. (2009) Targeted Intracellular Delivery of Hydrophobic Agents using
Mesoporous Hybrid Silica Nanoparticles as Carrier Systems (2009)
Nano Letters 9: 3308-3311. # shared corresponding authorship
Rosenholm J.M., Meinander A., Peuhu E., Niemi R., Eriksson J.E.,
Sahlgren C#., and Linden M#. (2009) Targeting of porous hybrid
silica nanoparticles to cancer cells. ACSNano 3: 197-206. # shared
corresponding authorship
Jin S., Hansson E.M., Ihalainen S., Sahlgren C., Baumann M.,
Kalimo H., and Lendahl U. (2008) Notch signaling regulates PDGFreceptorb expression in vascular smooth muscle cells. Circulation
Research 102: 1483-91.
Sahlgren C., Gustafsson M., Jin S., Poellinger L. and Lendahl U.
Notch signaling mediates hypoxia induced tumor cell migration and
invasion. (2008) Proceedings of National Academy of Sciences of the
United States of America, PNAS 105:6392-7. EDITORS’ CHOICE
in Science Signaling: Sci. Signal. 1 (18), ec163. [DOI:10.1126/
stke.118ec163]: Notching Up Tumor Progression
Chapman G.,# Liu L.,# Sahlgren C., Dahlqvist C. and Lendahl, U. (2006)
High levels of Notch signaling downregulate Numb and Numblike.
Journal of Cell Biology, 175: 535-40. # authors contributed equally
Sahlgren C. and Lendahl U. (2006) Notch, stem cell control
and integration with other signaling mechanisms. Regenerative
Medicine 1: 195-20
Sahlgren C., Pallari H.-M., He T., and Eriksson J.E. (2006) A nestin
scaffold links Cdk5 signaling to oxidant-induced cell death. EMBO
Journal 25: 4808-19.
Rosenholm J.M., Sahlgren C#., Linden M.# (2010) Towards
intelligent, targeted drug delivery systems using mesoporous
silicananoparticles – Opportunities & Challenges Nanoscale 2:
1870-1883. #shared corresponding authorship
Rosenholm J.M., Peuhu E., Tabe Bate-Eya L., Eriksson J.E.,
Sahlgren C.,# and Lindén M.# (2010) Cancer-Cell Specific Induction
of Apoptosis using Mesoporous Silica Nanoparticles as Drug
Delivery Vectors Small 6:1234-1241. #Sahlgren &Linden shared
corresponding authorship
de Thonel A., Ferraris S.E., Pallari H-M., Imanishi S.Y., Kochin V.,
Hosokawa T., Hisanga S., Sahlgren C. and Eriksson J.E. (2010).
PKCz regulates CDK5/p25 signaling during myogenesis. Molecular
Biology of the Cell 21: 1423-1434.
Main H., Lee K.L., Yang H., Haapa-Paananen S., Edgren H., Jin
S., Sahlgren C., Kallioniemi O., Poellinger L., Lim B. and Lendahl,
U. (2010). Integration between Notch- and hypoxia-induced
transcritpomes in embryonic stem cells. Experimental Cell Research
316: 1610-1624.
108
From left to right: Sara Sarinko, Veronika Mamaeva, Neeraj Prabhakar Habib
Baghiro, Santhosh Kumar, Sebastian Landor, Daniel Antfolk, Marika Sjöqvist,
Cecilia Sahlgren and Christian Antila.
109
TARGETING STRATEGIES
FOR GENE THERAPY
Mikko Savontaus, M.D., Ph.D. Address: Turku Centre for Biotechnology,
Biocity, Tykistökatu 6B, P.O. Box 123, FIN-20521 Turku, Finland.
Tel. +358 2 333 8025, Fax +358 2 333 8000.
E-mail: mikko.savontaus@btk.fi
Biography:
Mikko Savontaus (b. 1970) received his M.D. in 1996 and Ph.D. in
1997 from the University of Turku. He was a postdoctoral fellow at
the Institute for Gene Therapy and Molecular Medicine at Mount
Sinai School of Medicine in New York during 1999-2002. He did
his training for internal medicine and cardiology at Turku University
Hospital in 2003-2008. He is currently a group leader at the Turku
Centre for Biotechnology as well as a cardiologist at the Department
of Medicine at Turku University Hospital.
Personnel:
Graduate students: Minttu Mattila, M.Sc., Kim Eerola, M.Sc.
Postdoctoral fellow: Raine Toivonen, Ph.D.
Gene therapy is rapidly developing into a novel biomedical discipline
that could have a major impact on health and healthcare in the
21st century. Traditionally gene therapy has been envisioned as a
means to cure monogenic diseases with precisely defined genetic
defects. However, recent clinical trials have demonstrated that gene
therapy for complex multigenic disorders such as cardiovascular
diseases and cancer are especially promising and may become a
routine treatment modality in the near future. On the other hand,
these trials have demonstrated that technical advances in gene
therapy vector development are a key issue in developing clinically
applicable gene therapy approaches.
Our laboratory endeavors to tackle this problem of developing
improved adenoviral gene therapy vectors for cardiovascular
diseases and cancer by attempting to meet two objectives: 1.
The expression of therapeutic genes must be tightly regulated
(transcriptional targeting). 2. The tropism of the gene delivery vector
must be restricted to the target tissue (transductional targeting).
Such targeted vectors will increase efficacy and diminish the
possibility of side effects by limiting transgene expression to the
target cell population. In our previous work we have constructed
conditionally replicating adenoviruses (CRADs) targeting tumor
endothelial cells and have demonstrated that these vectors are
able to specifically replicate in dividing endothelial cells and destroy
tumor vasculature. We have also demonstrated that a hybrid
Ad5/35 adenovirus, where the fiber gene of adenovirus serotype 5
has been replaced with the fiber from serotype 35, is highly efficient
in infecting endothelial cells.
efficiency for target cells have been constructed by combining
hybrid serotype vectors with transcriptional targeting. In addition,
we are utilizing lentivirus technology for long-term expression of
therapeutic genes for heart failure and hypertension. The effect of
these vectors is currently studied in vivo using ultrasound-guided
intramyocardial injection in mouse heart failure models. Our ultimate
goal is to develop gene therapy vectors for use in clinical trials by
combining these approaches.
Funding:
Finnish Medical Foundation, Turku University Hospital
Toivonen R., Mäyränpää M.I., Kovanen P.T. and Savontaus M.
(2010) Dilated cardiomyopathy alters the expression patterns of
CAR and other adenoviral receptors in human heart. Histochem
Cell Biol. 133: 349-57.
Toivonen R., Suominen E., Grenman R. and Savontaus, M. (2009)
Retargeting Improves the Efficacy of a Telomerase-Dependent
Oncolytic Adenovirus for Head and Neck Cancer. Oncology
Reports 21: 165-171.
Suominen E., Toivonen R., Grenman R. and Savontaus M. (2006)
Head and Neck Cancer Cells are efficiently infected by Ad5/35
Hybrid Virus. Journal of Gene Medicine 8: 1223-1231.
Shinozaki K., Suominen E., Carrick F., Sauter B., Kähäri V.-M.,
Lieber A., Woo S.L.C. and Savontaus M. (2006) Efficient infection
of endothelial cells by a capsid-modified adenovirus. Gene Therapy
13: 52-59.
Hutter R., Valdiviezo C., Sauter B.V., Savontaus M., Chereshnev
I., Carrick F.E., Bauriedel G., Luderitz B., Fallon J.T., Fuster V. and
Badimon, J.J. (2004) Caspase-3 and tissue factor expression in
lipid-rich plaque macrophages: evidence for apoptosis as link
between inflammation and atherothrombosis. Circulation 27 109:
2001-2008.
Ebert O., Shinozaki K., Huang T.-G., Savontaus M., Garcia-Sastre
A. and Woo S.L.C. (2003) VSV as oncolytic virus for treatment of
orthotopic hepatocellular carcinoma in immune-competent rats.
Cancer Research 63: 3605-3611.
Huang T.-G., Savontaus M., Shinozaki K., Sauter B. and Woo
S.L.C. (2003) Telomerase dependent oncolytic adenovirus for
cancer treatment. Gene Therapy 10: 1241-1247.
Savontaus M., Sauter B.V., Huang T.-G. and Woo S.L.C. (2002)
Transcriptional Targeting of conditionally Replicating Adenovirus to
Dividing Endothelial Cells. Gene Therapy 9: 972-979.
In our current projects we are building on these findings to develelop
gene therapy for cardiovascular disease. We have analyzed
adenovirus receptor expression and vector transduction efficiency
in samples from patients with ischemic or dilated cardiomyopathy.
Novel vectors with improved transcriptional and transductional
110
111
REGULATION AND FUNCTION OF
HEAT SHOCK TRANSCRIPTION
FACTORS
Lea Sistonen, Ph.D., Professor of Cell and Molecular Biology,
Department of Biosciences, Åbo Akademi University.
Laboratory address: Centre for Biotechnology, BioCity, Tykistökatu 6,
P.O.BOX 123, FIN-20521 Turku, Finland.
Tel. +358-2-333 8028, 215 3311; Fax +358-2-333 8000.
E-mail: lea.sistonen@btk.fi, lea.sistonen@abo.fi
Biography:
Lea Sistonen (b. 1959) completed her undergraduate studies at
Åbo Akademi University in 1984 and received her Ph.D. from the
University of Helsinki in 1990. She was a post-doctoral fellow at
Northwestern University in Dr. Richard I. Morimoto’s laboratory
in 1990-1993 (Fogarty International Fellowship 1991-1993). In
November 1993 she joined the Centre for Biotechnology as a
senior research fellow in molecular biology. In April 2000 she was
appointed as Professor of Cell and Molecular Biology at Åbo
Akademi University. During the 5-year period 2004-2009 she was
Academy Professor, the Academy of Finland.
Personnel:
Senior scientists: Eva Henriksson, Ph.D., Pia Roos-Mattjus, Ph.D.
Post-doctoral fellows: Johanna Ahlskog, Ph.D., Johanna Björk,
Ph.D., Anton Sandqvist, Ph.D., Malin Åkerfelt, Ph.D.
Graduate students: Marek Budzynski, M.Sc., Alexandra Elsing,
M.Sc., Jenny Joutsen, M.Sc., Petra Vainio, M.Sc., Anniina
Vihervaara, M.Sc.
Laboratory Technician: Helena Saarento, M.Sc.
Undergraduate students: Anna Aalto, Heidi Bergman, Malin Blom,
Joachim Hudd, Emine Lundsten, Mikael Puustinen, Hanser Jose
Seijas Biel, Jenni Vasara
The heat shock response is an evolutionarily well-conserved cellular
defence mechanism against protein-damaging stresses, such
as elevated temperatures, heavy metals, and viral and bacterial
infections. The heat shock proteins (Hsps) function as molecular
chaperones to protect cells by binding to partially denatured proteins,
dissociating protein aggregates, and regulating the correct folding
and intracellular translocation of newly synthesized polypeptides.
Hsps are transcriptionally regulated by heat shock factors, HSFs
(HSF1-4 in mammals). Although HSFs are best known as stressinducible transcriptional regulators, they are also important for
normal developmental processes. The repertoire of HSF targets
has expanded well beyond the Hsps, and HSF functions span from
the heat shock response to development, metabolism, lifespan
and disease, especially cancer and neurodegenerative disorders.
Our main topic is the molecular mechanisms by which the
different members of the HSF family are regulated during normal
development and under stressful conditions. In particular, we
investigate the expression and activity of HSF1 and HSF2. We
have found that HSF1 activity is primarily regulated by various
post-translational modifications (PTMs), e.g. acetylation,
phosphorylation and sumoylation. All these PTMs are induced by
112
stress stimuli but their effects on HSF1 vary. Upon stress, HSF1
undergoes phosphorylation-dependent sumoylation within a
bipartite motif, which we found in many transcriptional regulators
and gave name PDSM (phosphorylation-dependent sumoylation
motif). Stress-inducible hyperphosphorylation and sumoylation of
HSF1 occur very rapidly, whereas acetylation of HSF1 increases
gradually, indicating a role for acetylation in the attenuation phase
of the HSF1 activity cycle. Among multiple lysine residues targeted
by acetylation, K80 is located within the DNA-binding domain
of HSF1 and its acetylation is required for reducing HSF1 DNAbinding activity. Importantly, the duration of HSF1 DNA-binding
activity can be prolonged or diminished by chemical compounds
either activating or inhibiting the activity of the NAD+-dependent
deacetylase SIRT1. Our current focus is on a complex network of
PTMs to decipher the post-translational signature of HSF1.
In contrast to HSF1, which is a stable protein evenly expressed
in most tissues and cell types, the amount of HSF2 varies and
correlates with its activity. Recently, we reported the first evidence
for the ubiquitin E3 ligase APC/C (anaphase-promoting complex/
cyclosome) mediating ubiquitination and degradation of HSF2
during the acute phase of the heat shock response. The stressrelated composition and role of APC/C are unknown and form our
major future goal. We will also determine the stress effects on the
cell cycle, adding a new dimension to the research field.
Using mouse spermatogenesis as a model system, we discovered
an inverse correlation between the cell- and stage-specific wavelike expression patterns of HSF2 and a specific microRNA, miR-18,
which is a member of the Oncomir-1/miR-17~92 cluster. Intriguingly,
miR-18 was found to repress the expression of HSF2 by directly
targeting its 3’UTR. To investigate the in vivo function of miR-18,
we developed a novel method T-GIST (Transfection of Germ cells in
Intact Seminiferous Tubules) and showed that inhibition of miR-18 in
intact mouse seminiferous tubules leads to increased HSF2 protein
levels and altered expression of HSF2 target genes, including the
Y-chromosomal multi-copy genes that we previously had reported
as novel HSF2 targets in the testis. Our original finding that miR-18
regulates HSF2 activity in spermatogenesis links miR-18 to HSF2mediated physiological processes and opens a whole new window
of opportunities to elucidate the physiological and stress-related
functions of HSF2, either alone or in conjunction with HSF1.
We were the first to report that HSF2 forms a complex with HSF1
and regulates the heat shock response. Our studies on HSF1HSF2 heterotrimers and their impact on various target genes
are designed to elucidate the roles of HSFs in protein-misfolding
disorders, such as neurodegenerative diseases, as well as in aging
and cancer progression. Most studies have focused on HSF1,
but it is important to consider the existence of multiple HSFs and
interactions between them, especially when searching for potential
drugs to modify their expression and/or activity. Our ongoing
genome-wide ChIP-sequencing experiments to compare HSF1
and HSF2 occupancy in non-stressed and stressed cells for better
understanding their actions in various chromatin environments,
including cells arrested in mitosis, should give news insights on
these multi-faceted transcriptional regulators.
Funding:
The Academy of Finland, the Sigrid Jusélius Foundation, the Finnish
Cancer Organizations, Turku Doctoral Programme of Biomedical
113
Sciences (TuBS), and Åbo Akademi University (Centre of Excellence
in Cell Stress and Molecular Aging).
Collaborators:
Susumu Imanishi, Noora Kotaja and Jorma Toppari (University
of Turku), John Eriksson, Pia Roos-Mattjus, Peter Slotte and Kid
Törnquist (Åbo Akademi University), Marko Kallio (VTT Medical
Biotechnology, Turku), Valérie Mezger (University of Paris Diderot,
France), Rick Morimoto (Northwestern University, Evanston, IL,
USA), Jorma Palvimo (University of Eastern Finland, Kuopio), Andrea
Pichler (Max Planck Institute of Immunobiology, Freiburg, Germany),
Laszlo Vigh (Biological Research Center, Szeged, Hungary).
Selected Publications (2006-2011):
Anckar J. and Sistonen L. (2011) Regulation of HSF1 function in
the heat shock response: implications in aging and disease. Annu.
Rev. Biochem. 80: 1089-1115.
Ahlskog J.K., Björk J.K., Elsing A.N., Aspelin C., Kallio M., RoosMattjus P. and Sistonen L. (2010) Anaphase-promoting complex/
cyclosome participates in the acute response to protein-damaging
stress. Mol. Cell. Biol. 30: 5608-5620.
Östling P.*, Björk J.K.*, Roos-Mattjus P., Mezger V. and Sistonen
L. (2007) HSF2 contributes to inducible expression of hsp genes
through interplay with HSF1. J. Biol. Chem. 282: 7077-7086.
Chang Y.*, Östling P.*, Åkerfelt M., Trouillet D., Rallu M., Gitton Y.,
El Fatimy R., Fardeau V., Le Crom S., Morange M., Sistonen L. and
Mezger V. (2006) Role of heat shock factor 2 in cerebral cortex
formation and as a regulator of p35 expression. Genes Dev. 20:
836-847.
Anckar J.*, Hietakangas V.*, Denessiouk K., Thiele D.J., Johnson
M.S. and Sistonen L. (2006) Inhibition of DNA binding by differential
sumoylation of heat shock factors. Mol. Cell. Biol. 26: 955-964.
Hietakangas V.*, Anckar J.*, Blomster H.A., Fujimoto M.,
Palvimo J.J., Nakai A. and Sistonen L. (2006) PDSM, a motif for
phosphorylation-dependent SUMO modification. Proc. Natl. Acad.
Sci. USA 103: 45-50.
*equal contribution
Åkerfelt M.*, Vihervaara A.*, Laiho A., Conter A., Christians E.C.,
Sistonen L. and Henriksson E. (2010) Heat shock transcription
factor 1 localizes to sex chromatin during meiotic repression. J.
Biol. Chem. 285: 34469-34476.
Björk J.K.*, Sandqvist A.*, Elsing A.N., Kotaja N. and Sistonen
L. (2010) miR-18, a member of OncomiR-1, targets heat shock
transcription factor 2 in spermatogenesis. Development 137:
3177-3184.
Åkerfelt M., Morimoto R.I. and Sistonen L. (2010) Heat shock
factors: integrators of cell stress, development and lifespan. Nat.
Rev. Mol. Cell Biol. 11: 545-555.
Blomster H.A.*, Imanishi S.Y.*, Siimes J., Kastu J., Morrice N.A.,
Eriksson J.E. and Sistonen L. (2010) In vivo identification of
sumoylation sites by a signature tag and cysteine-targeted affinity
purification. J. Biol. Chem. 285: 19324-19329.
Blomster H.A., Hietakangas V., Wu J., Kouvonen P., Hautaniemi
S. and Sistonen L. (2009) Novel proteomics strategy brings insight
into the prevalence of SUMO-2 target sites. Mol. Cell. Proteomics
8: 1382-1390.
Westerheide S.D.*, Anckar J.*, Stevens S.M.Jr., Sistonen L. and
Morimoto R.I. (2009) Stress-inducible regulation of heat shock
factor 1 by the deacetylase SIRT1. Science 323: 1063-1066.
Sandqvist A., Björk J.K., Åkerfelt M., Chitikova Z., Grichine A.,
Vourc’h C., Jolly C., Salminen T.A., Nymalm Y. and Sistonen L.
(2009) Heterotrimerization of heat-shock factors 1 and 2 provides a
transcriptional switch in response to distinct stimuli. Mol. Biol. Cell
20: 1340-1347.
Åkerfelt M.*, Henriksson E.*, Laiho A., Vihervaara A., Rautoma K.,
Kotaja N. and Sistonen L. (2008) Promoter ChIP-chip analysis in
mouse testis reveals Y chromosome occupancy by HSF2. Proc.
Natl. Acad. Sci. USA 105: 11224-11229.
114
From left to right: First Row: Johanna Björk, Pia Roos-Mattjus, Jenni Vasara,
Camilla Aspelin, Eva Henriksson, Anna Aalto, Emine Lundsten, Anniina Vihervaara,
Heidi Bergman, Marek Budzynski and Beata Paziewska Second row: Lea Sistonen,
Helena Saarento, Johanna Ahlskog, Noémi To´th, Tim Crul, Petra vainio, Jenny
Joutsen, Alexandra Elsing and Anton Sanqvist
115
CANCER CELL SIGNALING
addition, our aim is to purify new protein complexes related cancer
cell signaling.
Jukka Westermarck, M.D., Ph.D., Professor.
Address: Turku Centre for Biotechnology, BioCity, Tykistökatu 6 B,
P.O. Box 123, FIN-20251 Turku, Finland.
Tel. +358-2-333 8621, Fax +358-2-333 8000.
E-mail: jukwes@utu.fi
Home page: http://www.btk.fi/research/research-groups/
westermarck-jukka-cancer-cell-signaling/
Funding:
The Academy of Finland, Medical Research Fund of Tampere
University Hospital, Turku Graduate School of Biomedical Sciences,
Tampere Graduate School in Biomedicine and Biotechnology,
Sigrid Juselius Foundation, Cancer Research Foundation of
Finland, Association of International Cancer Research (UK).
Biography:
Jukka Westermarck (b. 1969) received his M.D. in 1996 and Ph.D
in 1998 at the University of Turku. He was a postdoctoral fellow at
European Molecular Biology Laboratory in Heidelberg, Germany,
in Dr. Dirk Bohmann´s laboratory during 1999-2001. He was an
Academy of Finland senior scientist during 2002-2007 and 20062009 he was appointed as a Group leader at Institute of Medical
Technology (IMT), University of Tampere, Finland. In 2008 he was
appointed to a Research Professor position at the Finnish Cancer
Institute. 2009 he was appointed to Research director position at
Turku Centre for Biotechnology (leave of absence until 2014). 2011
he was appointed to part-time position as Professor of cancer
biology at Department of Pathology, University of Turku (until 2104).
Personnel:
Post-doctoral researchers: Anna Cvrljevic, Ph.D., Juha Okkeri,
Ph.D., Yuba Pokharel, Ph.D., Sami Ventelä, M.D., Ph.D. Graduate
students: Tuuli Halonen, M.Sc., Otto Kauko, M.Sc., Amanpreet
Kaur, M.Sc., Anchit Khanna, M.Sc. (IMT), Anni Laine, M.Sc., Minna
Niemelä, M.Sc., Qiao Xi, M.Sc., Eleonora Sittig, M.Sc. Laboratory
Technicians: Taina Kalevo-Mattila, Inga Pukonen.
The goal of our research group is to identify novel signaling
mechanisms involved in malignant cell growth by isolating protein
complexes associated with proteins previously demonstrated to
have an important role in cancer progression. To identify protein
complexes, we use tandem affinity purification (TAP) and Streptag purification methods, both proven to be suitable for purification
of signaling protein complexes from mammalian cells in culture.
Identification of novel proteins involved in malignant growth may
also reveal novel possibilities for intervention in the therapy of
cancer and other hyperproliferative diseases.
Based on our recent work, we have identified several novel
interacting proteins for signaling proteins such as AP-1 transcription
factor c-Jun, MAPK kinase MEK1, and protein phosphatase PP2A.
Most of our future work will be focused on characterization of
PP2A interaction partner CIP2A, that we have demonstrated to
inhibit PP2A in human malignancies. As PP2A inhibition has been
recognized as a prerequisite for human cell transformation, it is
plausible that further understanding of the function of CIP2A will
reveal fundamental novel information about the basic mechanisms
of cancer progression. The overall goal of the proposed project
is to study the function and importance of CIP2A in cancer
progression by using combination of molecular biology, cell biology
and functional genetics methods. As our current results suggest
that targeting CIP2A could be beneficial in the treatment of cancer,
our goal is also to develop research models for evaluating the
suitability of CIP2A as a novel drug target for cancer therapies. In
116
Collaborators:
Tuula Kallunki (Danish Cancer Society), Rosalie Sears (Oregon
Health and Science University), Owen Sansom (Beatson Institute
for Cancer Research, Glasgow), Sampsa Hautaniemi (University
of Helsinki), Ari Ristimäki (University of Oulu), Jorma Toppari
(University of Turku), Veli-Matti Kähäri (Turku University Hospital),
Heikki Joensuu (Helsinki University Hospital).
Niemelä M., Kauko O., Mpindi J.-P., Sihto H., Nicorici D.,
Kallioniemi O.-P., Joensuu H., Hautaniemi S. and Westermarck,
J. (2011). CIP2A signature reveals MYC dependency of CIP2Aregulated phenotypes and its clinical association with breast
cancer subtypes. Oncogene, in press.
Mathiasen D.P., Egebjerg C., Andersen S.H., Rafn B., Puustinen P.,
Khanna A., Daugaard M., Valo E., Tuomela S., Bøttzauw T., Nielsen
C.F., Willumsen B.M., Hautaniemi S., Lahesmaa R., Westermarck
J., Jäättelä M. and Kallunki T. (2011). Identification of a c-Jun
N-terminal kinase 2 dependent signal amplification cascade that
regulates c-Myc levels in Ras transformation. Oncogene, in press.
Khanna A., Okkeri J., Bilgen T., Tiirikka T., Vihinen V., Visakorpi T.
and Westermarck J. (2011). ETS1 mediates MEK1/2-dependent
overexpression of cancerous inhibitor of protein phosphatase 2A
(CIP2A) in human cancer cells. PLoS One 6: e17979.
Ovaska K., Laakso M., Haapa-Paananen S., Louhimo R., Chen P.,
Aittomäki V., Valo E., Nunez-Fontarnau J., Rantanen V., Karinen S.,
Nousiainen K., Lahesmaa-Korpinen A.-M., Miettinen M., Saarinen
L., Kohonen P., Wu J., Westermarck J. and Hautaniemi S. (2010).
Large scale data intergration framework provides a comprehensive
view on glioblastoma multiforme. Genome Med. 2: 65.
Heikkinen P.T., Nummela M., Leivonen S.K., Westermarck J., Hill
C.S., Kähäri V.M. and Jaakkola P.M. (2010). Hypoxia activated
Smad3-specific dephosphorylation by PP2A. J. Biol. Chem. 285:
3740-3749.
Come C., Laine A., Chanrion M., Edgren H., Mattila E., Liu X.,
Jonkers J., Ivaska J., Isola J., Darbon J.-M., Kallioniemi O.-P.,
Thezenas S. and Westermarck J. (2009). CIP2A is associated with
human breast cancer aggressivity. Clin. Cancer Res. 15: 50925100.
Khanna A., Böckelman C., Hemmes A., Junttila M.R., Wiksten
J.-P., Lundin P., Junnila S., Murphy D., Evan G.I., Haglund C.,
Westermarck J.* and Ristimäki A.* (2009). c-Myc-dependent
regulation and prognostic role of CIP2A in gastric cancer. J. Natl.
Cancer Inst. 101: 793-805. *equal contribution
117
Puustinen P., Junttila M.R., Vanhatupa S., Sablina A.A., Hector
M.E., Teittinen K., Raheem O., Ketola K., Lin S., Kast J.,
Haapasalo H., Hahn W.C. and Westermarck J. (2009). PME-1
protects extracellular signal-regulated pathway activity from protein
phosphatase 2A-mediated inactivation in human malignant glioma.
Cancer Res. 69: 2870-2877.
Wu J., Vallenius T., Ovaska K., Westermarck J., Mäkelä T.P. and
Hautaniemi S. (2009). Integrated network analysis platform for
protein-protein interactions. Nat. Methods 6: 75-77.
Westermarck J. and Hahn W.C. (2008). Multiple pathways
regulated by the tumor suppressor PP2A in transformation. Trends
Mol. Med. 14: 152-160.
Junttila M.R., Li S.-P. and Westermarck J. (2008). Phosphatasemediated cross
talk between MAPK signaling pathways in the
regulation of cell survival. FASEB J. 22: 954-965.
Junttila M.R., Puustinen P., Niemelä M., Ahola R., Arnold H.,
Böttzauw T., Ala-aho R., Nielsen C., Ivaska J., Taya Y., Lu S.L.,
Li S., Chan E.K.L., Wang X.-J., Grenman R., Kast J., Kallunki T.,
Sears R., Kähäri V.-M. and Westermarck J. (2007). CIP2A inhibits
PP2A in human malignancies. Cell 130: 51–62.
From left to right: Juha Okkeri, Anni Laine, Taina Kalevo-Mattila, Anna Cvrljevic,
Yuba Pokharel, Otto Kauko, Jukka Westermarck, Amanpreet Kaur and Eleonora
Sittig
118
Adenosine Deaminases
Andrey Zavialov, Ph.D., Academy of Finland Research Fellow,
Group leader, Turku Centre for Biotechnology, University of Turku,
Tykistökatu 6, FI-20520,Turku, Finland,
Tel. +358403776216, Fax. +358-2-3338000
Email: azaviyal@btk.fi
Biography:
Andrey Zavialov (b. 1975) has obtained his M.S. in Biotechnology
from Russian Chemical Technology University (Moscow) and a
Ph.D. in Molecular Biology from Uppsala University (Sweden).
Between 2005-2010 Dr Zavialov received his postdoctoral training
in Immunology at Institute of Cellular and Molecular Pharmacology
(France) and worked as a research scientist and an assistant
research professor at A*-STAR’s Singapore Immunology Network
(SIgN) and University of Hawaii at Manoa (U.S.A.). Dr. Zavialov is
a recipient of the Harold M. Weintraub graduate student Award,
EMBO and HFSP long-term fellowships. In 2011 he was selected
as a Research Fellow of the Academy of Finland.
Personnel:
Graduate students: Maksym Skaldin (M.S.), Salim Reza (M.S.)
Two distinct enzymes of adenosine deaminase, ADA1 and ADA2,
have been found in humans. Inherited mutations in ADA1 result in
severe combined immunodeficiency (SCID). This observation led
to extensive studies of the structure and function of this enzyme
that have revealed its important role in lymphocyte activation. In
contrast, the physiological role of ADA2 is unknown. ADA2 activity
in serum is increased in various diseases in which monocytes/
macrophages are activated. We have found that ADA2 is a heparinbinding protein. This allowed us to obtain highly purified enzyme
and to study its biochemistry. ADA2 was identified as a member
of a new class of adenosine deaminase related growth factors
(ADGF), which are present in almost all organisms from flies to
humans. Biochemical data suggest that ADA2 may be active at
sites of inflammation during hypoxia and in areas of tumor growth
where the adenosine concentration is significantly elevated and
the extracellular pH is low. We showed that ADA2 is secreted
by monocytes undergoing differentiation into macrophages or
dendritic cells, and that activated T cells are likely the main target
for ADA2. T cells bound the enzyme via A2A and A2B adenosine
receptors expressed on their cell surface. It has been further
demonstrated that ADA2 induces T cell proliferation independently
of their activation with antigen, and that the resulting proliferating
cells are CD4+ T-helper cells. Moreover, our recent results show
that ADA2 binds to CD39+CD25+ T regulatory cells and induces
proliferation of Th17- polarized T helper cells in the presence of
Tregs, monocytes and ADA2. While this function is shared with
ADA1, the unique role of ADA2 is to promote CD4+ T cell dependent
differentiation of monocytes into macrophages. The recently solved
structure of ADA2 allows us to establish the role of unique ADA2
domains in the enzyme’s interaction with its specific receptor. The
comparison of catalytic centres in the structure of ADA1 and ADA2
reveals differences in the binding pockets for the ADA inhibitor,
deoxycoformycin. This opens the possibility of using structurebased drug design to find a specific inhibitor for ADA2, which
119
could be chemically synthesize and tested in vitro. Our studies will
explore the possibility that ADA2 is an immunomodulatory protein,
which may directly or indirectly affect immune responses against
intracellular pathogens or tumor cell proliferation. Our goal is to
establish the physiological role of ADA2 in inflammation and tumor
immunity and to explore its therapeutic potential.
Funding:
The Academy of Finland
Collaborators:
Dr. Anton Zavialov (University of Turku), Dr. Yuanan Lu (University of
hawaii, U.S.A.), Dr. Rafael Franco (University of Barcelona, Spain),
Dr. Sergey Lavrenov ( Gauze Institute of new antibiotics, Moscow,
Russia).
Frank, J., Sengupta J., Gao H., Li W., Valle M., Zavialov A. and
Ehrenberg M. (2005) The role of tRNA as a molecular spring in
decoding, accommodation, and peptidyl transfer. FEBS Lett. 579:
959-962.
Allen, G. S., Zavialov A., Gursky R., Ehrenberg M. and Frank J.
(2005) The cryo-EM structure of a translation initiation complex
from Escherichia coli. Cell 121: 703-712.
Zavialov, A. V., and Ehrenberg M. (2003) Peptidyl-tRNA regulates
the GTPase activity of translation factors. Cell 114: 113-122.
Valle, M., Zavialov A., Sengupta J., Rawat U., Ehrenberg M. and
Frank J. (2003) Locking and unlocking of ribosomal motions. Cell
114: 123-134.
Zavialov, A. V., Yu X., Spillmann D., and Lauvau G. (2010) Structural
basis for the growth factor activity of human adenosine deaminase
ADA2. J. Biol. Chem. 285: 12367-12377.
Valle, M., Zavialov A., Li W., Stagg S.M., Sengupta J., Nielsen
R.C., Nissen P., Harvey S.C., Ehrenberg M. and Frank J. (2003)
Incorporation of aminoacyl-tRNA into the ribosome as seen by
cryo-electron microscopy. Nat. Struct. Biol. 10: 899-906.
Zavialov, A. V., Gracia E., Glaichenhaus N., Franco R., and Lauvau
G. (2010) Human adenosine deaminase 2 induces differentiation
of monocytes into macrophages and stimulates proliferation of T
helper cells and macrophages. J. Leukoc. Biol 88: 279-290.
Rawat, U. B., Zavialov A.V., Sengupta J., Valle M., Grassucci R.A.,
Linde J., Vestergaard B., Ehrenberg M., and Frank J. (2003) A
cryo-electron microscopic study of ribosome-bound termination
factor RF2. Nature 421: 87-90.
Gao, N., Zavialov A.V., Ehrenberg M., and Frank J. (2007). Specific
interaction between EF-G and RRF and its implication for GTPdependent ribosome splitting into subunits. J. Mol. Biol. 374:
1345-1358.
Pedersen, K., Zavialov A.V., Pavlov M.Y., Elf J., Gerdes K. and
Ehrenberg M. (2003) The bacterial toxin RelE displays codon-specific
cleavage of mRNAs in the ribosomal A site. Cell 112: 131-140.
Gao, H., Zhou Z., Rawat U., Huang C., Bouakaz L., Wang C.,
Cheng Z., Liu Y., Zavialov A., Gursky R., Sanyal S., Ehrenberg M.,
Frank J. and Song H. (2007) RF3 induces ribosomal conformational
changes responsible for dissociation of class I release factors. Cell
129: 929-941.
Rawat, U., Gao H., Zavialov A., Gursky R., Ehrenberg M. and Frank
J. (2006) Interactions of the Release Factor RF1 with the Ribosome
as Revealed by Cryo-EM. J. Mol. Biol. 357: 1144-1153.
Mora, L., Zavialov A., Ehrenberg M and Buckingham R.H. (2003)
Stop codon recognition and interactions with peptide release factor
RF3 of truncated and chimeric RF1 and RF2 from Escherichia coli.
Mol. Microbiol. 50: 1467-1476.
Klaholz B. P., Pape T., Zavialov A.V., Myasnikov A.G., Orlova E.V.,
Vestergaard B., Ehrenberg M., and van Heel M. (2003) Structure
of the Escherichia coli ribosomal termination complex with release
factor 2. Nature 421: 90-94.
Hauryliuk, V., Zavialov A., Kisselev L., and Ehrenberg M. (2006)
Class-1 release factor eRF1 promotes GTP binding by class-2
release factor eRF3. Biochimie 88: 747-757.
Zavialov, A. V., Mora L., Buckingham R.H. and Ehrenberg M. (2002)
Release of peptide promoted by the GGQ motif of class 1 release
factors regulates the GTPase activity of RF3. Mol. Cell 10: 789798.
Zavialov, A. V., Hauryliuk V.V. and Ehrenberg M. (2005) Splitting
of the posttermination ribosome into subunits by the concerted
action of RRF and EF-G. Mol. Cell 18: 675-686.
Zavialov, A. V., Buckingham R.H. and Ehrenberg M. (2001) A
posttermination ribosomal complex is the guanine nucleotide
exchange factor for peptide release factor RF3. Cell 107: 115-124.
Zavialov, A. V., Hauryliuk V.V and Ehrenberg M. (2005) Guaninenucleotide exchange on ribosome-bound elongation factor G
initiates the translocation of tRNAs. J. Biol. 4: 9.
Zavialov, A. V., and Engstrom A. (2005) Human ADA2 belongs to
a new family of growth factors with adenosine deaminase activity.
Biochem J. 391: 51-57.
Gao, N., Zavialov A.V., Li W., Sengupta J., Valle M., Gursky R.P.,
Ehrenberg M. and Frank J. (2005) Mechanism for the disassembly
of the posttermination complex inferred from cryo-EM studies. Mol.
Cell 18: 663-674.
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Ph.D. DEFENCES
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LIFE OUTSIDE THE LAB
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TURUN BIOTEKNIIKAN KESKUS
ÅBO BIOTEKNIKCENTRUM
TURKU CENTRE FOR BIOTECHNOLOGY
TURUN BIOTEKNIIKAN KESKUS
Tykistökatu 6 B
P.O.BOX 123
FI 20521 Turku, Finland
Tel: +358 2 333 8603, Fax 358 2 333 8000

TURKU CENTRE FOR BIOTECHNOLOGY REPORT 2011

Transcription

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