TURKU CENTRE FOR BIOTECHNOLOGY – REPORT 2012

Transcription

TURKU CENTRE
FOR BIOTECHNOLOGY
REPORT 2012
CONTENTS
Organization.................................................................................2
Chairman’s Foreword ...................................................................3
From the Director .........................................................................4
Year 2012 in a Nutshell.................................................................5
Funding and Statistics .................................................................9
Publications 2012.......................................................................12
Personnel 2012..........................................................................19
Annual Report 2012
Turku Centre for Biotechnology
Published by:
Turku Centre for Biotechnology
P.O. Box 123, FI-20521 Turku, Finland
Tel. int. +358-2-333 8603, Fax int. +358-2-251 8808
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
Linnéa Linko
Harri Lähdesmäki
Matti Nykter
Tassos Papageorgiou
Cecilia Sahlgren
Mikko Savontaus
Lea Sistonen
Juha Strandén
Mikael Wasberg
Jukka Westermarck
Andrey Zavialov
Photographs:
KUV@TEHDAS Roni Lehti, Photograph archives of the Centre for
Biotechnology. Cover images: Roni Lehti.
Painosalama Oy, Turku 2013
ISSN 1237-5217
The Finnish Microarray and Sequencing Centre..........................23
Cell Imaging Core.......................................................................27
Proteomics Facility......................................................................29
Protein Crystallography Core Facility ..........................................32
Bioinformatics Core....................................................................34
Virus Vector Facility.....................................................................36
Mechanisms and Biosensors of Gtpases....................................38
Protein Kinase Regulation of Brain Development and Disease....42
Translational Proteomics.............................................................48
Organisation of Neuronal Signaling Pathways.............................51
Structural Bioinformatics.............................................................55
Data Mining and Modelling.........................................................57
Cytoskeletal and Survival Signaling.............................................61
Epigenomics...............................................................................67
Cell Adhesion and Cancer..........................................................69
Hypoxia in Cell Survival...............................................................72
Bioenergy Group........................................................................75
Mitosis and Drug Discovery........................................................77
Molecular Systems Immunology and Stem Cell Biology..............80
Computational Systems Biology.................................................86
Cell Culture Models for Tumor Cell Invasion and Epithelial Plasticity.88
Complex Biosystems Modeling...................................................91
Metabolome in Health and Disease.............................................93
Protein Crystallography...............................................................97
Cell Fate...................................................................................101
Targeting Strategies for Gene Therapy .....................................105
Regulation and Function of Heat Shock Transcription Factors..107
Cancer Cell Signaling ...............................................................112
Adenosine Deaminases............................................................116
Ph.D. Defences........................................................................119
Life Outside the Lab.................................................................120
ORGANIZATION
CHAIRMAN’S FOREWORD
Board of Trustees 2012
When looking back over the year 2012 it is easy to remember the
inspiring 22nd Annual BioCity Symposium “Personal Genomics
– From Technologies to Applications” in August as well as the
many excellent Frontiers of Science seminars, most prominently
the memorable lecture given by professor, Nobel laureate Martin
Chalfie. The annual BioCity publication prize, the Elias Tillandz prize
was shared by two papers, both published in the Nature series
journals, which tells about the high impact of research performed
in the Turku Centre for Biotechnology (CBT), and in the BioCity
community in general.
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 Biosciences
Secretary
LAHESMAA Riitta, Professor, Director, Turku Centre for
Biotechnology
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, Department of
Biology
TERHO Perttu, Project Engineer, Turku Centre for Biotechnology
TÖRNQUIST Kid, Professor, Åbo Akademi University, Department
of Biosciences
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,Turku
Centre for Biotechnology
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, Department of
Biology
SLOTTE J. Peter, Professor, Åbo Akademi University, Department
of Biosciences
VUORELA Pia, Professor, Åbo Akademi University, Department of
Biosciences
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While Turku researchers have continued their excellent
performances the turmoil in the Finnish universities has continued.
Despite many uncertainties there have also been positive
developments. Especially the continuation of the Biocenter Finland
process is very good news for core facilities, their personnel and
customers. The decision carried out by the rectors of the biocenter
universities will hopefully guarantee that also in the future the
modern technologies and top-of-the-line instruments are available
for life science researchers in Finland. The processes aiming to
connect the Finnish research infrastructure to European networks
(ESFRI) has also moved forward together with the update of the
Finnish research infrastructure road map. In the latter, Biocenter
Finland successfully passed the first phase of the evaluation.
Since 1995 most of the graduate students have participated in the
activities of local or national graduate schools. In the life science
area the schools have done excellent work in the training of Ph.D.
candidates and they have been an important resource for the
research field. The recent change in the national policy has led to
the sad decision to terminate the present graduate schools. I want
to take this opportunity to thank on the behalf of the entire BioCity
Turku community, the directors and coordinators of the graduate
schools, who have worked long hours for Ph.D. training and
generated the exceptional spirit of the schools. Despite the change
in the graduate school system your work has not been in vain. You
have given an enormous contribution to life science in Finland that
will be remembered by thankful students and supervisors. I also
hope that the same persons who have actively developed the old
graduate schools could continue their good work in the new system.
The exceptional motivation for science and improvement of research
technologies has made CBT one
of the most import resources in the
molecular life science area in Turku.
There is no doubt that the staff of
CBT will, also in the future, continue
its excellent performance in research
and provide essential core services
for all researchers in Turku, as well as
in other biocenters.
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
3
FROM THE DIRECTOR
YEAR 2012 IN A NUTSHELL
Our Centre had a very active year 2012. During the now finished three
year budgeting period (2010-12) our Centre excelled in exceeding the
goals set and agreed with our host universities. Altogether 32 PhDs
and 193 publications were produced during 2010-12. Moreover, our
investigators won several major research grants and awards.
RESEARCH AND EDUCATION
David Goodlett started at the Centre as a Finnish Distinguished
Professor (FiDiPro) in biomarker discovery and cutting-edge
proteomics technologies. Jane Zhi Chen was appointed an
Academy Fellow, a highly competitive award by the Academy of
Finland (AoF). Jukka Westermarck received a large grant from the
Sigrid Jusélius Foundation. A new Centre of Excellence (CoE) in
“Molecular Systems Immunology and Physiology” was kicked off. In
this AoF CoE, Riitta Lahesmaa is responsible for molecular systems
immunology, and the Centre’s affiliated group leaders Matej Oresic
(VTT) and Harri Lähdesmäki (Aalto) play central roles in leading the
CoE and directing the computational systems biology, respectively.
Eleanor Coffey and Johanna Ivaska won the Tillandz prize for the
best publications of Biocity Turku and Johanna Ivaska’s publication
was further awarded the Medix prize.
Our core facilities continued to be key players in the Biocenter
Finland infrastructure network and, based on an evaluation by
external international experts, were able to raise significant external
funding to further develop the services. The Biocenter Finland
networks have made an important impact in developing the Finnish
research infrastructure and providing Finnish scientists access to
state-of-the art technologies. Very important for the continuation of
these activities was that in 2012 the Rectors of host universities of
biocenters decided to partially continue Biocenter Finland funding,
obtained in 2010-12 from the Ministry of Education.
Our SAB composed of Dr. Doreen Cantrell (chair, University of
Dundee, Scotland, UK), 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) visited the Centre in
2012. They were impressed with the breadth of the technologies
on offer and complimented us on the cost efficiency with which
the core facilities are run as well as on the scientific achievements.
Our CBT ship has been sailing through storms and winds of
change during the past three years. There have been multiple
changes in the entire university
structure, restructuring processes
and introduction of new administrative
systems. In spite of all this we have
succeeded in exceeding our scientific
and educational goals.I am grateful to
all CBT scientists and personnel who
have made significant contributions
towards achieving our goals. I look
forward to an exciting journey forward!
Riitta
Riitta Lahesmaa, M.D., Ph.D., Professor
Director Turku Centre for Biotechnology
University of Turku and Åbo Akademi
University
4
DEVELOPMENT OF INFRASTRUCTURE, RESEARCH
SERVICES AND CORE FACILITIES
Finnish Microarray and Sequencing Centre
· The Centre got substantial competitive funding through
Biocenter Finland to continue developing and providing
national services in the area of gene expression, its regulation
and epigenetics.
· The Centre has set up and now offers its new Epigenomics
services for DNA methylation analysis (Enrichment based
meDNA-seq, Whole Genome Bisulphite Sequencing,
Reduced Representation Bisulphite Sequencing); and
histone mark profiling (ChIP-seq) for analysis of chromatin
status at gene enhancers, promoters and bodies.
Acquisition of MiSeq Personal Sequencer from Ilumina
to set up and provide services for RNA and smallRNA
sequencing, targeted and small genome resequencing and
metagenomics applications.
· The bioinformatics team of the Centre has set up a new
computer cluster to increase the computation power
and storage capacity that the new next-generation
sequencing instruments require. Data analysis pipeline has
been developed for various next-generation sequencing
applications including RNA-seq, Chip-seq, DNA methylation
and target enrichment resequencing to detect small genetic
variants.
Proteomics and Mass spectrometry Laboratory
· A one-week “Basic proteomics course” was organized
· Avinash Jadav, Thaman Chand and Santhosh Thatikonda
completed their Masters degree.
· Tanya Lukash started in February as a visiting researcher
· Mimi Nguyen was recruited as a senior scientist in June
· New instruments: Q Exactive and TSQ Vantage are installed
and in operation
· Various new software and upgrades for quantitative
proteomics installed and in operation
· The LTQ Orbitrap Velos has been upgraded to LTQ Orbitrap
Velos Pro.
· SRM based targeted quantitative proteomics method was
set up as a new service
· Organised 6th Dubrovnik Mass Spectrometry in Biotechnology
and Medicine Summer School organised
· Organised Cancer Crosslinks Turku Seminar, 22 August
2012
· Organised Ourense Conference on Imaging Mass
Spectrometry, Ourense, Spain, 3-5 September 2012
5
Cell Imaging Core
· Pasi Kankaanpää started as coordinator of the Cell Imaging
Core, and Ketlin Adel started as part-time technician for flow
cytometry.
· Several new instruments (e.g. Zeiss LSM780 confocal) were
installed and several more were made available to users via
CIC, thanks to new collaboration agreements.
· CIC services were used by more than 300 people from
more than 100 research groups, with 20% outside users.
This resulted in more than 30 peer reviewed scientific
publications.
· CIC personnel conducted more than 100 hours of teaching
on various national and international courses and workshops,
and started the popular Lost in Imaging webinar series.
· CIC continued its role as the key light microscopy unit of
the Turku BioImaging umbrella organization, and had active
roles in national and international organizations such as
Finnish BioImaging and Euro-BioImaging.
Protein crystallography facility
· Participation in several courses (Medical Biochemistry,
TERBIO, Protein Crystallography and Structural Genomics,
Master’s degree program in Autonomous University of
Barcelona) with lectures and demonstrations. Our course
‘Basic X-ray crystallography techniques: How to solve a
protein structure’ was held in February-March.
· The new X-ray generator run smoothly throughout the year. A
vacuum problem was easily resolved. The Oxford cryosystem
was repumped several times owing to vacuum problems and
a future replacement with a newer model was put forward.
· Organization committee of the annual meeting of the Finnish
crystallographic and structural biology groups (FINNBOX)
hosted in Turku (June 6th).
· 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. The molecular graphics and protein
crystallization rooms moved to new locations, offering better
functionalities.
Viral vector facility
· The viral vector facility produced 115 viral preps as a service
and hosted 50 registered users of the BSL2 lab
· The BSL2 lab was expanded in capacity for viral vector
production and analysis. The lab infrastructure was
enhanced and new laminar and incubator space enables
higher user numbers.
· Titrations and tests for replication competence were added
to our services.
· An aerosol filtration system was added to the cell sorter so
that users with virally transduced cells can sort without risk.
This particularly eases the production of stably transfected
cell lines.
Quality Assurance Unit
· Organized courses for the university on (1) quality assurance
and metrology and (2) how to assure the reliability of your
laboratory test results
· Individual training for graduate and post-graduate students
· 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
Bioinformatics Unit
· 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
· 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 data for 26
Next Generation Sequencing projects and 13 microarray
projects.
6
7
FUNDING AND STATISTICS
PhD and MSc Theses
PhD Theses (p. 119)
Name
Supervisor
Site besides CBT
Sirkku Pollari
Olli Kallioniemi
UTU/Department of
Pharmacology, Drug
Development and Therapeutics
Elisa Närvä
Riitta Lahesmaa
UTU/Department of Medical
Microbiology and Immunology
Anna-Leena Salmela
Marko Kallio
UTU/Department of
Biochemistry and Food
Chemistry
Krista Rantanen
Panu Jaakkola
Biochemistry and Genetics
Minna Niemelä
Jukka Westermarck
Juha Tapio Korhonen
Riitta Lahesmaa, Mirja
Puolakkainen
Tapio Lönnberg
Riitta Lahesmaa, Matej UTU/Department of Medical
Oresic
Sources of funding received by Center for Biotechnology
in 2012 (12,4 Million €)
Biocenter
Finland 7%
Services
18%
Academy of
Finland
18%
EU
5%
Others
9%
TEKES
3%
MSc Theses
Name
Supervisor
Site besides CBT
Heidi A. Bergman
Alexandra Elsing, Lea
Sistonen
ÅA/Department of Biosciences
Anna Aalto
Johanna Ahlskog, Lea
Sistonen
Jenni Vasara
Jenny Joutsen, Lea
Sistonen
Thatikonda Santhosh
Kumar
Cecilia Sahlgren, Garry ÅA/Department of Biosciences
Corthals
Ghimire Bishwa Raj
Tapio Salakoski,
Attila Gyenesei
University of Turku/Department
of Information Technology
Pradeep Battula
Tassos Papageorgiou
Thaman Chand
Garry Corthals, Jukka
Teuhola
Avinash Yadav
Garry Corthals, Pentti
Riikonen
Lotta Oikari
Zhi Jane Chen, Verna
Salo, Riitta Lahesmaa
of Biology
Cecilia Granqvist
Cecilia Sahlgren
Habib Baghiro
Cecilia Sahlgren,
Jessica Rosenholm
Adel Asghar
Marko Kallio
A.I.Virtanen Institute for
Molecular sciences, Kuopio
Noora Jaakola
Garry Corthals, Jyrki
Heino
of Biochemistry and Food
Chemistry
8
Universities 41%
External funding 2006-2012
9
Citations in each year to CBT publications
10
From left to right: Jouko Sandholm, Petri Vahakoski, Hannele Vuori, Mårten Hedman, Virpi Korpiranta, Mikael Wasberg, Linnéa Linko, Sarita Heinonen, Markku Saari, Susanna Pyökäri, Juha Strandén, Päivi Junni,
Pasi Viljakainen, Marjo Hakkarainen, Riitta Lahesmaa, Eva Hirvensalo, Sirkku Grönroos and Anne Lahdenperä.
Number of graduates 2006-2012
11
PUBLICATIONS 2012
Ph.D. Theses 2012
1. Sirkku Pollari: Dissecting the molecular mechanisms of
breast cancer bone metastasis for therapeutic targeting,
University of Turku, p. 120
2. Elisa Närvä: Pluripotency and genetic stability of human
pluripotent stem cells. University of Turku, 134 p.
3. Anna-Leena Salmela: The Spindle assembly checkpoint
as a drug target - novel small-molecule inhibitors of aurora
kinases. University of Turku, 159 p.
4. Krista Rantanen: The dual role of HIF hydroxylase PHD3 in
cancer cell survival. University of Turku, 171 p.
5. Minna Niemelä: Identification and characterization of CIP2A
as a novel oncogenic inhibitor of PP2A. University of Turku,
139 p.
6. Juha Tapio Korhonen: Bacterium - host cell interaction in
Chlamydia pneumoniae infection: the bacterial invasion and
intracellular growth. University of Turku, 107 p.
7. Tapio Lönnberg: System-wide approaches to uncover Th2
cell lineage commitment. University of Turku, 143 p.
Publications 2012
1. Äijö T, Edelman S, Lönnberg T, Larjo A, Kallionpää H,
Tuomela S, Engström E, Lahesmaa R and Lähdesmäki
H, (2012) An integrative computational systems biology
approach identifies lineage specific dynamic transcriptome
signatures which drive the initiation of human T helper cell
differentiation, BMC Genomics, 3:572. IF 4.1
2. Arjonen A, Alanko J, Veltel S, Ivaska J. (2012) Distinct
Recycling of Active and Inactive β1 Integrins. Traffic. 2012
Jan 5. IF 4.9
3. Benatti C, Valensisi C, Blom JM, Alboni S, Montanari C,
Ferrari F, Tagliafico E, Mendlewicz J, Brunello N, Tascedda F.
J (2012) Transcriptional profiles underlying vulnerability and
resilience in rats exposed to an acute unavoidable stress. J
Neurosci Res. 90(11):2103-15. IF 2.7
4. Benson MJ, Aijö T, Chang X, Gagnon J, Pape UJ,
Anantharaman V, Aravind L, Pursiheimo JP, Oberdoerffer
S, Liu XS, Lahesmaa R, Lähdesmäki H, Rao A (2012)
Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL)
and elongation factor, RNA polymerase II, 2 (ELL2) are
regulators of mRNA processing in plasma cells. Proc Natl
Acad Sci U S A 109(40):16252-7. IF 9.7
5. Björkblom, B, Padzik, A., Mohammad, H., Westerlund, N.,
Komulainen, E., Hollos, P., Parviainen, L., Papageorgiou,
A.C., Iljin, K., Kallioniemi, O., Kallajoki, M., Courtney,
M.J., Mågård, M., James, P. & Coffey, E.T. (2012). JNK
phosphorylation of MARCKSL1 determines actin stability
12
and migration in neurons and in cancer cells. Mol. Cell. Biol.
32: 3513-3526. IF 5.5
6. Björkman M, Östling P, Härmä V, Virtanen J, Mpindi JP,
Rantala J, Mirtti T, Vesterinen T, Lundin M, Sankila A,
Rannikko A, Kaivanto E, Kohonen P, Kallioniemi O, Nees
M (2012) 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. 31(29):3444-56. IF 6.4
7. Chouhan B., Denesyuk A., Heino J. Johnson MS and
Denessiouk K. (2012) Evolutionary Origin of the alphaC Helix
in Integrins. WASET 65: 546-549.
8. Chronopoulou EG, Papageorgiou AC, Markoglou A,
Nikolaos E. Labrou NE (2012) Inhibition of human glutathione
transferases by pesticides: Development of a simple
analytical assay for the quantification of pesticides in water.
Journal of Molecular Catalysis B: Enzymatic. 81:43–51. IF
2.7
9. Gómez-Gallego C, Collado MC, Ilo T, Jaakkola UM, Bernal
MJ, Periago MJ, Salminen S, Ros G, Frias R (2012) Infant
formula supplemented with polyamines alters the intestinal
microbiota in neonatal BALB/cOlaHsd mice. J Nutr Biochem.
23(11):1508-13. IF 3.9
10.Elo LL, Kallio A, Laajala TD, Hawkins RD, Korpelainen E,
Aittokallio T (2012) Optimized detection of transcription
factor-binding sites in ChIP-seq experiments. Nucleic Acids
Res. 40(1):e1. IF 8.0
11.Ferraris SE, Isoniemi K, Torvaldson E, Anckar J, Westermarck
J, and Eriksson JE (2012) Nucleolar AATF regulates
c-Jun-mediated apoptosis. Molecular Biology of the Cell,
23(21):4323-4332. IF 5.4
12.Frias R, Steiner JM, Williams DA, Sankari S, Westermarck E
(2012) Urinary recovery of orally administered 51chromiumlabeled ethylenediamine tetra-acetic acid, lactulose,
rhamnose, D-xylose, 3-O-methyl-D-glucose and sucrose in
healthy adult male laboratory Beagles. American Journal of
Veterinary Research. 73 (5): 654-658. IF 1.3
13.Frias R, Strube K, Ternes W, Collado MC, Spillmann T,
Sankari S, Westermarck E (2012) Comparison of 51Cr-EDTA
and iohexol as blood markers for intestinal permeability
testing in Beagle dogs.Vet J. 192(1):123-5. IF 2.2
14.Gómez-Gallego C, Collado MC, Ilo T, Jaakkola UM, Bernal
MJ, Periago MJ, Salminen S, Ros G, Frias R (2012) Infant
formula supplemented with polyamines alters the intestinal
microbiota in neonatal BALB/cOlaHsd mice. J Nutr Biochem.
(11):1508-13. IF 3.9
15.Gyenesei A, Moody J, Laiho A, Semple CA, Haley CS,
Wei WH (2012) BiForce Toolbox: powerful high-throughput
computational analysis of gene-gene interactions in genomewide association studies. Nucleic Acids Res. 40(Web Server
issue):W628-32. IF 8.0
13
16.Gyenesei A, Moody J, Semple CA, Haley CS, Wei WH
(2012) High-throughput analysis of epistasis in genomewide association studies with BiForce. Bioinformatics.
28(15):1957-64. IF 5.5
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, Nees M (2012) Lysophosphatidic
acid and sphingosine-1-phosphate promote morphogenesis
and block invasion of prostate cancer cells in threedimensional organotypic models. Oncogene. 31(16):207589. IF 6.4
18.Ivaska J. (2012) Unanchoring integrins in focal adhesions.
Nat. Cell. Biol.14:981-983 (Invited commentary). IF 19.5
19.Jonsdottir K, Zhang H, Jhagroe D, Skaland I, Slewa A,
Björkblom B, Coffey ET, Gudlaugsson E, Smaaland R,
Janssen EA, Baak JP (2012) The prognostic value of
MARCKS-like 1 in lymph node-negative breast cancer.
Breast Cancer Res Treat. 135(2):381-90. IF 5.2
20.Karaman DS, Diti Desai D, Senthilkumar R, Johansson
EM, Råtts N, Odén M, Eriksson JE, Sahlgren C, Toivola
DM and Rosenholm JM* (2012) Shape engineering vs
organic modification of inorganic nanoparticles as a tool
for enhancing cellular internalization. Nanoscale Res Lett.
7(1):358. IF 2.7
21.Köhnke M, Schmitt S, Ariotti N, Piggott AM, Parton RG,
Lacey E, Capon RJ, Alexandrov K, Abankwa D (2012)
Design and Application of In Vivo FRET Biosensors to
Identify Protein Prenylation and Nanoclustering Inhibitors.
Chem Biol. 19(7):866-74. IF 5.8
22.Korhonen JT, Puolakkainen M, Häivälä R, Penttilä T,
Haveri A, Markkula E, Lahesmaa R (2012) Flotillin-1
(Reggie-2) contributes to Chlamydia pneumoniae growth
and is associated with bacterial inclusion. Infect Immun.
80(3):1072-8. IF 4.2
23.Korhonen JT, Puolakkainen M, Haveri A, Tammiruusu A,
Sarvas M, Lahesmaa R (2012) Chlamydia pneumoniae entry
into epithelial cells by clathrin-independent endocytosis.
Microb Pathog. 52(3):157-64. IF 2.1
24.Laiho A, Kiraly A, Gyenesei A. GeneFuncster: A Web Tool for
Gene Functional Enrichment Analysis and Visualisation, D.
Gilbert and M. Heiner (Eds.): CMSB 2012, LNCS 7605, pp.
382-385, 2012. Springer-Verlag Berlin Heidelberg 2012.
25.Lehtinen L, Vainio P, Wikman H, Reemts J, Hilvo M, Issa R,
Pollari S, Brandt B, Oresic M, Pantel K, Kallioniemi O, Iljin K
(2012) 15-Hydroxyprostaglandin dehydrogenase associates
with poor prognosis in breast cancer, induces epithelialmesenchymal transition, and promotes cell migration in
cultured breast cancer cells. J Pathol. 226(4):674-86. IF 6.3
26.Levula M, Oksala N, Airla N, Zeitlin R, Salenius JP, Järvinen
O, Venermo M, Partio T, Saarinen J, Somppi T, Suominen
V, Virkkunen J, Hautalahti J, Laaksonen R, Kähönen M,
Mennander A, Kytömäki L, Soini JT, Parkkinen J, Pelto-
14
Huikko M, Lehtimäki T (2012) Genes involved in systemic
and arterial bed dependent atherosclerosis--Tampere
Vascular study. PLoS One. 7(4):e33787 IF 4.1
27.Lund RJ, Närvä E, Lahesmaa R (2012) Genetic and
epigenetic stability of human pluripotent stem cells. Nat Rev
Genet. 13(10):732-44. IF 38.1
28.Lund RJ, Nikula T, Rahkonen N, Närvä E, Baker D, Harrison
N, Andrews P, Otonkoski T, Lahesmaa R (2012) Highthroughput karyotyping of human pluripotent stem cells.
Stem Cell Res. 9(3):192-195. IF 5.2
29.Mamaeva V, Sahlgren C, Lindén M (2012) Mesoporous silica
nanoparticles in medicine-Recent advances. Adv Drug Deliv
Rev. pii: S0169-409X(12)00248-7. IF 11.5
30.Mathiasen DP, Egebjerg C, Andersen SH, Rafn B, Puustinen
P, Khanna A, Daugaard M, Valo E, Tuomela S, Bøttzauw
T, Nielsen CF, Willumsen BM, Hautaniemi S, Lahesmaa
R, Westermarck J, Jäättelä M, and Kallunki T (2012)
Identification of a c-Jun N-terminal kinase-2-dependent
signal amplification cascade that regulates c-Myc levels in
ras transformation. Oncogene, 31, 390-40. IF 6.4
31.McDonnell L, Andrén PE, Corthals GL. (2012) Preface. J
Proteomics. 75(16):4881-2. IF 4.9
32.McDonnell LA, Heeren RM, Andrén PE, Stoeckli M, Corthals
GL (2012) Going forward: Increasing the accessibility of
imaging mass spectrometry. J Proteomics. 75(16):5113-21.
IF 4.9
33.Närvä E, Rahkonen N, Emani MR, Lund R, Pursiheimo JP,
Nästi J, Autio R, Rasool O, Denessiouk K, Lähdesmäki H, Rao
A, Lahesmaa R (2012) 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(3):452-60. IF 7.8
34.Niemelä M, Kauko O, Sihto H, Mpindi J-P, Nicorici D,
Pernilä P, Kallioniemi O-P, Joensuu H, Hautaniemi S, and
Westermarck J (2012) CIP2A signature reveals the MYC
dependency of CIP2A-regulated phenotypes and its clinical
association with breast cancer subtypes. Oncogene,
31(39):4266-4278. IF 6.9
35.Nilsson EM, Brokken LJ, Narvi E, Kallio MJ, Härkönen PL
(2012) Identification of fibroblast growth factor-8b target
genes associated with early and late cell cycle events in
breast cancer cells. Mol Cell Endocrinol. 358(1):104-15. IF
4.2
36.Paatero I, Jokilammi A, Heikkinen PT, Iljin K, Kallioniemi OP,
Jones FE, Jaakkola PM, Elenius K (2012) Interaction with
ErbB4 promotes hypoxia-inducible factor-1α signaling. J
Biol Chem. 287(13):9659-71. IF 4.8
37.Peet A, Kool P, Ilonen J, Knip M, Tillmann V; for the
DIABIMMUNE Study Group. Collaborators (42) Koski
K, Koski M, Härkönen T, Ryhänen S, Hämäläinen AM,
Ormisson A, Ulich V, Kuzmicheva E, Mokurov S, Markova
S, Pylova S, Isakova M, Shakurova E, Petrov V, Dorshakova
15
NV, Karapetyan T, Varlamova T, Kiviniemi M, Alnek K,
Janson H, Uibo R, Salum T, von Mutius E, Weber J, Ahlfors
H, Kallionpää H, Laajala E, Lahesmaa R, Lähdesmäki H,
Moulder R, Nieminen J, Ruohtula T, Vaarala O, Honkanen
H, Hyöty H, Kondrashova A, Oikarinen S, Harmsen HJ, De
Goffau MC, Welling G, Alahuhta K, Virtanen SM (2012) Birth
weight in newborn infants with different diabetes-associated
HLA genotypes in three neighbouring countries: Finland,
Estonia and Russian Karelia. Diabetes Metab Res Rev.
28(5):455-461. IF 3.4
38.Pellinen T, Rantala JK, Arjonen A, Mpindi JP, Kallioniemi
O, Ivaska J (2012) A functional genetic screen reveals new
regulators of β1-integrin activity. J Cell Sci. 125(Pt 3):64961. IF 6.1
39.Perdomo MF, Hosia W, Jejcic A, Corthals GL, Vahlne A
(2012) Human serum protein enhances HIV-1 replication
and up-regulates the transcription factor AP-1. Proc Natl
Acad Sci U S A. 109(43):17639-44. IF 9.7
40.Pollari S, Käkönen RS, Mohammad KS, Rissanen JP, Halleen
JM, Wärri A, Nissinen L, Pihlavisto M, Marjamäki A, Perälä
M, Guise TA, Kallioniemi O, Käkönen SM (2012) Heparinlike polysaccharides reduce osteolytic bone destruction
and tumor growth in a mouse model of breast cancer bone
metastasis. Mol Cancer Res. 10(5):597-604. IF 4.4
41.Pollari S, Leivonen SK, Perälä M, Fey V, Käkönen SM,
Kallioniemi O (2012) Identification of microRNAs inhibiting
TGF-β-induced IL-11 production in bone metastatic breast
cancer cells. PLoS One. 7(5):e37361. IF 4.1
42.Pouwels J, Nevo J, Pellinen T, Ylänne J, Ivaska J (2012)
Negative regulators of integrin activity. J Cell Sci. 125(Pt
14):3271-80. IF 6.1
43.Rintanen N, Karjalainen M, Alanko J, Paavolainen L, Mäki
A, Nissinen L, Lehkonen M, Kallio K, Cheng RH, Upla P,
Ivaska J, Marjomäki V (2012) Calpains promote α2β1
integrin turnover in nonrecycling integrin pathway. Mol Biol
Cell. 23(3):448-63. IF 4.9
44.Rissanen J, Moulder R, Lahesmaa R, Nevalainen OS
(2012) Pre-processing of Orbitrap higher energy collisional
dissociation tandem mass spectra to reduce erroneous
iTRAQ ratios. Rapid Commun Mass Spectrom. 26(17):2099104. IF 2.8
45.Rosenholm JM, Mamaeva V, Sahlgren C, Lindén M (2012)
Nanoparticles in targeted cancer therapy: mesoporous
silica nanoparticles entering preclinical development stage.
Nanomedicine (Lond). 7(1):111-20. IF 6.2
46.Salmela AL, Pouwels J, Kukkonen-Macchi A, Waris S,
Toivonen P, Jaakkola K, Mäki-Jouppila J, Kallio L, Kallio
MJ (2012) The flavonoid eupatorin inactivates the mitotic
checkpoint leading to polyploidy and apoptosis. Exp Cell
Res. 318(5):578-92. IF 3.6
47.Sandri C, Caccavari F, Valdembri D, Camillo C, Veltel S,
Santambrogio M, Lanzetti L, Bussolino F, Ivaska J, Serini G
16
(2012) The R-Ras/RIN2/Rab5 complex controls endothelial
cell adhesion and morphogenesis via active integrin
endocytosis and Rac signaling. Cell Res. 22(10):1479-501.
IF 8.2
48.Santos HM, Kouvonen P, Capelo JL, Corthals GL (2012)
Isotopic labelling of peptides in tissues enhances mass
spectrometric profiling. Rapid Commun Mass Spectrom.
26(3):254-62. IF 2.8
49.Sen Karaman D, Desai D, Senthilkumar R, Johansson
EM, Råtts N, Odén M, Eriksson JE, Sahlgren C, Toivola
DM, Rosenholm JM (2012) Shape engineering vs organic
modification of inorganic nanoparticles as a tool for
enhancing cellular internalization. Nanoscale Res Lett.
7(1):358. IF 2.7
50.Skopelitou K, Dhavala P, Papageorgiou AC, Labrou NE (2012)
A glutathione transferase from Agrobacterium tumefaciens
reveals a novel class of bacterial GST superfamily. PLoS
One. 7(4):e34263. IF 4.1
51.Skopelitou K, Muleta AW, Pavli O, Skaracis GN, Flemetakis E,
Papageorgiou AC, Labrou NE (2012) Overlapping protective
roles for glutathione transferase gene family members in
chemical and oxidative stress response in Agrobacterium
tumefaciens. Funct Integr Genomics. 12(1):157-72. IF 2.8
52.Sundvall M, Korhonen A, Vaparanta K, Anckar J, Halkilahti
K, Salah Z, Aqeilan RI, Palvimo JJ, Sistonen L, Elenius K
(2012) Protein Inhibitor of Activated STAT3 (PIAS3) Protein
Promotes SUMOylation and Nuclear Sequestration of
the Intracellular Domain of ErbB4 Protein. J Biol Chem.
287(27):23216-26. IF 4.8
53.Teittinen KJ, Grönroos T, Parikka M, Junttila S, Uusimäki
A, Laiho A, Korkeamäki H, Kurppa K, Turpeinen H, Pesu
M, Gyenesei A, Rämet M, Lohi O (2012) SAP30L (Sin3Aassociated protein 30-like) is involved in regulation of cardiac
development and hematopoiesis in zebrafish embryos. J
Cell Biochem. 113(12):3843-52. IF 2.9
54.Tnimov Z, Guo Z, Gambin Y, Nguyen UT, Wu YW, Abankwa
D, Stigter A, Collins BM, Waldmann H, Goody RS,
Alexandrov K (2012) Quantitative Analysis of Prenylated
RhoA Interaction with Its Chaperone, RhoGDI. J Biol Chem.
287(32):26549-62. IF 4.8
55.Toivonen R, Koskenvuo J, Merentie M, Söderström M, YläHerttuala S, Savontaus M. (2012) Intracardiac injection of a
capsid-modified Ad5/35 results in decreased heart toxicity
when compared to standard Ad5. Virol J. 9:296. IF 2.3
56.Tripathi P, Sahoo N, Ullah U, Kallionpää H, Suneja A,
Lahesmaa R, Rao KV (2012) A novel mechanism for ERKdependent regulation of IL4 transcription during human
Th2-cell differentiation. Immunol Cell Biol. 90(7):676-87. IF
3.7
57.Tuomela S, Salo V, Tripathi SK, Chen Z, Laurila K, Gupta B,
Äijö T, Oikari L, Stockinger B, Lähdesmäki H, Lahesmaa R
(2012) Identification of early gene expression changes during
17
human Th17 cell differentiation. Blood. 119(23):e151-60. IF
10.6
58.Ullah U, Tripathi P, Lahesmaa R, Rao KV (2012) Gene set
enrichment analysis identifies LIF as a negative regulator of
human Th2 cell differentiation. Sci Rep. 2:464.
59.Vainio P, Mpindi JP, Kohonen P, Fey V, Mirtti T, Alanen KA,
Perälä M, Kallioniemi O, Iljin K (2012) High-Throughput
Transcriptomic and RNAi Analysis Identifies AIM1, ERGIC1,
TMED3 and TPX2 as Potential Drug Targets in Prostate
Cancer. PLoS One. 7(6):e39801. IF 4.1
60.Ventelä S, Come C, Mäkelä J-A, Hobbs RM, Mannermaa
L, Kallajoki M, Chan EK, Pandolfi PP, Toppari J, and
Westermarck J (2012) CIP2A promotes proliferation of
spermatogonial progenitor cells and spermatogenesis in
mice. PLoS One, 7(3), e33209. IF 4.1
61.Ventelä S, Mäkelä J-A, Kulmala J, Westermarck J, and
Toppari J (2012) Identification and regulation of a stagespecific stem cell niche enriched by Nanog positive
spermatogonial stem cells in the mouse testis. Stem Cells,
30(5), 1008-1020. IF 7.8
62.Vesala L, Salminen TS, Laiho A, Hoikkala A, Kankare M
(2012) Cold tolerance and cold-induced modulation of
gene expression in two Drosophila virilis group species with
different distributions. Insect Mol Biol. 21(1):107-18. IF 2.5
63.Virtakoivu R, Pellinen T, Rantala JK, Perälä M, Ivaska J
(2012) Distinct roles of AKT isoforms in regulating β1-integrin
activity, migration and invasion in prostate cancer. Mol Biol
Cell. 23(17):3357-69. IF 4.9
64.Wei WH, Hemani G, Gyenesei A, Vitart V, Navarro P, Hayward
C, Cabrera CP, Huffman JE, Knott SA, Hicks AA, Rudan
I, Pramstaller PP, Wild SH, Wilson JF, Campbell H, Hastie
ND, Wright AF, Haley CS (2012) Genome-wide analysis
of epistasis in body mass index using multiple human
populations. Eur J Hum Genet. 20(8):857-62. IF 4.4
65.Wilhelmsson U, Faiz M, de Pablo Y, Sjöqvist M, Andersson D,
Widestrand A, Potokar M, Stenovec M, Smith PL, Shinjyo N,
Pekny T, Zorec R, Ståhlberg A, Pekna M, Sahlgren C, Pekny
M (2012) Astrocytes Negatively Regulate Neurogenesis
through the Jagged1-Mediated Notch Pathway. Stem Cells.
30(10):2320-9. IF 7.8
66.Ylipaasto P, Smura T, Gopalacharyulu P, Paananen A,
Seppänen-Laakso T, Kaijalainen S, Ahlfors H, Korsgren O,
Lakey JR, Lahesmaa R, Piemonti L, Oresic M, Galama J,
Roivainen M (2012) Enterovirus-induced gene expression
profile is critical for human pancreatic islet destruction.
Diabetologia. 55(12):3273-83. IF 6.8
18
PERSONNEL 2012
Administration
LAHESMAA Riitta, Director, Professor,
Group Leader
ALANKO Satu, Coordinator
GRÖNROOS Sirkku, Senior
Administrative Assistant
HIRVENSALO Eva, Clerical Official
JASMAVAARA Aila, Clerical Official
LAHDENPERÄ Anne, Coordinator
SUVANTO Tuula, Project Secretary
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
WASBERG Mikael, Laboratory Manager
Finnish Microarray and Sequencing
Centre
FEZAZI Bogata, Laboratory Technician
GYENESEI Attila, Senior Scientist
GHIMIRE Bishwa, Undergraduate
Student
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
KANKAANPÄÄ Pasi, Coordinator of the
Cell Imaging Core
COFFEY Eleanor, Academy of Finland
Research Fellow, Head of the Cell
Imaging Core
ADEL Ketlin, Research Technician
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, Senior Scientist
KOUVONEN Petri, Researcher
MUTH-PAWLAK Dorotha, Senior
Scientist
ROKKA Anne, Senior Scientist
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
Virus Vector facility
COFFEY Eleanor, Group Leader,
Coordinator
ADEL Ketlin, Laboratory Technician
Mechanisms and Biosensors of
GTPases
ABANKWA Daniel, Group Leader,
Academy of Finland Research Fellow
BLAZEVICS Olga, Postdoctoral Fellow
GUZMAN Camilo, Postdoctoral Fellow
LIGABUE Alessio, Postdoctoral Fellow
MAI Anja, Postdoctoral Fellow
KAJA NAJUMUDEEN Arafath,
Graduate Student
OETKEN-LINDHOLM Christina,
Postdoctoral Fellow
SILJAMÄKI Elina, Postdoctoral Fellow
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
FOUROTAN Behnoush, Undergraduate
Student
FREEMANTLE Erika, Postdoctoral
researcher
HOLLOS Patrik, Graduate Student
19
KOMULAINEN Emilia, Graduate
Student
MOHAMMAD Hasan, Graduate
Student
MYSORE Raghavendra, Graduate
Student
PADZIK Artur, Postdoctoral researcher
NGUYEN Phuoc Hung, Graduate
Student
PYÖKÄRI Susanna, Laboratory
technician
ZDROJEWSKA Justyna, Graduate
Student
Translational Proteomics
CORTHALS Garry, Group Leader, Head
of Proteomics
BULBUL Ahmed, Undergraduate
Student
CHAND Thaman, Graduate Student
EEROLA Sini, Laboratory Technician
HAAPANIEMI Pekka, Laboratory
Technician
HAKANEN Emmi, Laboratory
Technician
HEINONEN Arttu, Project Engineer
IMANISHI Susumu, Senior Scientist
JAAKKOLA Noora, Undergraduate
Student
KANNASTE Olli, Graduate Student
KOTTAHACHCHI Darshana, Graduate
Student
KOUVONEN Petri, Senior Scientist
(visiting ETH Zurich 2011-2013)
KUMAR Santosh, Undergraduate
Student
LUKASH Tanya, Senior Scientist
MUTH-PAWLAK Dorotha, Senior
Scientist
NEES Susanne, Coordinator
NGUYEN Elizabeth, Postdoctoral
Fellow
ROKKA Anne, Senior Scientist
SAEIDI Firouz, Undergraduate Student
DE SANTOS Hugo, Graduate Student
SUNI Veronika, Graduate Student
THATIKONDA Santosh, Undergraduate
Student
VEHMAS Anni, Graduate Student
YADAV Avinash, Graduate Student
Organisation of Neuronal Signaling
Pathways
COURTNEY Michael, Affiliated 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
de MERA, Melero-Fernandez
MIN Jungah, Senior Scientist
RAI Surya, Undergarduate Student
SEPPÄNEN Aila, Laboratory Technician
VERGUN Olga, Postdoctroal
Researcher
WANG Xijun, Graduate Student
20
Structural Bioinformatics
DENESSIOUK Konstantin, Docent,
Group Leader
CHOUHAN Bhanupratap Singh,
Graduate Student
HEININEN-BROWN Mari,
Data Mining and Modeling
ELO Laura, Group Leader, Adjunct
Professor
AITTOKALLIO Tero, Affiliated Group
NEVALAINEN Olli, Affiliated Group
Leader, Professor
HEISKANEN Marja, Graduate Student
JAAKKOLA Maria, Undergraduate
Student
KOSKINEN Anna, Undergraduate
Student
LINDEN Rolf, Graduate Student
OKSER Sebastian, Graduate Student
RANNIKKO Sami, Undergraduate
Student
SALMI Jussi, Postdoctoral Fellow
SANTA Harri, Undergraduate Student
SEYEDNASROLLAH Fatemehsadat,
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, Graduate Student
HYDER Claire, Graduate Student
LINDQVIST Julia, Graduate Student
LINDSTRÖM Michelle, Undergraduate
Student
MOHANASUNDARAM Ponnuswamy,
Graduate Student
NIEMELÄ Erik, Undergraduate Student
ISONIEMI Kimmo, Graduate Student
JOKO Alia, Graduate Student
PAZIEWSKA Beata, Secretary
PAUL Preethy, Post-doctoral fellow
PYLVÄNÄINEN Joanna, Graduate
Student
RAJENDRAN Senthil Kumar,
Postdoctoral Fellow
SAARENTO Helena, Research
Associate
TORVALDSON Elin, Graduate student
Molecular Systems Immunology
and Stem Cell Biology
LAHESMAA Riitta, Director, Professor,
Group Leader
BALA Kanchan, Postdoctoral fellow
CHEN Zhi Jane, Senior Scientist
EDELMAN Sanna, Postdoctoral fellow
ELO-UHLGREN Laura, Adjunct
Professor, Senior Scientist
FEZAZI Bogata, Laboratory Technician
GOODLETT David R., Visiting Professor
HAKANEN Emmi, Undergraduate
Student
HAKKARAINEN Marjo, Laboratory
Technician
HEINONEN Mirkka, Graduate Student
HEINONEN Sarita, Laboratory
Technician
HÄMÄLISTÖ Saara, Postdoctoral fellow
JUNNI Päivi, Laboratory Technician
KALLIONPÄÄ Henna, Graduate
Student
KANDURI Kartiek, Graduate Student
KHAN MOHN Moin, Graduate Student
KORHONEN Juha, Graduate Student
KYLÄNIEMI Minna, Graduate Student
LAAJALA Essi, Graduate Student
LEHTIMÄKI Sari, Postdoctoral fellow
LUND Riikka, Senior Scientist
LÖNNBERG Tapio, Graduate Student
MAURINEN Krista, Undergraduate
Student
MOULDER Robert, Senior Scientist
MYLLYVIITA Johanna, Undergraduate
Student
NGYEN Elizabeth, Postdoctoral Fellow
NÄRVÄ, Elisa, Graduate Student
OIKARI Lotta, Undergraduate Student
PIETILÄ Elina, Laboratory Technician
RAHKONEN Nelly, Graduate Student
RAJAMÄKI Anna, Undergraduate
Student
RAJAVUORI Anna, Undergraduate
Student
RAO Anjana, Visiting Professor
RAO Kanury, Visiting Professor
RASOOL Omid, Adjunct Professor,
Senior Scientist
REDDY Emaheswa, Postdoctoral fellow
SALMI Jussi, Senior scientist
SALO Verna, Graduate Student
SARAPULOV Alexey, Graduate Student
STOCKINGER Brigitta, Visiting
Professor
TAHVANAINEN Johanna, Postdoctoral
fellow
TRIPATHI Subhash, Graduate Student
TUOMELA Soile, Graduate Student
ULLAH Ubaid, Postdoctoral Fellow
ÖLING Viveka, Postdoctoral Fellow
Quality Assurance Unit
LINKO Linnéa, Group Leader, Adjunct
Professor
Computational Systems Biology
LÄHDESMÄKI Harri, Affiliated Group
Leader, Professor
ERKKILÄ Timo, Graduate Student
INTOSALMI Jukka, Postdoctoral Fellow
KANDURI Kartiek, Graduate Student
KONG Lingjia, Graduate Student
KÄHÄRÄ Juhani, Undergraduate
Student
LAAJALA Essi, Graduate Student
LARJO Antti, Graduate Student
LAURILA Kirsti, Postdoctoral fellow
MALONZO Maia, Graduate Student
MANNERSTRÖM Henrik, Graduate
Student
NOUSIAINEN Kari, Graduate Student
OSMALA Maria, Graduate Student
RAUTIO Sini, Undergraduate Student
SOMANI Juhi, Undergraduate Student
ÄIJÖ Tarmo, Graduate Student
Cell Culture Models For Tumor Cell
Invasion and Epithelial Platicity
NEES Matthias, Affiliated Group Leader
AHONEN Ilmari, Graduate student
HÄRMÄ Ville, Postdoctoral fellow
MISHRA Mrinal, Undergraduate
Student
SIMVARANAN Chamudeesvari,
TOIVONEN Pauliina, Laboratory
technician
VIRTANEN Johannes, Laboratory
technician
ÅKERFELT Malin, Postdoctoral fellow
Complex Biosystems Modeling
NYKTER Matti, Affiliated Group Leader
ANNALA Matti, Graduate Student
GRANBERG Kirsi, Post-doctoral Fellow
HÄYRYNEN Sergei, Undergraduate
Student
KALLIO Aleksi, Undergraduate Student
KARTASALO Kimmo, Undergraduate
Student
KESSELI Juha, Post-doctoral Fellow
KIVINEN Virpi, Graduate Student
KYTÖLÄ Ville,Undergraduate Student
LEPPÄNEN Simo-Pekka,
LIUKSIALA Thomas, Undergraduate
Student
SARBU Septimia, Graduate Student
SOININEN Tero, Undergraduate
Student
SORSA Liisa-Ida, Undergraduate
Student
SORSA Saija, Undergraduate Student
WALTERING Kati, Post-doctoral Fellow
YLIPÄÄ Antti, Graduate Student
Metabolome In Health And Disease
OREŠIČ Matej, Affiliated Group Leader
BONDIA PONS Isabel, Research
scientist
HILVO Mika, Research scientist
HYÖTYLÄINEN Tuulia, Team leader
JÄNTTI Sirkku, Research scientist
KIVILOMPOLO Maarit, Research
scientist
KOIVUNIEMI Artturi, Research scientist
LAHTINEN Ulla, Laboratory technician
LIETZEN Niina, Research scientist
LINDFORS Erno, Research scientist
MARINKOVIĆ Tijana, Research
scientist
MATTILA Ismo, Research scientist
NYGREN Heli, Research scientist
PEDDINTI Gopal, Research scientist
PÖHÖ Päivi, Research scientist
RUSKEEPÄÄ Anna-Liisa, Laboratory
technician
SYSI-AHO Marko, Team leader
YETUKURI Laxman, Research scientist
ZHAO Han, Laboratory technician
ÖHRNBERG Leena, Laboratory
technician
Protein Crystallography
PAPAGEORGIOU Tassos, Group
BATTULA Pradeep, Undergraduate
Student
21
FRIOUX Cleménce, Undergraduate
Student
MATTSSON Jesse, Undergraduate
Student
MULETA Abdi, Graduate Student
OUDOT Anthony, Undergraduate
Student
PRIETO LOPEZ Carlos, Undergraduate
Student
SUBEDI Bishwa, Graduate Student
Cell fate
SAHLGREN Cecilia, Group Leader,
ANTFOLK Daniel, Undergraduate
Student
ANTILA Christian, Graduate Student
LANDOR Sebastian, Graduate Student
LERCHE Martina, Undergraduate
Student
MAMAEVA Veronika, Postdoctoral
Fellow
NIEMI Rasmus, Undergraduate
Student
NIINIMAKI Jenni, Undergraduate
Student
PRABHAKAR Neeraj, Graduate
Student
RÅTTS Natalie, Laboratory Technician
SAARENTO, Helena, Laboratory
Technician
SARINKO Sara, Undergraduate
Student
SJÖQVIST Marika, Graduate Student
Targeting Strategies for Gene
Therapy
SAVONTAUS Mikko, Affiliated Group
EEROLA Kim, Graduate Student
MATTILA Minttu, Graduate Student
Regulation and Function of Heat
Shock Transcription Factors
SISTONEN Lea, Group Leader,
Professor
AHLSKOG Johanna, Postdoctoral
Fellow
ASPELIN Camilla, Graduate Student
BERGMAN Heidi, Graduate Student
BJÖRK Johanna, Postdoctoral Fellow
BLOM Malin, Undergraduate Student
BUDZYNSKI Marek, Graduate Student
CRUL Tim, Visiting Scientist
DA SILVA Alejandro, Undergraduate
Student
ELSING Alexandra, Graduate Student
HENRIKSSON Eva, Senior Scientist
HIMANEN Samu, Undergraduate
Student
JOUTSEN Jenny, Graduate Student
LUNDSTEN Emine, Undergraduate
Student
LUSTIG Heidi, Undergraduate Student
PUUSTINEN Mikael, Undergraduate
Student
ROOS-MATTJUS Pia, Senior Scientist
SAARENTO Helena, Research
Assistant
SANDQVIST Anton, Postdoctoral
Fellow
TÓTH Noémi, Visiting Scientist
VAINIO Petra, Graduate Student
VASARA Jenni, Research Assistant
VIHERVAARA Anniina, Graduate
Student
Cancer Cell Signaling
WESTERMARCK Jukka, Group Leader,
Professor
ARSIOLA Tiina, Coordinator
CVRLSEVIC Anna, Postdoctoral Fellow
KALEVO-MATTILA Taina, Laboratory
Technician
KAUKO Otto, Graduate Student
KAUR Amanpreet, Graduate Student
LAINE Anni, Graduate Student
NIEMELÄ Minna, Postdoctoral Fellow
OKKERI Juha, Postdoctoral Fellow
POKHAREL Yuba, Postdoctoral Fellow
PUKONEN Inga, Laboratory Technician
SITTIG Eleonora, Graduate Student
XI Qiao, Graduate Student
Adenosine Deaminases
ZAVIALOV Andrey, Group Leader,
HASSAN KHAN Meraj, Graduate
Student
LIU Chengquian, Graduate Student
MUKIIENKO Yuliia, Graduate Student
RAI Balwant, Graduate Student
SKALDIN Maksym, Graduate Student
VERWIJMEREN Joyce, Undergraduate
Student
THE FINNISH MICROARRAY AND
SEQUENCING CENTRE
http://fmsc.btk.fi
Contact information:
Turku Centre for Biotechnology, BioCity,
Tykistökatu 6A, P.O. Box 123, FIN-2050 Turku, Finland.
Tel. +358-2-333 8041 Fax +358-2-251 8808.
Email: fmsc@btk.fi
Heads/Coordinators
Prof. Riitta Lahesmaa
Dr. Attila Gyenesei (FMSC operation and services; bioinformatics)
Dr. Riikka Lund (Next-generation sequencing, epigenomics and
chromatin structure applications)
Dr. Juha-Pekka Pursiheimo (Next-generation sequencing and
personal sequencing applications)
Affiliated group leaders:
Bioinformatics: Dr. Reija Autio, Dr. Laura Elo-Uhlgren,, Prof. Harri
Lähdesmäki, Prof. Matti Nykter. Next-generation sequencing: Prof.
Jorma Palvimo
Technical Team:
Bishwa Ghimire, Bogata Fezazi, Päivi Junni, Sini Junttila, Leni
Kauko, Leena Kytömäki, Asta Laiho, Oso Rissanen, Reija Venho,
Eveliina Virtanen, Sanna Vuorikoski
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)
Core facility description:
The Finnish Microarray and Sequencing Centre (FMSC) is an
internationally recognized Functional Genomics Core Facility that
provides state-of-the-art research technologies and services
in the areas of genomics, epigenomics, transcriptomics and
bioinformatics for the Finnish and international scientific community.
The main services include next-generation sequencing (NGS) and
microarray based services mainly focusing on gene expression and
its regulation as well as on epigenetics. We also provide quantitative
Real-Time PCR and traditional DNA sequencing services. Our
services cover 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. Seminars and practical courses on microarrays, NGS and
related bioinformatics are held frequently to facilitate knowledge
transfer within the field.
Since 2010 FMSC has had a key role within the Biocenter Finland
national infrastructure program. According to the division of tasks
within the Genome-wide Methods network, our Centre focuses
22
23
From left to right: Back row: Bogata Fezazi, Leni Kauko, Juha-Pekka Pursiheimo, Päivi Junni, Attila Gyenesei and Riikka Lund. Front row: Sanna Vuorikoski, Pasi Soidinsalo, Eveliina Virtanen, Asta Laiho, Sini
Junttila, Cristina Valensisi, Reija Venho, Oso Rissanen and Kalyan Pasumarthy.
on developing technologies in the areas of gene expression and
its regulation; one of the key goals in the Centre is to develop
and implement advanced techniques and provide services for
epigenomic applications.
Funding:
Biocenter Finland
University of Turku
Åbo Akademi University
Users:
FMSC has provided genomics and transcriptomics services for
over a decade, and thereby has gained a large customer base.
FMSC processes annually thousands of microarray and NGS
samples. In 2012 the Centre carried out 80 projects on NGS and
microarray platforms from 51 research groups and analysed more
than 2300 samples. The QPCR service ran > 2000 plates and was
used by 116 research groups. The Centre’s Sanger sequencing
service analysed > 4000 samples for 83 research projects. With
our contribution, many papers were published during the last
few years in high-quality journals (such as Nature Immunology,
Immunity, Science).
Publications with FMSC contributions and coauthors in 20102012
Publications
24
2012
FMSC contributions
FMSC coauthors
2012
46
13
2011
36
2
2010
30
6
25
CELL IMAGING CORE
http://www.btk.fi/cell-imaging/
Coordinator:
Pasi Kankaanpää, M.Sc.,
Turku Centre for Biotechnology,
BioCity, Tykistökatu 6B, FI-20520 Turku, Finland.
Tel. +358 40 522 1090. Email: pasi.kankaanpaa@btk.fi
Technical Team/Technical Team leaders:
Jouko Sandholm, M.Sc., Senior Researcher Microscopy, Email:
jouko.sandholm@btk.fi; Markku Saari, M.Sc., Researcher
Microscopy, Email: msaari@btk.fi; Jari Korhonen, M.Sc.,
Researcher Microscopy, Email: jari.korhonen@abo.fi; Perttu Terho,
M.Sc., Technical Engineer Flow Cytometry, Email: perttu.terho@
btk.fi; Ketlin Adel, Researcher Flow Cytometry, Email: kadel@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
From left to right. Back row: Jouko Sandholm, Eleanor Coffey and Jari Korhonen.
Front row: Markku Saari, Pasi Kankaanpää, Ketlin Adel and Perttu Terho.
26
The mission of the Cell Imaging Core (CIC) is to provide state-ofthe-art cell imaging and flow cytometry instruments and services to
scientists and students mainly in the Turku area, but also elsewhere.
Importantly, CIC is open to both academic and industrial researchers,
and our goal is to have an open access policy that serves the national
and international research community broadly. CIC services include
a wide range of flow cytometry and cell sorting instruments and
both basic and advanced light microscopes and other instruments.
A total of more than 25 instruments are available, supporting a wide
range of applications. Our services also include technical training to
local and visiting researchers, consultation on experimental design
and image acquisition, assistance in device maintenance, and
providing ongoing education in theory and practice by organizing
training courses and international workshops. We also constantly
evaluate new methods and tools, implement relevant advances
in hardware and software, and function as an organizing node
in the cell imaging development of the Turku campus. Because
reliably processing and quantifying data obtained with imaging
devices has become as important as the data acquisition itself,
CIC is also actively involved in the development of free software
both for flow cytometry (Flowing Software, www.flowingsoftware.
com) and microscopy (BioImageXD, www.bioimagexd.net). We
also offer data analysis and visualization services and training and
provide a high-end workstation for the post-processing needs of
our customers. Other areas of expertise at CIC included STED
super-resolution microscopy, live cell imaging, advanced confocal
microscopy applications, FCS, laser-capture micro-dissection,
high-throughput cell sorting and atomic force microscopy.
27
In 2012 CIC streamlined its economy, user policies, and quality
control. We also acquired several new instruments, such as a
Carl Zeiss LSM780 high-end confocal microscope, and a BioRad
ChemiDoc gel imaging device. Importantly, we also established
collaboration agreements with other major owners of light
microscopes in BioCity, and now offer these instruments (e.g.
Leica STED super-resolution, Leica Matrix high-throughput and
Leica multi-photon confocal microscopes) as services through CIC.
These collaboration agreements enable us to offer a wider range of
services to our customers in a centralized manner, and they help
the local light microscopy community to improve its economy and
device maintenance. In 2012 CIC personnel taught on different
courses and workshops in total more than 100 hours, among these
a Turku BioImaging Summer School on image processing and a
Turku Bionet workshop on how to prepare images for publication.
CIC also introduced a new popular seminar series, Lost In Imaging,
which focuses on practical and technical issues instead of scientific
ones. Importantly, Lost in Imaging seminars are broadcast as
webinars and recorded for later online viewing.
In 2012 CIC services were used in approximately 33 peer reviewed,
high quality scientific publications, among them the publication of
the BioImageXD software in Nature Methods. CIC also continued to
be the central representative of light microscopy and cell imaging in
the Turku BioImaging organization, which has successfully brought
all bioimaging in Turku under the same umbrella, the effects
of which can be seen as increased funding and user numbers.
Turku BioImaging has also improved our overall reputation and
recognizability both nationally and internationally, and provides a
positive atmosphere of collaboration under which bioimaging can
be effectively developed. In 2012 CIC also actively continued to
participate in the national Finnish BioImaging organization, and
in the extensive Euro-BioImaging organization, which is currently
under construction phase.
Recent statistics show that CIC has grown to become the largest
and most actively used light microscopic imaging facility in Finland.
In 2012, our services (including collaboration instruments) were
used by more than 300 people from more than 100 research
groups, 20% of who came from outside our home universities. As
the number of instruments continues to increase, and the activities
in national and European organizations continue to become more
prominent, we expect our usage numbers to continue to rise. This
is a major challenge for CIC, requiring seamless collaboration with
our customers, and secure funding for salaries for our personnel,
including software and IT services.
The cell imaging core is best contacted by our new designated email
addresses and phone numbers for microscopy: microscopy@btk.
fi, 044 - 923 1356, and for flow cytometry: flow@btk.fi, 044 - 923
1322. We warmly thank our users and collaborators for 2012 and
look forward to future challenges together!
Funding:
The Academy of Finland, University of Turku, Åbo Akademi
University, BioCity Turku Research Groups, Biocenter Finland,
Health and Welfare Ministry
28
PROTEOMICS FACILITY
http://www.btk.fi/proteomics
Director:
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. +358-2-2158808.
E-mail: garry.corthals@btk.fi
Personnel:
Senior scientists: Anne Rokka, Ph.D.; Dorota Muth-Pawlak, Ph.D.;
Susumu Imanishi, Ph.D.; Laboratory Engineer: Arttu Heinonen,
M.Sc.; Technician: Pekka Haapaniemi, M.Sc.
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 (University of Turku), 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 mass spectral methods
and instrumentation to meet the needs in molecular biotechnology
and medicine. Our goals are to identify new areas appropriate
for mass spectrometry in biological sciences and to develop
new approaches involving mass spectrometry, to apply cuttingedge mass spectrometry to tackle critical questions in biological
sciences, and train students, postdoctoral fellows and practicing
scientists in the use of mass spectrometry 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
29
in academia and industry, both locally and nationally through
Biocentre Finland coordinated activities.
A full representation of our services in 2012 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 is offered.
· Label-free quantitation – we have established a framework
for label-free quantitative analysis, particularly useful for
large-scale clinical studies.
· Targeted quantitation – sensitive and selective qualitative or
quantitative measurements of specific sets of proteins were
introduced.
· 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 determination are offered.
· Protein separation – numerous separation technologies
including liquid chromatography and a variety of gel based
methods such as 1-DE, 2-DE and peptide-IEF are available.
· Bioinformatics – in all areas of proteomics bioinformatics
services are offered including identification, quantitation and
validation studies, and software development.
Major mass spectrometry instrumentation:
· For ESI-MS/MS – Q-Star Elite, LTQ Velos Orbitrap Pro with
ETD, Q Exactive and TSQ Vantage
· For MALDI-MS/MS – Ultrafelx II
Funding:
University of Turku Åbo Akademi University, Biocenter Finland, The
Academy of Finland, City ofTurku, Ministry of Education, Centre of
Expertise of Southwest Finland, ?, the Systems Biology Research
Program and European Cooperation in Science and Technology
(e-COST), Seventh Framework Programme (FP7).
Users:
The Turku Proteomics Facility assists costumers from national and
international universities, research institutes and companies.in their
scientific objectives.
From left to right. Back row: Susumu Imanishi, Arttu Heinonen and Anne Rokka.
Front row: Pekka Haapaniemi, Dorota Muth and Garry Corthals.
30
31
PROTEIN CRYSTALLOGRAPHY
CORE FACILITY
http://www.btk.fi/crystallography/
Head:
Anastassios C. Papageorgiou, Ph.D.,
Adjunct Professor in Biochemistry and Structural Biology
BioCity, Tykistökatu 6A, FI-20521 Turku, Finland.
Tel. +358-2-3338012, Fax +358-2-3338000.
E-mail: tassos.papageorgiou@btk.fi
structure-function relationship of biological macromolecules in key
biological processes.
Funding:
Systems Biology research program, Biocenter Finland, University
of Turku
Users
Main users include groups from UTU and ÅA as listed in http://
www.sci.utu.fi/projects/biokemia/bioxlabs/. Each group has at
least three other collaborations.
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 (COOT, CCP4mg, PyMol,
Chimera, O, XtalView, Grasp), 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 various 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 multi-disciplinary
approach and we are especially interested in bringing together
expertise from various groups in order to better understand the
32
The X-ray generator and imaging plate detector.
Diffraction image recorded in the facility from a crystal grown by Anton Zavialov’s
group.
33
BIOINFORMATICS CORE
http://www.btk.fi/bioinformatics
Contact information:
Tykistökatu 6A, P.O. Box 123, FIN-2050 Turku, Finland.
Tel. +358-2-333 8041 Fax +358-2-251 8808.
Email: bioinfo@btk.fi
Heads/Coordinators
Dr. Konstantin Denessiouk (Structural Bioinformatics)
Dr. Attila Gyenesei (High-throughput Bioinformatics)
· Computer-based ligand docking
· Analysis and prediction of effects of molecular recognition
and mutations on protein function
Funding:
Biocenter Finland
University of Turku
Åbo Akademi University
Users:
The Bioinformatics core has users from Finnish universities,
biocenters and research institutes in the field of biosciences.
Technical Team:
Bhanupratap Singh Chouhan, Sini Junttila, Asta Laiho, Leena
Kytömäki, Bishwa Ghimire, Janne Isojärvi
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
34
35
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.
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
· propagates adenoviruses and produces lenti vectors
expressing genes of interest, as a research service
· maintains a fully equipped bio-safety level-2 lab where all
equipment for viral production and safe sample monitoring
are provided
· supplies working protocols and consultation 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 lenti 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. They are also used in vivo in for transduction of cells
in brain 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.
From left to right: Mikko Savontaus, Eleanor Coffey and Ketlin Adel.
36
37
MECHANISMS AND BIOSENSORS
OF GTPASES
Principle 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
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
vivo biophysical measurements, we have recently described a
novel switch III. This is formed by the β2-β3 loop and helix α5,
and is associated with the orientation of the G domain on the
membrane. Thus the Ras orientation is stabilized by the HVR and
helix α4 (Figure). We also showed that this orientation-switch is
specific for different Ras isoforms, regulates GTPase signalling and
combines with lateral segregation of Ras.
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 Heinrich-Heine 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 holding an
Academy of Finland Research Fellowship.
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 the identification of novel
isoform specific drugs.
· What is the (path)physiological role of nanoclustering?
Personnel:
Postdocs: Olga Blazevics, Camilo Guzman, Alessio Ligabue,
Anja Mai, Christina Oetken-Lindholm, Elina Siljamäki; Graduate
students: Arafath Kaja Najumudeen, MSc; Maja Solman, MSc
The novel orientation-switch III – the coding mechanism for small GTPase
isoform specificity. Membrane anchored H-ras exists in two orientationconformers. 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 α4 (blue; right).
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 GTP-mediated
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.
Funding:
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.
38
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)
Selected Publications:
Köhnke M, Schmitt S, Ariotti N, Piggott AM, Parton RG, Lacey E,
Capon RJ, Alexandrov K & Abankwa D (2012) Design and
Application of In Vivo FRET Biosensors to Identify Protein Prenylation
and Nanoclustering Inhibitors. Chemistry & Biology 19: 866–874
39
Sinha B, Köster D, Ruez R, Gonnord P, Bastiani M, Abankwa D,
Stan RV, Butler-Browne G, Vedie B, Johannes L, Morone N,
Parton RG, Raposo G, Sens P, Lamaze C & Nassoy P (2011)
Cells respond to mechanical stress by rapid disassembly of
caveolae. Cell 144: 402–413
Abankwa D, Gorfe AA, Inder K & Hancock JF (2010) Ras membrane
orientation and nanodomain localization generate isoform
diversity. Proceedings of the National Academy of Sciences
107: 1130–1135
Bastiani M, Liu L, Hill MM, Jedrychowski MP, Nixon SJ, Lo HP,
Abankwa D, Luetterforst R, Fernandez-Rojo M, Breen MR,
Gygi SP, Vinten J, Walser PJ, North KN, Hancock JF, Pilch PF
& Parton RG (2009) MURC/Cavin-4 and cavin family members
form tissue-specific caveolar complexes. J Cell Biol 185: 1259–
1273
Hill MM, Bastiani M, Luetterforst R, Kirkham M, Kirkham A, Nixon
SJ, Walser PJ, Abankwa D, Oorschot VMJ, Martin S, Hancock
JF & Parton RG (2008) PTRF-Cavin, a conserved cytoplasmic
protein required for caveola formation and function. Cell 132:
113–124
Abankwa D, Hanzal-Bayer MF, Ariotti N, Plowman SJ, Gorfe AA,
Parton RG, McCammon JA & Hancock JF (2008) A novel switch
region regulates H-ras membrane orientation and signal output.
EMBO J 27: 727–735
Abankwa D, Gorfe AA & Hancock JF (2008) Mechanisms of Ras
membrane organization and signalling: Ras on a rocker. Cell
Cycle 7: 2667–2673
Abankwa D, Gorfe AA & Hancock JF (2007) Ras nanoclusters:
molecular structure and assembly. Semin Cell Dev Biol 18: 599–
607
From left to right. Back row: Maja Solman, Camillo Guzman, Elina Siljamäki, Cristina
Oetken-Lindholm, Arafath Najumudeen, Alessio Ligabue and Olga Blaževitš. Front
row: Daniel Abankwa and Anja Mai.
40
41
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/index.php?id=1240
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 directs the Cell Imaging Core
at Turku Centre for Biotechnology and coordinates the nordic
network on Imaging in Biology and Medicine. She was appointed
to an Academy of Finland Research Fellow post from 2008 to
2013.
Personnel:
Postdoctoral researchers: Erika Freemantle, Ph.D., Artur Padzik,
Ph.D. Graduate Students: Justyna Zdrojewska, M.Sc., Emilia
Komulainen, M.Sc., Hasan Mohammed, M.Sc., Prasannakumar
Deshpande, M.Sc., Patrik Hollos, B.Sc., Hung Phuoc, M.Sc.,
Raghavendra Mysore, M.Sc., Undergraduate student: Dani
Flinkman, Behnoush Fourotan, Ravi Adusmalli. Technical staff:
Susanna Pyökäri.
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
42
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
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, CIMO, Magnus Ehrnrooth’s
Stiftelse, Suomen Kultuuri Rahasto.
43
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).
Björkblom B*, Padzik A*, Mohammad H, Westerlund N,
Komulainen E, Hollos P, Parviainen L, Papageorgiou AC, Iljin
K, Kallioniemi O, Kallajoki M, Courtney MJ, Mågård M, James
P, Coffey ET. JNK Phosphorylation of MARCKSL1 Determines
Actin Stability and Migration in Neurons and in Cancer Cells.
Molecular and Cellular Biology. 2012 32(17):3513-26. *equal
contribution.
Jonsdottir K, Zhang H, Jhagroe D, Skaland I, Slewa A, Björkblom
B, Coffey ET, Gudlaugsson E, Smaaland R, Janssen EA, Baak
JP. The prognostic value of MARCKS-like 1 in lymph nodenegative breast cancer. Breast Cancer Research and Treatment.
2012 ;135(2):381-90.
Mai, A., Veltel, S., Pellinen, T., Padzik, A., Coffey, E., Marjomäki, V.,
Ivaska, J. Competetive binding of Rab21 and p120RasGAP to
integrins regulates receptor traffic and migration. Journal of Cell
Biology. 194(2), 291-306, 2011.
Westerlund N, Zdrojewska J, Padzik A, Komulainen E, Björkblom B,
Rannikko E, Tararuk T, Garcia-Frigola C, Sandholm J, Nguyen L,
Kallunki T, Courtney MJ, Coffey ET. Phosphorylation of SCG10/
stathmin-2 determines multipolar stage exit and neuronal
migration rate. Nat Neurosci. 2011, 14(3):305-13.
Mai A, Veltel S, Pellinen T, Padzik A, Coffey E, Marjomäki V, Ivaska
J. Competitive binding of Rab21 and p120RasGAP to integrins
regulates receptor traffic and migration. J Cell Biol. 2011 Jul
25;194(2):291-306.
Matlawska-Wasowska K, Finn R, Mustel A, O’Byrne CP, Baird
AW, Coffey ET, Boyd A. The Vibrio parahaemolyticus Type III
Secretion Systems manipulate host cell MAPK for critical steps
in pathogenesis. BMC Microbiol. 2010 Dec 30;10:329.
Uusi-Oukari M, Kontturi LS, Coffey ET, Kallinen SA. (2010) AMPAR
signaling mediating GABA(A)R delta subunit up-regulation in
cultured mouse cerebellar granule cells. Neurochem Int.
Filén S, Ylikoski E, Tripathi S, West A, Björkman M, Nyström J,
Ahlfors H, Coffey E, Rao KV, 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 CW, Coffey ET, Davis RJ, Attisano
L. (2010) Microtubule stabilization by bone morphogenetic
protein receptor-mediated scaffolding of c-Jun N-terminal
kinase promotes dendrite formation. Mol Cell Biol. 30:22412250.
44
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 JC, Hongisto V, Herdegen T, Courtney MJ,
Coffey ET. (2008) All JNKs can kill, but nuclear localization is
critical for neuronal death. Journal of Biological Chemistry,
283:19704-13.
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, 285:1515-27.
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.
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(4):436-443.
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.,
Runeberg-Roos, 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.
45
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: 43354345.
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.
From top to bottom. Left side: Artur Padzik, Hung Phuoc, Eleanor Coffey, Susanna
Pyökäri, Dani Flinkman and Hasan Mohammad. Right side: Prasannakumar
Deshpande, Patrik Hollos, Justyna Zdrojewska and Erika Freemantle.
46
47
TRANSLATIONAL PROTEOMICS
Principal investigator:
Garry Corthals, Ph.D.
Address: Turku Centre for Biotechnology, BioCity, Tykistökatu 6,
FI-20521 Turku, Finland.
Tel. +358-2-333 8889, Fax. +358-2-2158808.
E-mail: garry.corthals@btk.fi
Biography:
Garry Corthals received his PhD in 1997 and has since worked in
the field of biomedical proteomics. He has held positions at the
Medical School, University of Washington, Seattle, the Garvan
Institute for Medical Research, Sydney, and Geneva University
Hospital and Medical Faculty. He is now leads a research group
in Translational Proteomics at the Turku Centre for Biotechnology
that focuses on developing and applying proteomics methods to
improve personalized therapies and to understand protein level
changes related to diseases primarily through the use of mass
spectrometry and bioinformatics. Amongst his publications and
books is the first book that appeared on Biomedical Applications in
Proteomics. Besides the research group Dr Corthals is the Director
of the Turku Proteomics Facility, is Chair of the Finnish Proteomics
and Metabolomics technology platform, the Nordic Quantitative
Proteomics network of research schools, the Nordic Signals
research network and the Nordic MS imaging network and Chairs
the new Developments Committee of the European Proteomics
Association (EuPA). His is also co-chair of the pan European
Imaging MS network.
Personnel:
Senior scientists: Anne Rokka, PhD; Dorota Muth-Pawlak, PhD;
Mimi Nguyen, PhD; Susumu Imanishi, PhD; Tanya Lukash, PhD;
Petri Kouvonen, PhD (visiting ETH Zurich 2011-2013)
Graduate students: Anni Vehmas, Olli Kannaste, Veronika Suni,
Darshana Kottahachchi, Thaman Chand, Avinash Yadav
Lab engineer: Arttu Heinonen
Technician: Pekka Haapaniemi
Undergraduate students: Santosh Thatikonda
Coordinator: Susanne Nees
Description of the project:
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
48
method of choice to discover, measure and characterize 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
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.
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, COST.
Collaborators:
Johanna Ivaska, Jukka Westermarck, Tiina Pakula (VTT), Laura
Ruohonen (VTT), Laura Elo, Tuula Nyman, Marko Pesu
Koch S, Scifo E, Rokka A, Trippner P, Lindfors M, Korhonen
R, Corthals G, Virtanen I, Lalowski M and Tyynelä J. (2013)
49
Cathepsin D deficiency induces cytoskeletal changes and affects
cell migration pathways in the brain. Neurobiol Dis. 50:107-119
Perdomo MF, Hosia W, Jejcic A, Corthals GL and Vahlne A. (2012)
Human serum protein enhances HIV-1 replication and upregulates the transcription factor AP-1. Proc Natl Acad Sci U S
A. 109(43):17639-17644.
McDonnell L, Andrén PE and Corthals GL. J Proteomics. (2012)
Imaging mass spectrometry: a user’s guide to a new technique
for biological and biomedical research. Preface. J Proteomics
75(16): 4881–4882.
McDonnell LA, Heeren RM, Andrén PE, Stoeckli M and Corthals
GL. (2012) Going forward: Increasing the accessibility of imaging
mass spectrometry. J Proteomics. 75(16):5113-5121.
Santos HM, Kouvonen P, Capelo JL and Corthals GL. (2012) Isotopic
labelling of peptides in tissues enhances mass spectrometric
profiling. Rapid Commun Mass Spectrom. 26(3):254-262.
ORGANISATION OF NEURONAL
SIGNALING PATHWAYS
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 BTK from 1998, he was appointed
from 2000 to a position at the A.I. Virtanen Institute, Kuopio and
from 2006 to BTK. He has been affiliated with the Cell Imaging Core
in Turku since its inception, and established and is director of 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: Peter Martinsson
Ph.D., Melero-Fernandez de Mera Ph.D., Ph.D, Olga Vergun Ph.D.;
Graduate students: Lili Li, M.Sc., Xijun Wang, M.Sc. Technician Aila
Seppänen;
From left to right. Back Row: Susumu Imanish, Olli Kannaste, Dorota Muth, Pekka
Haapaniemi, Elizabeth Nguyen, Susanne Nees, Darshana Kottahachchi and
Thaman Chand. Fron row: Arttu Heinonen, Garry Corthals, Anne Rokka and Tanya
Lukash.
50
Neuronal cells possess a complex architecture consisting
of multiple subcellular compartments. Disease states place
cells under stressful conditions. The p38 and JNK stressactivated 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
51
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 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 are combining these with libraries of RNAi
tools, expression plasmids and compounds. 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 facilities for live cell High-Content Analysis
(HCA), High-Throughput Microscopy (HTM) and the associated
liquid handling facilities, as well as 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). A second
imaging station with similar sample capacity, interfaced
with pipetting robot and plate reader, is under further
development. This nationally unique Biocentre Finland (BF)
infrastructure platform is supported by two BF networks. Our
52
group continues to establish assays permitting application
of HCA methods to primary cultured neurons, stem cells
and in vivo models. More details can be found via the links
at www.uef.fi/aivi/muic.
Funding:
The Academy of Finland, the photonics programme of the
th
Academy of Finland the EU 7 framework project “MEMOLOAD”,
The University of Eastern Finland, The Doctoral Programme in
Molecular Medicine.
Collaborators:
Eleanor Coffey and Tassos Papageorgiou (BTK, Åbo Akademi
and University of Turku), Denise Manahan-Vaughan (University of
Bochum), Mark Spaller (Brown University, Providence, RI), Antti
Poso and Jari Koistinaho (University of Eastern Finland) and Anita
Truttman (CHUV, Lausanne University Hospital).
Li L-L, Ginet V, Liu X, Vergun O, Tuittila M, Mathieu M, Bonny C,
Puyal J, Truttmann AC, Courtney MJ. The nNOS-p38MAPK
pathway is mediated by NOS1AP during neuronal death. J
Neurosci, in press.
Björkblom B, Padzik A, Mohammad H, Westerlund N, Komulainen
E, Hollos P, Parviainen L, Papageorgiou AC, Iljin K, Kallioniemi O,
Kallajoki M, Courtney MJ, Mågård M, James P, Coffey ET. c-Jun
N-terminal kinase phosphorylation of MARCKSL1 determines
actin stability and migration in neurons and in cancer cells. Mol
Cell Biol. 2012 Sep;32(17):3513-26.
D’Orsi B, Bonner H, Tuffy LP, Düssmann H, Woods I, Courtney MJ,
Ward MW, Prehn JH (2012) Calpains Are Downstream Effectors
of bax-Dependent Excitotoxic Apoptosis. J. Neurosci. 32:184758.
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. 14:305-13.
Yang H., Courtney, M.J., Martinsson, P., 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.,33:1647-55.
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, 873-80
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, 21676-85.
53
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-3β is critical for trophic
deprivation induced neuronal death. Mol. Cell. Biol. 28, 15151527.
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 p38α 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.
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 p38α 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.
54
STRUCTURAL BIOINFORMATICS
Principal Investigator:
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), Undergraduate
Student.
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 proteinligand 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 β-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,
55
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.
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 αC 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: 452-460.
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
“donor-acceptor-donor” edges of adenine and adenosinecontaining ligands. J. Mol. Biol. 333: 1025-1043.
56
DATA MINING AND MODELLING
Principal investigators:
Laura Elo, Ph.D.,
Adjunct Professor in Biomathematics,
Department of Mathematics and Statistics,
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, 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 Biomathematics at the Department of Mathematics
and Statistics, 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 EMBL Group Leader at FIMM.
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:
Marja Heiskanen, M.Sc.,
Teemu Daniel Laajala, M.Sc.,
Rolf Linden, M.Sc.,
Sebastian Okser, M.Sc.,
Tomi Suomi, M.Sc.,
Johannes Tuikkala, M.Sc.,
Heidi Vähämaa, M.Sc.
Undergraduate students:
Maria Jaakkola,
Anna Koskinen,
Sami Rannikko,
Harri Santa,
Fatemehsadat Seyednasrollah
We develop mathematical modelling methods and implement
computational data analysis tools for biological and biomedical
57
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.
Rissanen, J., Moulder, R., Lahesmaa, R., Nevalainen, O.S. (2012)
Pre-processing of Orbitrap higher energy collisional dissociation
tandem mass spectra to reduce erroneous iTRAQ ratios. Rapid
Commun. Mass Spectrom. 26: 2099-2104.
The large number of molecular components together with
high technical and biological variability can make it difficult to
extract pertinent biological information from background noise.
Therefore, computational models and tools are needed that
can effectively integrate, analyse and visualise 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.
Elo, L.L. and Schwikowski, B. (2012) Mining proteomic data for
biomedical research. Invited review in WIREs Data Mining Knowl.
Discov. 2: 1-13.
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 clinicallyoriented 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., 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.
Laajala, T.D., Corander, J., Saarinen, N.M., Mäkelä, K., Savolainen,
S., Suominen, M.I., Alhoniemi, E., Mäkelä, S.I., Poutanen, M.
and Aittokallio, T. (2012) Improved statistical modeling of tumor
growth and treatment effect in pre-clinical animal studies with
highly heterogeneous responses in vivo. Clin. Cancer Res. 18:
4385-4396.
58
Pahikkala, T., Okser, S., Airola, A., Salakoski, T. and Aittokallio, T.
(2012) Wrapper-based selection of genetic features in genomewide association studies through fast matrix operations.
Algorithms Mol. Biol. 7: 11.
Tuikkala, J., Vähämaa, H., Salmela, P., Nevalainen, O.S. and
Aittokallio, T. (2012) A multilevel layout algorithm for visualizing
physical and genetic interaction networks, with emphasis on
their modular organization. BioData Min. 5 2.
Nylund, C., Rappu, P., Pakula, E., Heino, A., Laato, L., Elo, L.L.,
Vihinen, P., Pyrhönen, S., Owen, G.R., Larjava, H., Kallajoki,
M. and Heino, J. (2012) Melanoma-associated cancer-testis
antigen 16 (CT16) regulates the expression of apoptotic and
antiapoptotic genes and promotes cell survival. PLoS One 7:
e45382.
Heiskanen, M.A. and Aittokallio, T. (2012) Mining high-throughput
screens for cancer drug targets - lessons from yeast chemicalgenomic profiling and synthetic lethality. Invited Focus Article in
WIREs Data Mining Knowl. Discov. 2: 263-272.
Tringham, M., Kurko, J., Tanner, L., Tuikkala, J., Nevalainen,
O.S., Niinikoski, H., Näntö-Salonen, K., Hietala, M., Simell,
O., Mykkänen, J. (2012) Exploring the transcriptomic variation
caused by the Finnish founder mutation of lysinuric protein
intolerance (LPI). Mol. Genet. Metab. 105: 408-415.
Lindén, R. O., Eronen, V.P. and Aittokallio T. (2011) Quantitative
maps of genetic interactions in yeast - Comparative evaluation
and integrative analysis, BMC Syst. Biol. 5: 45.
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.
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 pre-clinical carotid atherosclerosis
-The Cardiovascular Risk in Young Finns Study, PLoS Genet. 6:
e1001146.
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.
Elo, L.L., Mykkänen, J., Järvenpää, H., Nikula, T., Simell, S.,
Aittokallio, T., Hyöty, H., Ilonen, J., Veijola, J., Simell, T., Knip, M.,
59
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: 7076.
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.
Aittokallio, T. (2010) Dealing with missing values in large-scale
studies - microarray data imputation and beyond, Invited Review,
Brief. Bioinform. 11: 253-264.
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.
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.
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.
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
1990-1993 (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
60
61
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 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 differentiation-related 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).
62
Funding:
The Academy of Finland, TEKES, the European Union, the Finnish
Cancer Organizations, the Sigrid Jusélius Foundation, and the Åbo
Akademi Foundation.
Ferraris SE, Isoniemi K, Torvaldson E, Anckar J, Westermarck J,
Eriksson JE. (2012) Nucleolar AATF regulates c-Jun-mediated
apoptosis. Mol Biol Cell. 23(21):4323-32.
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 cellto-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).
63
Inhibition of Akt signaling by the lignan matairesinol sensitizes
prostate cancer cells to TRAIL-induced apoptosis. Oncogene
29: 898-908.
Söderström, T.S., Nyberg, S., Nieminen, M.I. and Eriksson, J.E.
(2005) CD95 capping is ROCK-dependent and dispensable for
apoptosis. J. Cell Sci. 118: 2211-2223.
Imanishi S.Y., Kouvonen P., Smått J.H., Heikkilä M., Peuhu E.,
Mikhailov A., Ritala M., Lindén M., Corthals G.L. & Eriksson
J.E. (2009). Phosphopeptide enrichment with stable spatial
coordination on a titanium dioxide coated glass slide. Rapid
Commun. Mass Spectrom. 23: 3661-3667.
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.
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: 1380-1391.
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.
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: 1278-1291.
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.
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.
64
From left to right. Back row: John Eriksson, Rajendran Senthil, Kimmo Isoniemi, Elin
Torvaldsson, Claire Hyder, Helenta Saarento Julia Lindqvist, Erik Niemelä and Yves
Nkizinkiko. Front row: Joanna Pylvänäinen, Alia Joko, Beata Padziewska, Fang
Chen, Tomoko Asaoka, Josef Gulmets and Ponnuswamy Mohana Sundaram.
65
EPIGENOMICS
David Hawkins, Ph.D.,
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/
Personnel:
Post-doctoral researchers: Kalyan Kumar Pasumarthy, Ph.D.,
Cristina Valensisi, Ph.D.
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 multipotency of stem cells. We are also investigating the transcriptional
regulation and unique signatures of cellular differentiation.
Funding:
BioCenter Finland, Academy of Finland
Collaborators:
Riitta Lahesmaa, Turku Centre for Biotechnology
Harri Lähdesmäki, 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.
From left to right: Cristina Valensisi and Kalyan Pasumarthy.
66
Alvarado D.M., Hawkins R.D., Bashiardes S., Veile R.A., Powder
K.E., Speck J., Warchol M.E. and Lovett M. (2011) An RNAiBased Screen of Transcription Factor Gene Pathways During
Sensory Regeneration in the Avian Inner Ear. J Neurosci. 31:
4535-4543.
67
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; ^Cocorresponding 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 sequencingbased 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:
476-486.
Hawkins R.,D†., Hon G.C†., Lee L.K., Ngo Q., Lister R., Pelizzola
M., Kuan S., Edsall L.E., Ye Z., Espinoza C., AntosiewiczBourget 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.
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-typespecific gene expression. Nature. 459: 108-112.
68
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,
email: 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 postdoctoral fellow at Cancer Research UK LIR 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.
Personnel:
Post-doctoral researchers: Elina Mattila, Ph.D.; Jeroen Pouwels,
Ph.D.; Emilia Peuhu, Ph.D.; Ghaffar Muharram, 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., Habib Baghirov, M.Sc. Research
assistant: Markku Saari, M.Sc (CIC, part-time). Technicians: Jenni
Siivonen, Laura Lahtinen, Petra Laasola (VTT, part-time)
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 and regulators of integrin activity to gain novel
insight into integrin signaling and traffic in cancer cells. Based on
these findings we are currently actively investigating these topics:
1) regulation of integrin activity by SHARPIN in cell migration,
development and cancer. 2) Co-operation between integrins
and receptor-tyrosine kinases like Met. 3) Integrin endo/exocytic
traffic in cancer cell invasion. 4) The functional role of vimentin and
adhesion in EMT. With all these projects we aim to understand
adhesion regulated signaling and the biological function of integrin
membrane traffic in human malignancies.
69
Arjonen, A., Alanko, J., Veltel, S., Ivaska, J. (2012) Distinct Recycling of
Active and Inactive β1 Integrins. Traffic Jan 5 [Epub ahead of print].
Pellinen, T., Rantala, J.K., Arjonen, A., Mpindi, J-P., Kallioniemi, O.
and Ivaska, J. (2012) A functional genetic screen reveals new
regulators of β1-integrin activity. J Cell Sci. 125:649-661.
Virtakoivu, R., Pellinen, T., Rantala, J.K., Perälä, M. and Ivaska, J.
(2012) Distinct roles of AKT isoforms in regulating β1-integrin
activity, migration and invasion in prostate cancer. Mol. Biol. Cell.
17:3357-3369.
Högnäs, G., Tuomi, S., Veltel, S., Mattila, E., Murumägi, A., Edgren,
H., Kallioniemi, O. and Ivaska, J. (2012) Cytokinesis failure due
to derailed integrin traffic induces aneuploidy and oncogenic
transformation in vitro and in vivo. Oncogene 31:3597-3606.
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.
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.
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.
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 α-subunits and suppresses integrin activity and invasion.
Oncogene 29:6452-6463.
From left to right: Jenni Siivonen, Antti Arjonen, Emilia Peuhu, Reetta Virtakoivu,
Laura Lahtinen, Ghaffar Muharram, Markku Saari, Riina Kaukonen, Elina Mattila,
Nicola De Franceschi, Jonna Alanko, Habib Baghirov, Pranshu Sahgal and Johanna
Ivaska
Tuomi, S., Mai, A., Nevo, J., Laine, JO, Vilkki, V., Öhman, TJ.,
Gahmberg, CG., Parker, PJ. and Ivaska, J. (2009) PKCε
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.
Mattila, E., Koskinen, K., Salmi, M. and Ivaska, J. (2008) Protein
tyrosine phosphatase TCPTP controls VEGFR-2 signalling. J.
Cell Sci. 121:3570-80.
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 173:767-80.
Mattila E., Pellinen, T., Nevo, J., Vuoriluoto, K. Arjonen, A. and Ivaska,
J (2005) Negative regulation of EGFR signalling via integrin α1β1mediated activation of protein tyrosine phosphatase TCPTP.
Nat. Cell Biol. 7: 78-85.
70
71
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 3338566, 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 2002-2007 he worked as a fellow of the Academy
of Finland. Currently he is appointed as a senior research fellow by
the medical faculty and is also a consultant at the department of
medical oncology and radiation therapy at Turku university hospital.
Personnel:
Post-doctoral fellow: Krista Rantanen, (PhD) Graduate students:
Heidi Högel, (M.Sc.), Petra Miikkulainen, (M.Sc.), Jonna Silen,
(M.Sc.), Pekka Heikkinen, (M.Sc.), Technicians: Taina Kalevo-Mattila
Hypoxia (reduced O2 tension) is the main tissue damaging factor
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 hypoxia-inducible
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 some 200 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. For example, we
have shown that the PHD3 isoform selectively regulates cell cycle
progression under hypoxia. Moreover, we have demonstrated a strong
interplay between the oxygen sensing and autophagy pathways for
example through p62/SQSTM1. Besides studying several aspects
of molecular and cellular biology of the hydroxylases, we study the
clinical importance of these factors having a particular interest in renal
clear cell and other carcinoma progression.
Funding:
The Academy of Finland, Sigrid Juselius Foundation, Finnish Cancer
Unions. Turku University Hospital (EVO), Turku University Foundation
72
Collaborators:
Peter Ratcliffe and Chris Pugh (Oxford University, UK), Eric Metzen
(Luebeck University, Germany), Heikki Minn (PET Centre, Turku
University Hospital)
Rantanen K., Pursiheimo J., Högel H., Miikkulainen P., Sundström
J. and, Jaakkola P.M. (2012). p62/SQSTM1 regulates hypoxia
response by attenuating normoxic PHD3 activity through aggregate
sequestration and enhanced degradation. J Cell Sci. Jan 23.
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(11):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(14):5984-93
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(6):3740-9. Epub 2009 Dec 1.
Pursiheimo J., Rantanen K., Heikkinen P.T., Johansen T.,
Jaakkola P.M. (2009). Hypoxia-activated autophagy accelerates
degradation of SQSTM1/p62. Oncogene, 28(3):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(5): 2231-40.
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(4):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
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. Targeting of HIF-alpha
to the von Hippel-Lindau ubiquitylation complex by O2-regulated
prolyl hydroxylation. (2001) Science 292; 468-72.
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.,
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.
Pursiheimo, J., Taskén, K., Jalkanen, M. and Jaakkola, P.
Involvement of Protein Kinase A in FGF-2 Activated Transcription.
(2000) Proc. Natl. Acad. Sci. USA, 97(1): 168–173.
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. Hypoxia inducible factor-alpha binding and ubiquitylation
by the von hippel-lindau tumor suppressor protein. (2000) J.
Biol. Chem. 275: 25733-25741.
73
From left to right: Back row: Anssi Rantasalo (guest), David Malatinszky, Pauli Kallio, Patrik Jones, Matts Nylund, Paulina Bartasun, Veronica Carbonell, Kati Thiel and Linda Vuorijoki. Front row: Tomas Zavrel
(guest), Hariharan Dandapani, Kalim Akhtar, Andras Pasztor, Sanna Kreula and Jari Kämäräinen.
74
BIOENERGY GROUP
Patrik R. Jones, Ph.D., Affiliated Group Leader at CBT
Department of Biochemistry and Food Chemistry, University of Turku,
Tykistökatu 6B, 4krs, FI-20520 Turku, Finland,
Tel.: +358-2-3337913,
Email: patjon@utu.fi,
Homepage: http://www.btk.fi/index.php?id=114
Biography:
Patrik R. Jones, born in Sweden 1968, is an Australian citizen that
carried out his undergraduate studies in Uppsala University and
University of Adelaide. He completed his PhD in Plant Biochemistry
at University of Adelaide (P.B. Høj) and the Royal Veterinary &
Agricultural University in Copenhagen (B. L. Møller). He did 2-year
post-doc’s in the laboratory of Kazuki Saito (Chiba Univ.) and the
Australian Wine Research Institute, followed by 3.5 years as P.I. at
a 100% for-profit company in Japan where he developed synthetic
model systems for evaluation of fermentative H2-production.
In 2009, he moved to University of Turku as a member of the
Collegium for Science and Medicine and Principal Investigator of
the Bioenergy group. In 2010 he was awarded an ERC Starting
Grant and the EU FP7 9-partner collaborative project DirectFuel
(http://www.directfuel.eu/) as coordinator. In Turku, the aim is to
develop photobiological systems for production of engine-ready
transport fuels using sunlight, H2O and CO2 as substrate.
Personnel:
Seniors scientists: Kalim Akhtar, Ph.D., Matts Nylund, Ph.D. Postdoctoral researchers: Pauli Kallio, Ph.D., Fernando Guerrero, Ph.D.
Graduate students: Veronica Carbonell, M.Sc., Jari Kämäräinen,
M.Sc., Andras Pasztor, M.Sc., Francy El Souki, M.Sc., Linda
Vuorijoki, M.Sc., Sanna Kreula, M.Sc. Technicians: Katie Thiel,
M.Sc. Undergraduate students: Hariharan Dapandani, M.Sc.
Our research group is pursuing applied and fundamental projects
with the aim to contribute towards the development of renewable
fuel production using autotrophic and heterotrophic prokaryotes.
Although the ultimate objective is to contribute towards application,
the majority of our research is better described as fundamental.
Even fuel pathway engineering operates far from practical reality,
with a focus on understanding factors that influence pathway flux
in model systems. Likewise, although our group currently is named
‘Bioenergy Group’ our research is best summarized as Engineering
and Understanding Prokaryotic Metabolism.
We are developing metabolic pathways for renewable fuel
production and optimizing host metabolism to favor those
pathways. We have selected fuels that potentially can be directly
separated from the process: Short- to medium-chain alkanes
and H2. The engineering is carried out in two prokaryotic model
systems: Escherichia coli and Synechocystis sp. PCC6803. Also
renewable fertilizer is targeted in recent projects.
To aid the engineering, we are carrying out targeted prospecting
for potential enzymes and also studying what factors influence
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their functionality. In order to engineer prokaryotic metabolism
we are studying how metabolism is regulated, in both E. coli and
Synechocystis sp. PCC 6803. This includes the regulation of
NADP(H) metabolism and the assembly and repair of iron-sulfur
clusters. These studies are complemented by computational
analysis of multi-level networks and stoichiometry. In collaboration
with the group of Filip Ginter we are also developing the use of
species-independent meta network analysis and methods to
integrate distinct data-types.
Funding:
The Academy of Finland project PhotoBioH2, Nordic Energy
Research AquaFEED project, EU FP7 collaborative projects DEMA
and DirectFuel, EU FP7 Marie Curie training network PHOTO.
COMM and ERC Starting project PhotoBioFuel.
Collaborators:
Within the DirectFuel consortium we have important collaborations
ongoing with the groups of Ralf Steuer (Humboldt Univ. Berlin),
Ladislav Nedbal (Global Change Research Centre, Czech Republic),
Neil Marsh (Univ. Michigan), Wolfgang Hess (Univ. Freiburg) and
Nigel Scrutton (Univ. Manchester). Without joint funding, locally
in Turku, the groups of Ginter (UTU), Petre (ÅA) and Aitokallio
(FIMM). Outside of Finland, we currently have active projects
ongoing with the following collaborators without joint funding:
Guy Hanke (Osnabruck Univ.), John Golbeck (Penn State), Toivo
Kallas (UW Oshkosh), Sofie Van Landeghem (Ghent Univ.), Ron
Milo (Weizmann Institute), Patrick Hallenbeck (Univ. Montreal) and
Alison Smith (Univ. Cambridge).
Akhtar, M.K., Turner, N.J., Jones, P.R. (2012). Carboxylic acid
reductase is a versatile enzyme for the conversion of fatty acids
into fuels and chemical commodities. Proc. Natl. Acad. Sci.
USA, doi: 10.1073/pnas.1216516110
Guerrero, F., Carbonell, V., Cossu, M., Correddu, D., Jones,
P.R. (2012) Ethylene Synthesis and Regulated Expression of
Recombinant Protein in Synechocystis sp. PCC 6803. PLOS
One 7(11): e50470. doi:10.1371/journal.pone.0050470.
Kämäräinen, J., Knoop, H., Stanford, N.J., Guerrero, F., Akhtar,
M.K., Aro, E.M., Steuer, R., Jones, P.R. (2012) Physiological
tolerance and stoichiometric potential of cyanobacteria for
hydrocarbon fuel production. J. Biotechnol. 162, 67-74.
Eser, B.E., Das, D., Jaehong, H., Jones, P.R., and Marsh, E.N.G.
(2011) Oxygen-Independent Alkane Formation by Non-Heme
Iron-Dependent Cyanobacterial Aldehyde Decarbonylase:
Investigation of Kinetics and Requirement for an External
Electron Donor. Biochem. 50, 10743Akhtar, M.K. and Jones, P.R. (2009) Construction of a synthetic
YdbK-dependent pyruvate:H2 pathway in Escherichia coli
BL21(DE3). Metabol. Eng. 11, 139-147.
MITOSIS AND DRUG DISCOVERY
Marko Kallio, Ph.D. Docent, Principal Scientist and Team Leader,
Affiliated Group Leader at CBT, VTT Biotechnology for Health and
Wellbeing,
Itäinen Pitkäkatu 4C, FI-20521, Turku,Finland and
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. During his early career
Dr. Kallio was in three laboratories; 1996-98 as a Post-doctoral
fellow in the laboratory of Prof. Gary Gorbsky (Univ. Virginia, USA),
1998-2000 as a Senior Post-doctoral fellow in the laboratories of
Prof. John Eriksson and Prof. Lea Sistonen (Univ. Turku, Finland)
and 2000-2003 as an Assistant Research Professor at the
University of Oklahoma HSC, USA. His research group received
a Marie Curie Excellence grant for 2004-2008. In early 2004, Dr.
Kallio moved back to Finland and has since been a Team leader at
VTT Biotechnology for Health and Wellbeing, a research institute
affiliated with the University of Turku.
Personnel:
Post-doctoral researchers: 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.
Under-graduate student: Sofia Pruikkonen
Description of the projects:
The Mitosis and Drug Discovery Team investigates mechanisms
of cell division in somatic cells and in meiotic systems. Study of
cell division errors may help to explain origin of genomic instability
and can lead to discovery of novel therapeutic possibilities and
diagnostics opportunities in the fight against cancer. We are
especially interested of conditions that suppress cancer cell’s
viability as a consequence of premature inactivation of the spindle
assembly checkpoint (SAC), a conserved signalling pathway which
monitors the fidelity of mitosis. In our main projects, we are working
to validate the mechanism of action of our putative anti-Hec1
compounds and SAC targeting miRNAs that effectively perturb
normal mitosis and trigger cancer cell killing in cell culture assays.
Funding:
VTT Technical Research Centre of Finland, Academy of Finland,
TuBS and DDGS Graduate Schools,
Bayer Schering Pharma AG
Collaborators:
Gary Gorbsky (OMRF, Oklahoma USA), Todd Stukenberg (Univ.
Virginia, USA), Lauri Aaltonen (Biomedicum Helsinki), Lea Sistonen
(Turku Centre for Biotechnology), Pirkko Härkönen (Univ. Turku).
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77
Salmela AL, Pouwels J, Mäki-Jouppila J, Kohonen P, Toivonen
P, Kallio L, and Kallio M. (2012) Novel pyrimidine-2,4-diamine
derivative suppresses the cell viability and spindle assembly
checkpoint activity by targeting Aurora kinases. Carcinogenesis,
in press.
Nilsson EM, Brokken LJ, Narvi E, Kallio MJ, Härkönen PL. (2012)
Identification of fibroblast growth factor-8b target genes
associated with early and late cell cycle events in breast cancer
cells. Mol Cell Endocrinol, 358: 104-15
Salmela AL, Pouwels J, Kukkonen-Macchi A, Waris S, Toivonen
P, Jaakkola K, Mäki-Jouppila J, Kallio L, Kallio MJ. (2012) The
flavonoid eupatorin inactivates the mitotic checkpoint leading to
polyploidy and apoptosis. Exp Cell Res, 318: 578-92
Niittymäki I, Gylfe A, Laine L, Laakso M, Lehtonen HJ, Kondelin
J, Tolvanen J, Nousiainen K, Pouwels J, Järvinen H, Nuorva
K, Mecklin JP, Mäkinen M, Ristimäki A, Ørntoft TF, Hautaniemi
S, Karhu A, Kallio MJ, Aaltonen LA. (2011) High frequency of
TTK mutations in microsatellite-unstable colorectal cancer
and evaluation of their effect on spindle assembly checkpoint.
Carcinogenesis, 32: 305-11.
Vuoriluoto M, Laine LJ, Saviranta P, Pouwels J, Kallio MJ. (2011)
Spatio-temporal composition of the mitotic Chromosomal
Passenger Complex detected using in situ proximity ligation
assay. Mol Oncol, 5: 105-11.
Kukkonen-Macchi A, Sicora O, Kaczynska K, Oetken-Lindholm C,
Pouwels J, Laine L, and Kallio MJ. (2011) Loss of p38gamma
MAPK induces pleiotropic mitotic defects and massive cell
death. J Cell Sci, 124: 216-27.
From left to right: Mahesh Tambe, Leena Laine, Jenni Mäki-Jouppila, Sofia
Pruikkonen, Marko Kallio, Elli Narvi and Sebastian Winsel.
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MOLECULAR SYSTEMS
IMMUNOLOGY AND STEM CELL
BIOLOGY
Riitta Lahesmaa, M.D., Ph.D., Professor,
Tykistökatu 6A, FI-20521 Turku, Finland.
Tel. +358-2-333 8601, Fax. +358-2-333 8000.
Email: riitta.lahesmaa@btk.fi, homepage: www.btk.fi
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 BioCity Turku
Research Program “Turku Centre for Systems Biology” since 2000.
Personnel:
Senior scientists: Jane Zhi Chen, Ph.D., Laura Elo-Uhlgren, Ph.D.,
Riikka Lund, Ph.D., Robert Moulder, Ph.D., Omid Rasool, Ph.D.,
Jussi Salmi, Ph.D.
Post-doctoral researchers: Kanchan Bala, Sanna Edelman, Ph.D.,
Saara Hämälistö, Ph.D., Sari Lehtimäki, Ph.D., Elizabeth Ngyen,
Ph.D., Emaheswa Reddy, Ph.D., Ubaid Ullah, Ph.D., Viveka Öling,
Ph.D.
Visiting Scientists: David R. Goodlett, Ph.D., Professor, Finnish
Distinguished Professor, 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., 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.
Technicians: Bogata Fezazi, Marjo Hakkarainen, Sarita Heinonen,
Päivi Junni, Elina Pietilä
Undergraduate students: Krista Maurinen, Johanna Myllyviita,
Lotta Oikari, Anna Rajamäki
Our research group belongs to the new “Centre of Excellence
on Molecular Systems Immunology and Physiology” Academy of
Finland selected 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
80
and systems biology to reveal molecular mechanisms of cell
signaling, transcriptional and epigenetic programs that determine
cell differentiation and fate. These approaches are exploited to
understand molecular mechanisms of human immune mediated
diseases and certain types of cancer to provide novel therapeutic
means to modulate harmful cellular and immune responses.
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. Importantly, we identified for the first
time STAT6 target genes on a genome wide scale in human CD4+ T
cells - only small fraction of which were previously known to be STAT6 regulated. This study, published in Immunity, revealed that in human
surprisingly high proportion, up to 80% of IL-4 induced response is
STAT6 regulated revealing several new candidates for therapeutic
intevention (Elo L et al. 2010). This was the first study to identify
any STAT targets in human lymphocytes on a genome wide scale
(O’Shea et al. 2011). Our studies on IL-4 R signaling in lymphocytes
also resulted in identification of new IL4R/STAT-6 regulated proteins
in human and mice as well as mechanistic studies on their molecular
functions (Aflakian N, et al. 2009, Moulder R. et al. 2010, Tripathi
et al. 2011, Tuomela S. et al. 2009, Cho CH et al. 2009). We also
identified for the first time on a genome wide scale genes engaged
during the early stages of human Th17 cell specification (Tuomela
et al. 2012). 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, Ullah et al. 2012, Äijö et al. 2012). Elucidating
their functions further we discovered that ATF3, PIM kinases and
SATB1 are important regulators of human Th cell differentiation.
ATF3 and PIM kinases promote Th1 differentiation (Filen S et al.
2010, Tahvanainen et al. 2012) whereas SATB1 regulates multiple
genes during early Th cell differentiation (Ahlfors et al. 2010).
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 (Lund et al. 2012a). Our recent
results based on the use of high resolution microarray technology
demonstrate that it is essential to monitor 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
81
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.
Again, the results suggested that the whole genome analysis should
be included also as part of quality control of iPS cell lines to ensure
that these cells remained genetically normal after the reprogramming
process, before their use for studies and/or clinical applications.
(Hussein S, et al. 2011). A novel high-througghput karyotyping assay
was developed for this purpose (Lund et al. 2012b).
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. 2012).
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 β cell specific autoantibodies. Clinical
T1D occurs when 80-90% of the β cells have been destroyed. At this
point T1D patient is dependent on a 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
a significant reduction in the health care costs.
Our objective is to study molecular mechanisms of T1D and to discover
molecular markers that 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 of the data showed systematic differential expression
of 520 probesets. A network-based analysis revealed then 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 transciptomics, proteomics and integrating the data
with our previous metbolomics results (Oresic et al. 2008).
Funding:
The Academy of Finland, The National Technology Agency of
Finland (TEKES), 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),
82
Sanjeev Galande (IISER, Pune, India), Heikki Hyöty (U. Tampere),
Mikael Knip (U. Helsinki), Harri Lähdesmäki (Aalto University, CBT),
David Goodlett (University of Washington, Seattle, WA, USA and a
FiDiPro in CBT), Matej Oresic (VTT Technical Research Centre of
Finland, Turku, CBT), 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)
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.
Benson MJ, Aijö T, Chang X, Gagnon J, Pape UJ, Anantharaman
V, Aravind L, Pursiheimo JP, Oberdoerffer S, Liu XS, Lahesmaa
R, Lähdesmäki H, Rao A. (2012) Heterogeneous nuclear
ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA
polymerase II, 2 (ELL2) are regulators of mRNA processing in
plasma cells. Proc Natl Acad Sci U S A. 109: 16252-16257.
Cho SH, 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 LL#, Järvenpää H#, Tuomela S#, Raghav S#, Ahlfors H, Laurila
K, Gupta B, Lund RJ, Tahvanainen J, Hawkins RD, Orešič M,
Lähdesmäki H, Rasool O, Rao KVS*, 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 LL*, 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 JJ, Filén S, Moulder R, Tuomela S, Ahlfors H, West A,
Kouvonen P, Kantola S, Björkman M, Katajamaa M, Rasool
O, Nyman TA, 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 KVS, 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 KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho
A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin
SH, Rodig SJ, Daley GQ, Rao A. (2011) Tet1 and tet2 regulate
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20121015_0051.jpg
From left to right: Riitta Lahesmaa, Ida Koho, Anne Lahdenperä, Essi Laajala, Saara Hämälistö, Viveka Öling, Elisa Närvä, Lotta Oikari, Robert Moulder, Jussi Salmi, Kartiek Kanduri, Santosh Boshale, Nelly
Rahkonen, Omid Rasool, Päivi Junni, Sarita Heinonen, Moin Mohd Khan, Jane Chen Zhi, Subhash Tripathi, Marjo Hakkarainen, Minna Kyläniemi, Tapio Lönnberg and Mirkka Heinonen.
5-hydroxymethylcytosine production and cell lineage specification
in mouse embryonic stem cells. Cell Stem Cell 8:200-13.
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.
Lund RJ, Närvä E, Lahesmaa R. (2012) Genetic and epigenetic
stability of human pluripotent stem cells. Nat Rev Genet. 13:732744. Review.
Lund R*, Pykäläinen M*, Naumanen T, Dixon C, Chen Z, Ahlfors H,
Tuomela S, Tahvanainen J, Scheinin J, Henttinen T, Rasool O,
Lahesmaa R. (2007) Genome wide identification of Novel Genes
Involved in Early Th1 and Th2 Cell Differentiation. J. Immunol
178:3648-3660.
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 HD, Benvenisty N, Andrews PW, 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 MR, Lund R, Pursiheimo JP, Nästi J,
Autio R, Rasool O, Denessiouk K, Lähdesmäki H, Rao A, Lahesmaa
R. (2012) 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. 30:452-460.
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. 2008 205:2975-2984.
O’Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y.
(2011) Genomic views of STAT function in CD4(+) T helper cell
differentiation. Nat Rev Immunol. 11:239-250.
Tahvanainen J, Kallonen T, Lähteenmäki H, Heiskanen KM,
Westermarck J, Rao KV, Lahesmaa R. (2009) PRELI is a
mitochondrial regulator of human primary T helper cell apoptosis,
STAT6 and Th2 cell differentiation. Blood, 113:1268-1277.
Tahvanainen J, Kyläniemi MK, Kanduri K, Gupta B, Lähteenmäki
H, Kallonen T, Rajavuori A, Rasool O, Koskinen PJ, Rao KV,
Lähdesmäki H, Lahesmaa R. (2012) Proviral integration site for
Moloney murine leukemia virus (PIM) kinases promote human T
helper 1 cell differentiation. J Biol Chem. 2012 Dec 3.
Tuomela S, Salo V, Tripathi SK, Chen Z, Laurila K, Gupta B, Äijö
T, Oikari L, Stockinger B, Lähdesmäki H, Lahesmaa R. (2012)
Identification of early gene expression changes during human
Th17 cell differentiation. Blood. 119: e151-160.
Aijö T, Edelman S, Lönnberg T, Larjo A, Kallionpää H, Tuomela S,
Engström E, Lahesmaa R, Lähdesmäki H. (2012) An integrative
computational systems biology approach identifies differentially
regulated dynamic transcriptome signatures which drive the
initiation of human T helper cell differentiation. BMC Genomics
13: 572.
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COMPUTATIONAL SYSTEMS
BIOLOGY
Harri Lähdesmäki, D.Sc. (Tech), Assistant Professor (tenure track),
Academy Research Fellow, 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.
Tel. +358 9 47001, Fax. +358 9 470 23277,
E-mail: harri.lahdesmaki@aalto.fi, www-page:
http://users.ics.tkk.fi/harrila/research/
Biography:
Harri Lähdesmäki (b. 1977) graduated in bionformatics from
Tampere University of Technology in 2005.
Personnel:
Post-doctoral researchers: Jukka Intosalmi, Kirsti Laurila
Graduate students: Timo Erkkilä, Kartiek Kanduri, Lingjia Kong,
Essi Laajala, Antti Larjo, Maia Malonzo, Henrik Mannerström, Kari
Nousiainen, Maria Osmala, Tarmo Äijö
Undergraduate students: Juhani Kähärä, Sini Rautio, Juhi Somani
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.
Funding:
Academy of Finland, EU FP7, EraSysBio+, Tekes, Aalto University,
Emil Aaltonen Foundation, FICS and TISE graduate schools.
Collaborators:
Prof. Riitta Lahesmaa (University of Turku), Prof. Matej Orešič (VTT
Technical Research Centre of Finland), Prof. Mikael Knip (University
of Helsinki), Prof. Olli Simell (Hospital District of Southwest Finland)
Benson MJ, Äijö T, Chang X, Gagnon J, Pape UJ, Anantharaman
V, Aravind L, Pursiheimo J-P, Oberdoerffer S, Liu XS, Lahesmaa
R, Lähdesmäki H and Rao A. (2012) Heterogeneous nuclear
ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA
polymerase II, 2 (ELL2) are regulators of mRNA processing in
plasma cells. Proceedings of the National Academy of Sciences
of the USA, in press
Tuomela S, Salo V, Tripathi SK, Chen Z, Laurila K, Äijö T, Gupta B,
Oikari L, Stockinger B, Lähdesmäki H and Lahesmaa R. (2012)
Identification of early gene expression changes during human
Th17 cell differentiation. Blood, Vol. 119, No. 23, pp. e151-160.
Lehmusvaara S, Erkkilä T, Urbanucci A, Jalava S, Seppälä J, Kaipia
A, Kujala P, Lähdesmäki H, Tammela TLJ and Visakorpi T. (2012)
Goserelin and bicalutamide treatments alter the expression of
microRNAs in prostate. The Prostate, in press.
Lehmusvaara S, Erkkilä T, Urbanucci A, Waltering K, Seppälä
J, Tuominen V, Isola J, Kujala P, Lähdesmäki H, Kaipia A,
Tammela TLJ and Visakorpi T. (2012) Chemical castration and
antiandrogens induce differential gene expression in prostate
cancer. The Journal of Pathology, Vol. 227, No. 3, pp. 336--345.
Urbanucci A, Sahu B, Seppälä J, Larjo A, Latonen LM, Waltering
KK, Tammela TLJ, Vessella RL, Lähdesmäki H, Jänne OA
and Visakorpi T. (2012) Overexpression of androgen receptor
enhances the binding of the receptor to the chromatin in prostate
cancer. Oncogene, Vol. 31, No. 17, pp. 2153-2163.
Närvä E, Rahkonen N, Emani MR, Lund R, Pursiheimo J-P, Nästi
J, Autio R, Rasool O, Denessiouk K, Lähdesmäki H, Rao A and
Lahesmaa R. (2012) 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, Vol. 30,
No. 3, pp. 452-460.
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(5): e20059, 2011.
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(20):2571-2577.
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(6):727-862.
Selected recent publications:
Äijö T, Edelman S, Lönnberg T, Larjo A, Järvenpää H, Tuomela
S, Engström E, Lahesmaa R and Lähdesmäki H. (2012) An
integrative computational systems biology approach identifies
lineage specific dynamic transcriptome signatures which
drive the initiation of human T helper cell differentiation. BMC
Genomics, 13:572.
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CELL CULTURE MODELS FOR
TUMOR CELL INVASION AND
EPITHELIAL PLASTICITY
Matthias Nees, Ph.D., Docent for Genetics Affiliated Group
Leader at CBT
University of Turku, VTT Medical Biotechnology.
Itäinen Pitkäkatu 4C, FI-20520 Turku, Finland
Tel. +358-40-8314 839, Fax. +358-2 2840
Biography:
Matthias Nees (b. 1966) graduated from the University of Heidelberg,
Germany in 1993 for work in the field of head & neck cancers.
He received his Ph.D. in 1997 from the German Cancer Research
Center in Heidelberg, for work on Human Papillomaviruses (HPV).
He did post-doctoral research at the National Institutes of Health
(NCI, 1997-2001), and EMBL/Heidelberg University (2002 - 2005).
He is currently a principal investigator and team leader at VTT
Medical Biotechnology.
Personnel:
Post-doctoral researchers: Ville Härmä, Malin Åkerfelt
Graduate students: Ilmari Ahonen
Technicians: Pauliina Toivonen, Johannes Virtanen
Undergraduate students: Mrinal Mishra, Chamudeesvari
Simvaranan
Over the past years, our group (located at VTT, Pharmacity)
has systematically established a panel of organotypic, threedimensional cell- and tissue culture platforms for epithelial
cancers (focus on breast, prostate and ovarian carcinomas).
We have successfully utilized these models in both academic
and custom research applications. Generally, all of our
platforms aim to faithfully recapitulate the complex histology
and texture, epithelial differentiation, extracellular matrix (ECM)
and microenvironment (TME) of human cancer tissues, but also
their often extreme heterogeneity and dynamic. These aspects
are only poorly covered - if at all - by standard 2-dimensional
or monolayer culture on plastic. Most importantly, our 3D
platforms are thoroughly standardized and miniaturized, allowing
reproducible experimentation on a previously unprecedented
scale. Assays can be performed in 96- and 384-well plates,
using plate-based high-content readers (IncuCyte, PE Envision,
PE Operetta) for rapid experimental readout, or confocal
spinning-disc microscopy for more detailed imaging. Imaging
can be performed using a panel of methods, for example in
real-time, live cell settings (using fluorochromes and reactive
dyes), and subsequently analysed using end-point assays on
fixed multicellular structures or spheroids. End-point assays
are assisted by the use of suitable biomarkers and antibodies
for multiplex immune fluorescence, pathway-specific molecule
drugs, 3D siRNA transfection protocols, or specific reporter
constructs (LiveAct; small GTPases, etc). In both approaches,
88
the functional readout is mainly based on morphometric nature
and utilizes the phenotypic evaluation of spheroid structures by
microscopy; as a consequence VTT has developed the AMIDA
software package for automated image analyses that allows
rapid segmentation of large numbers of confocal image stacks,
together with statistical & machine learning solutions for the
subsequent data normalization and interpretation. Thus, our
approach strives to combine classic high-content screening
efforts (batch segmentation and analysis of image content) with
laboratory automation protocols (robotics) from high throughput
screening.
Morphological changes in the shape, size and morphology
tumour organoid have been demonstrated by us and others to
closely correlate with different stages of tumour histology and
pathological grading. In particular, dynamic phenotypic changes
(such as tumour cell invasion) are predictive for patient outcome.
Scientifically, we mainly address the mechanisms and molecular
pathways involved in the maintenance and loss of tissue
organization (homeostasis) and epithelial differentiation, which
is of surprisingly dynamic nature. Both the TME and ECM play
decisive roles in the regulation of tumour spheroid morphology.
Nevertheless, mature and well-differentiated structures are often
of only metastable nature. The most aggressive tumour cells can
undergo a spontaneous switch to invasive growth, demonstrating
the remarkable plasticity of epithelial tumours. We have explored
the functional role of proteases, G-protein coupled receptors
and down-stream signalling pathways in this decision-making
process, which could be a prerequisite for the formation of local or
distant metastases. Morphological switches may also transform
collective into single-cell patterns of invasion, or epithelial versus
mesenchymal modes of motility. Also these can be specifically
addressed with our models.
Most recently, we have started to develop 3D co-culture platforms
with stromal fibroblasts and cancer-associated (myo-)fibroblasts
(CAFs). These recapitulate additional, very critical aspects of
complex tumor biology (such as the role of the TME), and have
been thoroughly standardized and miniaturized as well. As with
simple 3D cultures, the goal here is to most faithfully recapitulate
tumour heterogeneity and dynamic processes, and to provide tools
for their experimental evaluation.
Funding:
The Academy of Finland (with Department of Biotechnology/India),
VTT, University of Turku, EU Innovative Medicines Initiative (IMI), EU
7th framework, K. Albin Johansson Foundation
Collaborators:
List your key collaborators as follows: Lea Sistonen (Åbo Akademi),
Pirkko Härkönen ( U. Turku), Olli Kallioniemi (FIMM), Varda Rotter
(Weizmann Institute of Science, Rehovot/Israel), Markku Kallajoki
(University Hospital Turku), Franz X. Bosch (Heidelberg University),
Roland Grafström/Bengt Fadeel (Karolinska Institute)
Björkman M., Östling 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., Nees M.: Systematic
89
knockdown of epigenetic enzymes identifies a novel histone
demethylase PHF8 overexpressed in prostate cancer with an
impact on cell proliferation, migration and invasion. Oncogene.
2012 Jul 19;31(29):3444-56.
Härmä V., Knuuttila M., Virtanen J., Mirtti T., Kohonen P., Kovanen
P., Happonen A., Kaewphan S., Ahonen I., Kallioniemi O.,
Grafström R., Lötjönen J., Nees M.: Lysophosphatidic acid
and sphingosine-1-phosphate promote morphogenesis and
block invasion of prostate cancer cells in three-dimensional
organotypic models. Oncogene. 2012 Apr 19;31(16):2075-89.
Härmä V., Virtanen J., Mäkelä R., Happonen A., Mpindi J.P.,
Knuuttila M., Kohonen P., Lötjönen J., Kallioniemi O., Nees M.:
A comprehensive panel of three-dimensional models for studies
of prostate cancer growth, invasion and drug responses. PLoS
One. 2010 May 3;5(5):e10431.
Björkman M., Rantala J., Nees M., Kallioniemi O.: Epigenetics of
prostate cancer and the prospect of identification of novel drug
targets by RNAi screening of epigenetic enzymes. Epigenomics.
2010 Oct;2(5):683-9.
Rantala J.K., Mäkelä R., Aaltola A.R., Laasola P., Mpindi J.P., Nees
M., Saviranta P., Kallioniemi O.: A cell spot microarray method
for production of high density siRNA transfection microarrays.
BMC Genomics. 2011 Mar 28;12:162.
COMPLEX BIOSYSTEMS MODELING
Matti Nykter, D. Sc. (Tech), Professor,. Affiliated Group Leader at CBT,
Institute of Biomedical Technology, University of Tampere
Biokatu 8 (Finn-Medi 2), 33520 Tampere, Finland
Tel. +358-40-8490651.
Email: matti.nykter@uta.fi
Home page: http://www.uta.fi/ibt/institute/research/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 2004-2005, and as a post-doctoral research at
the Institute for Systems Biology, Seattle, USA during 2007-2009.
From 2010 till 2012 he was a group leader at the Department
of Signal Processing at Tampere University of Technology. From
beginning of 2013 he is a professor of bioinformatics at the
Institute of Biomedical Technology, University of Tampere. His
research interests are focused on development and application
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, Sergei
Häyrynen, Ville Kytölä, Liisa-Ida Sorsa, Aleksi Kallio.
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. 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
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91
apply computational approach to uncover recipes for cell type
reprogramming experiments.
Funding:
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 (University of Eastern Finland), Olli YliHarja (Tampere University of Technology).
Parker B.C., Annala M., Cogdell D., Granberg K., Sun Y., Ji P.,
Gumin J., Zheng H., Hu L., Li X., Yli-Harja O., Haapasalo H.,
Visakorpi T., Liu X., Liu C.-G., Sawaya R., Fuller G.N., Chen
K., Lang F.L., Nykter M., and Zhang W. (2013) FGFR3-TACC3
fusion escapes miR-99a regulation and promotes tumorigenesis
in glioblastoma. Journal of Clinical Investigations, 123(2).
Moore L.M., Kivinen V., Liu Y., Annala M., Cogdell D., Liu X.,
Liu C.G., Sawaya R., Yli-Harja O., Shmulevich I., Fuller G.N.,
Zhang W., Nykter M. (2012) Transcriptome and Small RNA
Deep Sequencing Reveals Deregulation of miRNA Biogenesis in
Human Glioma. J Pathol (in press).
Holmes K.M., Annala M., Chua C.Y., Dunlap S.M., Liu Y., Hugen
N., Moore L.M., Cogdell D., Hu L., Nykter M., Hess K., Fuller
G.N., Zhang W. (2012) Insulin-like growth factor-binding protein
2-driven glioma progression is prevented by blocking a clinically
significant integrin, integrin-linked kinase, and NF-κB network.
Proc Natl Acad Sci USA 109(9):3475-3480
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.
92
METABOLOME IN HEALTH AND
DISEASE
Matej Orešič, Ph.D., Prof., Affiliated Group Leader at CBT,
VTT Technical Research Centre of Finland.
Tietotie 2, P.O. Box 1000, FIN-02044 VTT, Espoo, Finland.
E-mail: matej.oresic@vtt.fi. Home page: http://sysbio.vtt.fi/
Biography:
Prof. Matej Orešič 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. Orešič is a director of the newly
established Finnish Centre of Excellence in Molecular Systems
Immunology and Physiology Research (2012-2017). He is also a cofounder 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. Orešič has
initiated the popular MZmine open source project, leading to popular
software for metabolomics data processing. Prior to joining VTT,
Prof. Orešič 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), 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),
Niina Lietzen, PhD (metabolomics), Tijana Marinković, PhD
(computational systems biology, theoretical physics), Ismo Mattila,
MSc (analytical chemistry), Heli Nygren, PhD (metabolite analytics),
Gopal Peddinti, PhD (bioinformatics), Päivi Pöhö, MSc (analytical
chemistry), 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
for the characterization of complex phenotypes as well as for the
development of biomarkers for specific physiological responses.
We are investigating:
93
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)
Selected publications:
Sayin S.I., Wahlström A., Felin J., Jäntti .S, Marschall H.U., Bamberg
K., Angelin B., Hyötyläinen T., Orešič M., Bäckhed F. (2013)
Gut microbiota regulates bile acid metabolism by reducing the
levels of tauro-beta-muricholic acid, a naturally occurring FXR
antagonist. Cell Metab 17(2):225-35.
Orešič 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.
Orešič 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 Orešič 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 Orešič M. (2011) Association of
lipidome remodeling in the adipocyte membrane with acquired
obesity in humans, PLoS Biol. 9: e1000623.
Orešič M., Tang J., Seppänen-Laakso T., Mattila I., Saarni S. E.,
Saarni S. I., Lönnqvist J., Sysi-Aho M., Hyötyläinen T., Perälä J. and
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Suvisaari J. (2011) Metabolome in schizophrenia and other psychotic
disorders: a general population-based study, Genome Med. 3: e19.
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 Orešič 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 Orešič 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., Orešič
M. and Yki-Järvinen H. (2010) Splanchnic balance of free
fatty acids, endocannabinoids and lipids in subjects with
NAFLD, Gastroenterology 139: 1961-1971.
Yetukuri L., Söderlund S., Koivuniemi A., Seppänen-Laakso T.,
Niemelä P. S., Hyvönen M., Taskinen M.-R., Vattulainen I.,
Jauhiainen M. and Orešič 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., Orešič 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., Orešič
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 Orešič M. (2009) Dynamic network topology changes in
functional modules predict responses to oxidative stress in
yeast, Mol. BioSyst. 5: 276-287.
Orešič 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., Orešič 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 Orešič 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 Orešič 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.
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PROTEIN CRYSTALLOGRAPHY
Anastassios C. Papageorgiou, Ph.D.,
Adjunct Professor in Biochemistry and Structural Biology
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: Bishwa Subedi, Abdi Muleta
Undergraduate students: Anthony Oudot, Jesse Mattsson, Carlos
Prieto Lopez, Pradeep Battula, Cleménce Frioux
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, work on several new
mutants continued in order to understand better the iron core
formation using X-ray crystallography, microcalorimetry, EXAFS,
magnetization measurements, and Mössbauer spectroscopy.
From left to right. Tassos Papageorgiou, Pradeep Battula and Abdi Muleta.
Work on newly identified bacterial adhesins continued during
last year. With the increased resistance to antibiotics, adhesins
have become an attractive therapeutic target in the fight against
microbial diseases. Various constructs of two newly identified
bacterial adhesins containing leucine-rich repeats were used for
protein expression and purification. Small crystals were grown and
are currently in optimization. In addition, biochemical data and
docking calculations are in progress to study the precise binding
mechanism to receptors found on the membrane of host cells.
A third adhesin with galabiose-binding activity was expressed
and purified. Small crystals were found in various conditions but
instability and oligomerization problems have prompted us to look
at alternative constructs and homologues.
Studies on oxidative stress protection and detoxification
mechanisms continued on human-rat chimeric glutathione
transferases (GSTs) or mutants created through directed evolution
approaches to produce new GSTs with altered specificity for
new applications in biomedicine, environmental security, and
agriculture. Crystals of human GST-A1 have been grown in our
lab for use in structure-assisted drug design efforts. Docking
calculations were carried out to study the binding of diphenylether
herbicides in the active site. In addition, the structure of a novel
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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, the eta class, of
GSTs. Contrary to conventional GSTs that contain Ser or Tyr as
catalytic residues, an arginine residue adjacent to the sulphur atom
of the substrate analogue was found in the catalytic site.
In the theme of enzyme function and stability, we continued our
work on PhaZ7, an extracellular depolymerase involved in the
degradation of poly(R)-hydroxyalkanoates (PHAs), a group of
biodegradable thermoplastic polyesters considered as 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. Preliminary
data following soaking with a tetramer analogue have shown binding
and the structure is under refinement. Work on the Atu (acyclic
terpene utilization) catabolic pathway found in P. Aeruginosa has
continued 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.
Reprocessing of previously collected diffraction images gave a
better data set extended to 2.35 Å. The structure is currently under
rounds of refinement and extensive rebuilding.
Recent reports implicating phosphoserine aminotransferase
(PSAT), a vitamin B6 enzyme, in cancer and tuberculosis have led
us to investigate closer the substrate binding mechanism of this
enzyme for potential drug design efforts. Data of phosphoserinebound PSAT to 1.5 Å revealed local conformational changes
that facilitate substrate binding through the formation of a tight
phosphate-binding site.
Funding:
University of Turku, Biocenter Finland, Federation of European
Microbiology Societies, EU FP7 (access to synchrotrons), Cultural
Foundation of Southwestern Finland.
Collaborators:
Jukka Finne (University of Helsinki), Sauli Haataja (University of
Turku), Vuokko Loimaranta (University of Turku), Dieter Jendrossek
(University of Stuttgart), Nikos Labrou (Agricultural University of
Athens), Li Duochuan (Shandong Agricultural University), Eleanor
Coffey (ÅA),
Battula, P., Dubnovitsky, A.P. and Papageorgiou, A.C. (2012).
Structural basis of L-phosphoserine binding to phosphoserine
aminotransferase. Acta Crystallogr. D (in press).
MARCKSL1 determines actin stability and migration in neurons
and in cancer cells. Mol. Cell. Biol. 32: 3513-3526.
Skopelitou, K., Muleta, A.W., Pavli, O., Skaracis, G.N., Flemetakis,
E., Papageorgiou, A.C. & Labrou, N.E. (2012) Overlapping
protective roles for glutathione transferase gene family
members in chemical and oxidative stress response in
Agrobacterium tumefaciens. Funct. Integr. Genomics 12:157172.
Skopelitou, K., Dhavala, P., Papageorgiou, A.C. & Labrou,
N.E. (2012). A glutathione transferase from Agrobacterium
tumefaciens reveals a novel class of bacterial GST superfamily.
PLoS One 7(4): e34263.
Chronopoulou, E.G., Papageorgiou, A.C., Markoglou, A. & Labrou,
N.E. (2012). The inhibition of human glutathione transferases by
xenobiotics: development of simple analytical assays for the
quantification of pesticides in water. J. Mol. Catal. B 81: 43-51.
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
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-zinc
binding in the ferroxidase center of Strepococcus pyogenes Dpr.
Bichem. Biophys. Res. Comm. 398: 361-365.
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.
Papageorgiou, A.C. & Matsson, J. (2013) Protein analysis with
X-ray crystallography. Methods Mol. Biol. (in press).
Labrou, N., Papageorgiou, A.C. & Avramis, V.I. (2010) Structurefunction relationships and clinical applications of L-asparaginases.
Curr. Med. Chem. 17: 2183-2195.
Björkblom, B, Padzik, A., Mohammad, H., Westerlund, N.,
Komulainen, E., Hollos, P., Parviainen, L., Papageorgiou, A.C.,
Iljin, K., Kallioniemi, O., Kallajoki, M., Courtney, M.J., Mågård,
M., James, P. & Coffey, E.T. (2012) JNK phosphorylation of
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.
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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.
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
CELL FATE
Cecilia Sahlgren, PhD, Academy Research Fellow,
BioCity, Tykistökatu 6B, FI-20521 Turku, Finland.
Tel. 358-2-3338611, Fax. +358-2-251 8808
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: Marika Sjöqvist, M.Sc, Neeraj Prabhakar, M.Sc. Sebastian
Landor, M.Sc, Christian Antila, M.Sc, Laboratory Technician:
Helena Saarento, Natalie Ratts. Undergraduate students: Daniel
Antfolk, B.Sc, Jenni Niinimaki, B.Sc. Rasmus Niemi, B.Sc, Martina
Lerche, 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 7th NotchIT,
Turku Graduate school for Biomedical Sciences, Cancer Society of
Finland, Sigrid Juselius Foundation.
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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
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), Prof Carlijn Bouten, Dept of
biomedical engineering, Eindhoven University of Technology, Ass.
Professor Patricia Dankers, Dept for Chemcial Biology, Eindhoven
University of Technology.
Jin, S., A.P. Mutvei, I.V. Chivukula, E.R. Andersson, D. Ramskold,
R. Sandberg, K.L. Lee, P. Kronqvist, V. Mamaeva, P. Ostling, J.P.
Mpindi, O. Kallioniemi, I. Screpanti, L. Poellinger, C. Sahlgren,
and U. Lendahl. (2012) Non-canonical Notch signaling activates
IL-6/JAK/STAT signaling in breast tumor cells and is controlled
by p53 and IKKalpha/IKKbeta. Oncogene in press
Karaman, D.S., D. Desai, R. Senthilkumar, E.M. Johansson,
N. Ratts, M. Oden, J.E. Eriksson, C. Sahlgren, D.M. Toivola,
and J.M. Rosenholm. (2012) Shape engineering vs organic
modification of inorganic nanoparticles as a tool for enhancing
cellular internalization. Nanoscale research letters. 7:358.
Mamaeva, V., C. Sahlgren#, and M. Linden#. (2012) Mesoporous
silica nanoparticles in medicine-Recent advances. Advanced
drug delivery reviews in press (PubMed ahead of print). #shared
corresponding authorship
Rosenholm, J.M., V. Mamaeva, C. Sahlgren#, and M. Linden#.
(2012) Nanoparticles in targeted cancer therapy: mesoporous
silica nanoparticles entering preclinical development stage.
Nanomedicine (Lond). 7:111-120.
Wilhelmsson, U., M*. Faiz, Y. de Pablo*, M. Sjoqvist, D*. Andersson,
A. Widestrand, M. Potokar, M. Stenovec, P.L. Smith, N. Shinjyo,
T. Pekny, R. Zorec, A. Stahlberg, M. Pekna, C. Sahlgren, and
M. Pekny. 2012. Astrocytes negatively regulate neurogenesis
through the Jagged1-mediated Notch pathway. Stem Cells.
30:2320-2329.
Rosenholm J.M., Mamaeva, V., Sahlgren C.# and Lindén, M.#
(2011) Nanoparticles in targeted cancer therapy: Mesoporous
silica nanoparticles entering preclinical developmentstage.
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)
Hypo- and 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: 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
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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. MolecularBiology of the Cel/.
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.
DevelopmentalBiology 348: 153-166.
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. #shared
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).
PKC??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.
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. #shared corresponding authorship
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
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
PDGF-receptor expression in vascular smooth muscle cells.
Circulation Research 102: 1483-91.
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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.
TARGETING STRATEGIES FOR GENE
THERAPY
Mikko Savontaus, M.D., Ph.D., Affiliated Group Leader at CBT
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.
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.
From left to right: Jenni Niininmäki, Neeraj Prabhakar, Rasmus Niemi, Christian
Antila, Daniel Antfolk, Veronika Mamaeva, Cecilia Sahlgren, Sebastian Landor and
Hussein Shokry.
104
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.
105
Novel vectors with improved transcriptional and transductional
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, Koskenvuo J, Merentie M, Söderström M, YläHerttuala S, Savontaus M (2012) Intracardiac injection of a
capsid-modified Ad5/35 results in decreased heart toxicity when
compared to standard Ad5. Virol J. 2012 9:296
Toivonen R, Mäyränpää MI, Kovanen PT, Savontaus M. (2010)
Dilated cardiomyopathy alters the expression patterns of CAR
and other adenoviral receptors in human heart. Histochem Cell
Biol. 133(3):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(16):2001-8.
Ebert, O., Shinozaki, K., Huang, T.-G., Savontaus, M., GarciaSastre, A. and Woo S.L.C. (2003) VSV as oncolytic virus for
treatment of orthotopic hepatocellular carcinoma in immunecompetent rats. Cancer Research 63(13):3605-11.
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(15):1241-7.
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(14): 972-979
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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;
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.
Graduate students: Camilla Aspelin, M.Sc., Heidi Bergman, M.Sc.,
Marek Budzynski, M.Sc., Alexandra Elsing, M.Sc., Jenny Joutsen,
M.Sc., Petra Vainio, M.Sc., Anniina Vihervaara, M.Sc.
Research assistants: Helena Saarento, M.Sc., Jenni Vasara, M.Sc.
Undergraduate students: Malin Blom, Alejandro Da Silva, Samu
Himanen, Emine Lundsten, Heidi Lustig, Jens Luoto, Mikael
Puustinen, Katri Thiele
Visiting scientists: Tim Crul, Ph.D. and Noémi Tóth, Ph.D. (Biological
Research Center, Szeged, Hungary)
Description of the Project:
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 stress-inducible 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.
107
We are interested in 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
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.
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
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. Our ultimate goal is to determine the
PTM signatures for both HSF1 and HSF2.
In contrast to HSF1, which is a stable protein and evenly
expressed in most tissues and cell types, the amount of HSF2
varies and correlates with its activity. We have demonstrated that
the ubiquitin E3 ligase APC/C (anaphase-promoting complex/
cyclosome) mediates ubiquitylation 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 have expanded our studies to involve the
stress effects on the cell cycle, adding a new dimension to the
research field. To this end, our ChIP-sequencing studies, identifying
HSF1 and HSF2 target sites in cycling and mitotic human cells
under optimal growth conditions and upon acute heat stress,
are of most importance. Our results highlight an orchestrated
transcriptional response, mediated by both HSF1 and HSF2,
that controls a multitude of cellular processes in stressed cycling
cells. In mitosis, however, we found a limited capacity of HSF1 to
interact with the condensed chromatin and induce transcription,
whereas HSF2 is capable of binding to several targets, indicating
a specific impact of HSF2 on transcription throughout the cell
cycle progression.
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, miR18, 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
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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 HSF2-mediated 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.
Funding:
The Academy of Finland, the Sigrid Jusélius Foundation, the
Finnish Cancer Organizations, Turku Doctoral Programme of
Biomedical Sciences (TuBS), and Åbo Akademi University (Centre
of Excellence in Cell Stress and Molecular Aging).
Collaborators:
Klaus Elenius, Susumu Imanishi, Noora Kotaja and Jorma Toppari
(University of Turku), John Eriksson, Peter Slotte and Kid Törnquist
(Åbo Akademi University), Marko Kallio and Matthias Nees (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 (2006-2012):
Sundvall M.*, Korhonen A.*, Vaparanta K., Anckar J., Halkilahti K.,
Salah Z., Aqeilan R.I., Palvimo J.J., Sistonen L. and Elenius K.
(2012) Protein inhibitor of activated STAT3 (PIAS3) promotes
sumoylation and nuclear sequestration of the intracellular
domain of ErbB4. J. Biol. Chem. 287: 23216-23226.
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 proteindamaging stress. Mol. Cell. Biol. 30: 5608-5620.
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
109
From left to right: Johanna Björk, Petra Vainio, Eva Henriksson, Heidi Bergman, Beata Paziewska, Emine Lundsten, Anniina Vihervaara, Helena Saarento, Camilla Aspelin, Samu Himanen, Lea Sistonen, Oskar
Engberg, Jenny Joutsen, Sally Svartsjö, Alexandra Elsing, Pia Roos-Mattjus and Jenni Vasara.
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.
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
110
111
CANCER CELL SIGNALING
Jukka Westermarck, M.D., Ph.D., Professor.
BioCity, Tykistökatu 6B, FIN-20251 Turku, Finland.
Tel. +358-2-3338621, Fax +358-2-2158808.
E-mail: jukwes@utu.fi.
Homepage: http://www.btk.fi/research/research-groups/westermarck/
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 20022007. Between 2006
-2009 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, in 2009 to a
Research Director position at Turku Centre for Biotechnology
(leave of absence until 2014) and in 2011 to a part-time position
as a Professor of Cancer Biology at Department of Pathology,
University of Turku (until 2104).
Personnel:
Senior scientist: Jukka Westermarck, M.D., Ph.D. Post-doctoral
researchers: Anna Cvrljevic, Ph.D., Juha Okkeri, Ph.D., Yuba
Pokharel, Ph.D., Minna Niemelä, Ph.D. Graduate students: Otto
Kauko, M.D., M.Sc., Amanpreet Kaur, M.Sc., Anni Laine, M.Sc.,
Xi Qiao, M.Sc., Eleonora Sittig, B.Sc. Technicians: Taina KalevoMattila, Lab.Tech., Inga Pukonen, B.Eng. Coordinator: Tiina
Arsiola, Ph.D.
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
112
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
addition, our aim is to purify new protein complexes related cancer
cell signaling.
Funding:
The Academy of Finland, Sigrid Juselius Foundation, Turku
Graduate School of Biomedical Sciences, Cancer Research
Foundation of Finland, Biocenter Finland, Foundation of the Finnish
Cancer Institute.
Collaborators:
Rosalie Sears (Oregon Health and Science University), Owen
Sansom (Beatson Institute for Cancer Research, Glasgow),
Sampsa Hautaniemi (University of Helsinki), Ari Ristimäki and Caj
Haglund (University of Helsinki), Olli-Pekka Kallioniemi (FIMM,
Helsinki), Jorma Toppari (University of Turku), Veli-Matti Kähäri
(Turku University Hospital), Heikki Joensuu (Helsinki University
Hospital).
Laine, A., Sihto, H., Come, C., Zwolinska, A., Rosenfeldt, M.,
Khanna, A., Kähäri, V.-M., Evan, G.I., Junttila, M.R., Marine, J.-C.,
Ryan, K., Joensuu, H. and Westermarck, J. (2012). Senescence
sensitivity of breast cancer cells is defined by positive feedback
loop between CIP2A and E2F1. Cancer Discovery, in press.
Niemelä, M., Kauko, O., Sihto, H., Mpindi, J.-P., Nicorici, D.,
Pernilä, P., Kallioniemi, O.-P., Joensuu, H., Hautaniemi, S. and
Westermarck, J. (2012). CIP2A signature reveals the MYC
dependency of CIP2A-regulated phenotypes and its clinical
association with breast cancer subtypes. Oncogene 31: 42664278.
Ventelä, S., Mäkelä, J.-A., Kulmala, J., Westermarck, J. and Toppari,
J. (2012). Identification and regulation of a stage-specific stem
cell niche enriched by Nanog positive spermatogonial stem cells
in the mouse testis. STEM CELLS 30: 1008-1020.
Ventelä, S., Come, C., Mäkelä, J.-A., Hobbs, R.M., Mannermaa,
L., Kallajoki, M., Chan, E.K., Pandolfi, P.P., Toppari, J. and
Westermarck, J. (2012). CIP2A promotes proliferation of
spermatogonial progenitor cells and spermatogenesis in mice.
PLoS ONE 7: e33209.
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-2-dependent
signal amplification cascade that regulates c-Myc levels in ras
transformation. Oncogene 31: 390-401.
Khanna, A., Okkeri, J., Bilgen, T., Tiirikka, T., Vihinen, V., Visakorpi,
T. and Westermarck, J. (2011). ETS1 mediates MEK1/2dependent overexpression of cancerous inhibitor of protein
phosphatase 2A (CIP2A) in human cancer cells. PLoS One 6:
e17979.
113
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:
5092-5100.
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
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 crosstalk 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 top to bottom. Left row: Otto Kauko, Jukka Westermarck, Minna Niemelä and
Juha Okkeri. Right row: Xi Qiao, Inga Pukonen, Anni Laine, Taina Kalevo-Mattila,
Eleonora Sittig, Amanpreet Kaur and Tiina Arsiola
114
115
ADENOSINE DEAMINASES
Andrey Zavialov, Ph.D.,
Finnish Academy Research Fellow (group leader),
Turku Centre for Biotechnology, University of Turku,
Tykistokatu 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.), Meraj Hassan Khan
(M.S.), Chengquian Liu (M.S.), Yuliia Mukiienko (M.D.), Balwant Rai
(M.D.)
Undergraduate student: Joyce Verwijmeren
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
heparin-binding 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
116
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
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; CIMO
Collaborators:
Dr. Ivona Aksentijevich (NIH/NHGRI, U.S.A.), Dr. Urpo Lamminmäki
(University or Turku), Dr. Tuomas Mirtti (University of Helsinki), Prof.
Jose Parcel (Arnau de Vilanova University Hospital, Lleida, Spain),
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)
Zavialov, A. V., X. Yu, D. Spillmann, G. Lauvau and A.V. Zavialov.2010.
Structural basis for the growth factor activity of human adenosine
deaminase ADA2. J Biol Chem 285:12367-12377.
Zavialov, A. V., E. Gracia, N. Glaichenhaus, R. Franco, and
G. Lauvau. 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.
Gao, N., A. V. Zavialov, M. Ehrenberg, and J. Frank. 2007. Specific
interaction between EF-G and RRF and its implication for GTPdependent ribosome splitting into subunits. J Mol Biol 374:13451358.
Gao, H., Z. Zhou, U. Rawat, C. Huang, L. Bouakaz, C. Wang, Z.
Cheng, Y. Liu, A. Zavialov, R.
Gursky, S. Sanyal, M. Ehrenberg, J. Frank, and H. Song. 2007.
RF3 induces ribosomal conformational changes responsible for
dissociation of class I release factors. Cell 129:929-941.
Rawat, U., H. Gao, A. Zavialov, R. Gursky, M. Ehrenberg, and J.
Frank. 2006. Interactions of the Release Factor RF1 with the
Ribosome as Revealed by Cryo-EM. J Mol Biol 357:1144-1153.
Hauryliuk, V., A. Zavialov, L. Kisselev, and M. Ehrenberg. 2006.
Class-1 release factor eRF1 promotes GTP binding by class-2
release factor eRF3. Biochimie 88:747-757.
Zavialov, A. V., V. V. Hauryliuk, and M. Ehrenberg. 2005. Splitting
of the posttermination ribosome into subunits by the concerted
action of RRF and EF-G. Mol Cell 18:675-686.
117
Zavialov, A. V., V. V. Hauryliuk, and M. Ehrenberg. 2005. Guaninenucleotide exchange on ribosome-bound elongation factor G
initiates the translocation of tRNAs. J Biol 4:9.
Ph.D. DEFENCES
Zavialov, A. V., and A. Engstrom. 2005. Human ADA2 belongs to a
new family of growth factors with adenosine deaminase activity.
Biochem J 391:51-57.
Gao, N., A. V. Zavialov, W. Li, J. Sengupta, M. Valle, R. P. Gursky, M.
Ehrenberg, and J. Frank. 2005. Mechanism for the disassembly
of the posttermination complex inferred from cryo-EM studies.
Mol Cell 18:663-674.
Frank, J., J. Sengupta, H. Gao, W. Li, M. Valle, A. Zavialov, and
M. Ehrenberg. 2005. The role of tRNA as a molecular spring
in decoding, accommodation, and peptidyl transfer. FEBS Lett
579:959-962.
Allen, G. S., A. Zavialov, R. Gursky, M. Ehrenberg, and J. Frank.
2005. The cryo-EM structure of a translation initiation complex
from Escherichia coli. Cell 121:703-712.
Zavialov, A. V., and M. Ehrenberg. 2003. Peptidyl-tRNA regulates
the GTPase activity of translation factors. Cell 114:113-122.
Valle, M., A. Zavialov, J. Sengupta, U. Rawat, M. Ehrenberg, and J.
Frank. 2003. Locking and unlocking of ribosomal motions. Cell
114:123-134.
Valle, M., A. Zavialov, W. Li, S. M. Stagg, J. Sengupta, R. C.
Nielsen, P. Nissen, S. C. Harvey, M. Ehrenberg, and J. Frank.
2003. Incorporation of aminoacyl-tRNA into the ribosome as
seen by cryo-electron microscopy. Nat Struct Biol 10:899-906.
Rawat, U. B., A. V. Zavialov, J. Sengupta, M. Valle, R. A. Grassucci,
J. Linde, B. Vestergaard, M. Ehrenberg, and J. Frank. 2003. A
cryo-electron microscopic study of ribosome-bound termination
factor RF2. Nature 421:87-90.
Pedersen, K., A. V. Zavialov, M. Y. Pavlov, J. Elf, K. Gerdes, and
M. Ehrenberg. 2003. The bacterial toxin RelE displays codonspecific cleavage of mRNAs in the ribosomal A site. Cell
112:131-140.
Mora, L., A. Zavialov, M. Ehrenberg, and R. H. Buckingham.
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., T. Pape, A. V. Zavialov, A. G. Myasnikov, E. V. Orlova,
B. Vestergaard, M. Ehrenberg, and M. van Heel. 2003. Structure
of the Escherichia coli ribosomal termination complex with
release factor 2. Nature 421:90-94.
Zavialov, A. V., L. Mora, R. H. Buckingham, and M. Ehrenberg.
2002. Release of peptide promoted by the GGQ motif of class
1 release factors regulates the GTPase activity of RF3. Mol Cell
10:789-798.
Zavialov, A. V., R. H. Buckingham, and M. Ehrenberg. 2001. A
posttermination ribosomal complex is the guanine nucleotide
exchange factor for peptide release factor RF3. Cell 107:115124.
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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 2 251 8808

TURKU CENTRE FOR BIOTECHNOLOGY – REPORT 2012

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