TURKU CENTRE FOR BIOTECHNOLOGY REPORT 2013

Transcription

TURUN BIOTEKNIIKAN KESKUS
ÅBO BIOTEKNIKCENTRUM
TURKU CENTRE FOR BIOTECHNOLOGY
TURKU CENTRE
FOR BIOTECHNOLOGY
REPORT 2013
TURUN BIOTEKNIIKAN KESKUS
Tykistökatu 6 A
P.O.BOX 123
FI 20521 Turku, Finland
Tel: +358 2 333 8603, Fax +358 2 251 8808
Annual Report 2013
Turku Centre for Biotechnology
Published by:
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
Jane Zhi Chen
Eleanor Coffey
Garry Corthals
Michael Courtney
Laura Elo
John Eriksson
Attila Gyenesei
David Hawkins
Jyrki Heino
Johanna Ivaska
Panu Jaakkola
Marko Kallio
Linnéa Linko
Harri Lähdesmäki
Matti Nykter
Matthias Nees
Tassos Papageorgiou
Jeroen Powels
Cecilia Sahlgren
Lea Sistonen
Juha Strandén
Mikael Wasberg
Jukka Westermarck
Andrey Zavialov
Photographs:
Photographs: KUV@TEHDAS Roni Lehti, Photograph archives of
the Centre for Biotechnology. Front and back cover image: Reima
Nurmikko.
Painosalama Oy, Turku 2014
ISSN 1237-5217
CONTENTS
Contents......................................................................................1
Organization.................................................................................2
Chairman’s Foreword ...................................................................3
From the Director .........................................................................4
Year 2013 in a Nutshell.................................................................5
Funding and Statistics .................................................................9
Publications 2013.......................................................................12
Personnel 2013..........................................................................19
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
Lymphocytes and Inflammation..................................................43
Protein Kinase Regulation of Brain Development and Disease....45
Translational Proteomics.............................................................51
Organisation of Neuronal Signaling Pathways.............................53
Computational Biomedicine........................................................57
Cytoskeletal and Survival Signaling.............................................60
Epigenomics...............................................................................67
Cell Adhesion and Cancer..........................................................69
Hypoxia in Cell Survival...............................................................73
Mitosis and Drug Discovery........................................................77
Molecular Systems Immunology and Stem Cell Biology..............79
Computational Systems Biology.................................................84
Cell Culture Models for Tumor Cell Invasion and Epithelial
Plasticity.....................................................................................86
Computational Biology...............................................................90
Systems Medicine......................................................................92
Protein Crystallography...............................................................96
Integrin Activity in Disease........................................................102
Cell Fate...................................................................................106
Regulation and Function of Heat Shock Transcription Factors..111
Cancer Cell Signaling................................................................115
Adenosine Deaminases............................................................118
PhD Defences..........................................................................122
Life Outside the Lab.................................................................124
ORGANIZATION
CHAIRMAN’S FOREWORD
Board of Trustees 2013
Turku Centre for Biotechnology (CBT) is celebrating its 25th
anniversary in the year 2014. When the decision to establish
CBT was made in late ‘80s Turku looked very different to today.
Before the first Science Park building, DataCity, was built in 1988
Kupittaa was an industrial area with warehouses, a large cattle yard
belonging to a slaughterhouse and a sausage factory. A tall grain
elevator dominated the scenery. The present day buildings with
modern laboratories form quite a big contrast to that old picture
and pronounce the restructuring of Finnish industry.
Chairman
HEINO Jyrki, Professor, University of Turku, Department of
Biochemistry and Food Chemistry,
Scientific Director, BioCity Turku
Vice-chairman
ERIKSSON John, Professor, Åbo Akademi University, Department
of Biology
Secretary
LAHESMAA Riitta, Professor, Director, Turku Centre for
Biotechnology
Assistant Secretary
ALANKO Satu, Coordinator, Turku Centre for Biotechnology
and BioCity Turku
Members
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
RÖNNEMAA Tapani, Professor, University of Turku, Dean of the
Faculty of Medicine,
SAARI Markku, Research coordinator, Turku Centre for
Biotechnology
SAVILAHTI Harri, Professor, University of Turku, Department of
Biology
SUOMINEN Kalle-Antti, Professor, Vice-Rector of University of
Turku
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
HUOVINEN Pentti, Professor, University of Turku, Department of
Medical Microbiology and Immunology
LAHTI Reijo, Professor, University of Turku, Dean of the Faculty of
Mathematics and Natural Sciences
PRIMMER Craig, Professor, University of Turku, Department of
Biology
ROKKA Anne, Research coordinator, Turku Centre for
Biotechnology
SCHLEUTKER Johanna, Professor, University of Turku,
Department of Medical Biochemistry and Genetics
SLOTTE J. Peter, Professor, Åbo Akademi University, Department
of Biosciences
VUORELA Pia, Professor, Åbo Akademi University, Department of
Biosciences
2
During the past 25 years CBT has seen the ups and downs of Finnish
life science research and high-tech. The ‘90s brought at first a deep
economic depression but later a big increase in Finnish research
and development funding. In life sciences it meant significant
improvements in the infrastructure, the training of graduate students
and the quality of science. The positive and optimistic atmosphere
also initiated many translational projects, e.g. in drug development.
Some of them have very recently achieved their goals. In the 2000s
the development has been slower and in the global scale the relative
impact of Finnish science has constantly decreased. When writing
this, Finland’s economy has not grown for three years, which together
with the implication of a full-cost model by the research funding
agencies has significantly reduced the number of funded projects
and weakened the future prospects of many scientists, especially
the younger group leaders. Still many positive things have happened.
The Academy of Finland has plans to increase its funding for research
infrastructures and Turku researchers have actively participated in
the establishment of European infrastructure networks. We can
expect that also in the future Turku campus area will have up-to-date
equipment and technologies available for life science research. CBT
has during the past 25 years played a central role in the development
of technology platforms and the important work will also continue
in the future. Turku scientists have also been very successful in the
tough national competition for the Academy of Finland Centres of
Excellence and Academy Professor positions. The good quality
of science can also be seen in the number of high-impact papers
published by Turku researchers. From year 2004 the BioCity Turku
organization has given the Elias Tillandz -prize for the best publication
in Turku and the competition is clearly getting harder and harder
every year. Many of the winners have worked in CBT, which tells that
in addition to being a home for many important core laboratories,
CBT has been able to provide good
environment for scientific research.
I want to congratulate and thank the
director of CBT, its researchers and all
personnel for the hard and successful
work done during the past quarter
of century and also to wish them the
best of luck for the next 25 years.
Jyrki Heino, MD, PhD,
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 2013 IN A NUTSHELL
Our Centre had a productive and eventful year 2013. We once again
exceeded our pre-agreed goals with altogether 10 PhDs completed
and 68 publications produced during 2013. We also raised 6,2 M €
in external competitive funding from the Academy of Finland, TEKES,
Cancer Society of Finland, The Sigrid Jusélius Foundation, Juvenile
Diabetes Research Foundation, EU and others.
RESEARCH AND EDUCATION
We recruited two new talented group leaders: Jeroen Powels, PhD,
was appointed an Academy Fellow, a highly competitive position at
the Academy of Finland, and Laura Elo-Uhlgrén got a competitive
Juvenile Diabetes Research Foundation career development fiveyear grant to set up her independent group at the Centre. Riikka
Lund was awarded the prestigious Millennium Distinction Award by
Technology Academy Finland. Jyrki Heino’s and Riitta Lahesmaa’s
groups shared the Tillandz prize for the best publications of the
Biocity Community in 2012.
Finnish Microarray and Sequencing Centre
I am proud of our core facilities that continued to excel within the
Biocenter Finland infrastructure network and, based on evaluation by
external international experts, were able to raise significant external
funding to further develop the services. The impact of Biocenter Finland
networks is extraordinary as all the scientists working in Finland have
full access to our cutting-edge technologies. Importantly, University of
Turku decided to continue funding all CBT personnel who participate
to Biocenter Finland core facilities. Likewise, Åbo Akademi University
will continue to support these activities.
We carried out a survey on well-being of our personnel and
working groups were established to follow up and make proposals
for improving practices facilitating well-being at work. All our group
leaders have been encouraged to participate in an “Academic
leadership” training program organized by the University of Turku.
Based on our initiative, the program was organized for the first time
in English and we are grateful for the University of Turku for this
important contribution!
This year, in 2014 CBT is celebrating its 25th Anniversary. During this
time a large number of international scientists have been recruited,
hundreds of young scientists have been trained and exciting
research has been carried out. The state-of-the art core facilities
and technology platforms have been established and continuously
evaluated and updated to serve hundreds of users. Thus our key
mission to promote cutting edge research has been fulfilled in many
ways. CBT was established to centralize expensive technologies and
equipment and to bring resources of the two universities in Turku
together to enable cost efficient use of resources. This concept has
been evaluated for many times during the years and without exception
the CBT concept has always been fully
endorsed and supported. Today, due
to the current weak economic situation
it is even more important to continue to
make full and efficient use of our limited
resources.
Having sailed through storms and
winds of change our CBT ship is now
again getting wind in its sails and we
are continuing full speed ahead!
Thank you all CBT scientists and
personnel – you are awesome!
DEVELOPMENT OF INFRASTRUCTURE, RESEARCH
SERVICES AND CORE FACILITIES
• Altogether 6867 samples and 1256 plates were processed
by FMSC for 276 different projects
• Our services were used by 82 local, 20 other domestic, 6
foreign and 5 non-academic research groups or units
• FMSC contributed into 41 publications
• FMSC provided 12 lectures for undergraduate student or
researchers, 4 public seminars or workshops and several
tours into the FMSC facilities
Proteomics and Mass spectrometry Laboratory
• Petri Kouvonen returned from post-doctoral studies with R.
Aebersold , Zürich
• Dorota Muth-Pawlak finished her 2-year post.
• Several courses and workshops organized at CBT:
(1) Proteins at work course,
(2) Basic proteomics course,
(3) SRM workshop and
(4) two Skyline workshops.
• Organized 7th Summer School ‘Mass Spectrometry in
Biotechnology and Medicine’ in Dubrovnik
Cell Imaging Core
• CIC continued as a key player in Light Microscopy of the
Biocenter Finland National Infrastructure Network
• Ketlin Adel was appointed as a full-time project engineer
looking after flow cytometry
• The Laser TIRF 3 from Zeiss was installed
• Procurement procedures commenced for acquisition of a
high-throughput flow cytometer commenced
• CIC participated in the purchase of the IncuCyte ZOOM for
live content imaging
• CIC served ~300 users during 2013 from ~100 research
groups. 12% of our user base comprised external users.
• CIC provided over 100 hours teaching at national and
international events.
• The popular Lost in Imaging webinar series continued.
Riitta
Riitta Lahesmaa, MD, PhD, Professor Director
Turku Centre for Biotechnology University of
Turku and Åbo Akademi University
4
5
Viral vector facility
• The viral vector facility overhauled its service charging
system and started to provide user training as a charged
service
• Usage of the Biosafety Level 2 lab was added to the Asimov
electronic reservation system to facilitate access campuswide
• A new filtration system was purchased for the flow cytometry
unit according to the guidelines of the Board for Gene
Technology to enable safe sample analysis
Bioinformatics Core
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
• Supervising MSc- and PhD-theses
• 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
• High-throughput bioinformatics facility (HTB) analyzed data
for 28 projects (21 local, 6 domestic, 1 international).
• HTB continued the development of data analysis pipelines for
various next-generation sequencing applications including
RNA-seq, DNA methylation and targeted enrichment
resequencing.
•HTB started the work for setting up pipelines for
metagenomics data analysis to support 16s rRNA and
whole genome metagenome sequencing technologies.
• New commercial software tools were acquired to support
local users.
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. Several
demonstrations to university and secondary school students.
A 4-day course on protein complexes was organized
together with the Proteomics facility.
• Participation to several calls of Biocenter Finland, Finnish
Roadmap and Infrastucture. Participation in a successful bid
for a Finnish National Affiliated Center of INSTRUCT-Europe
• The new X-ray generator run smoothly throughout the year.
Several data sets were collected and structures deposited.
The Oxford cryosystem was repumped several times owing
to vacuum problems making a future replacement with a
newer model an urgent matter.
• 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.
6
7
FUNDING AND STATISTICS
PhD and MSc Theses
PhD Theses (p. 12)
Name
Supervisor
Site besides CBT
Soile Tuomela
Riitta Lahesmaa
UTU, Institute of Biomedicine,
Department of Medical
Biochemistry and Genetics
Nelly Rahkonen
Riitta Lahesmaa,
Riikka Lund
Microbiology and Immunology
Minna Kyläniemi
Riitta Lahesmaa
Gunilla Högnäs
Johanna Ivaska
Antti Arjonen
Johanna Ivaska
Artur Padzik
Eleanor Coffey
ÅA, Department of
Biosciences
Anni Laine
Jukka Westermarck
UTU, Department of
Pathology
Mari Björkman
Matthias Nees, Olli
Kallioniemi
Department of Pharmacology
Saima E. Ferraris
John Eriksson
ÅA, Department of
Biosciences
Tomoko Asaoka
John Eriksson
ÅA, Department of
Biosciences
Sources of funding received by Centre for Biotechnology
in 2013 (12.6 Million €)
External funding 2006-2013
MSc Theses
Krista Maurinen
Riitta Lahesmaa, Nelly University of Turku, Faculty of
Rahkonen
Medicine, Health Biosciences
Johanna Myllyviita
Riitta Lahesmaa,
Minna Kyläniemi
UTU, Department of
Biochemistry
Patrik Hollós
Eleanor Coffey
ÅA, Department of
Biosciences
Dani Flinkman
Eleanor Coffey
UTU, Department of
Biochemistry
Petra Miikkulainen
Panu Jaakkola, Heidi
Högel
Neeraj Prabhakar
Cecilia Sahlgren
ÅA, Department of
Biosciences
Sara Sarinko
Cecilia Sahlgren
ÅA, Department of
Biosciences
Rasmus Niemi
Cecilia Sahlgren
ÅA, Department of
Biosciences
Daniel Antfolk
Cecilia Sahlgren
ÅA, Department of
Biosciences
Iris Lahdeniemi
Cecilia Sahlgren,
Diana Toivola
ÅA, Department of
Biosciences
Harri Santa
Laura Elo, Olli
Nevalainen
UTU, Department of
Information Technology
Maria Jaakkola
Laura Elo, Marko
Mäkelä
UTU, Department of
Mathematics and Statistics
Emine Lundsten
Lea Sistonen
ÅA, Department of
Biosciences
Alejandro Da Silva
Lea Sistonen
ÅA, Department of
Biosciences
Erik Niemelä
John Eriksson
ÅA, Department of
Biosciences
8
9
Number of graduates 2006-2013
18
16
14
12
10
MSc
8
PhD
6
4
2
0
2006
2007
2008
2009
2010
2011
2012
2013
Publication impact factors
9 publications with
IF > 10
19 publications
with IF 5-10
40 publications
with IF < 5
Citations each year to CBT publications
From left to right. Upper row: Tuula Suvanto, Miina Nurmi, Riitta Lahesmaa, Pasi
Viljakainen, Taina Kalevo-Mattila, Marjo Hakkarainen, Juha Strandén, Elina Pietilä,
Susanna Pyökäri and Inga Pukonen. Bottom row: Petri Vahakoski, Mikael Wasberg,
Tiina Lummevuo, Markku Saari, Sarita Heinonen, Linnéa Linko, Jouko Sandholm,
Anne Lahdenperä and Mårten Hedman.
10
11
PUBLICATIONS 2013
PhD Theses 2013
1. Soile Tuomela: System-level characterization of TH2 cell
development and immune cell responses to ZnO and TiO2
nanoparticles, University of Turku, p. 90.
6. Dirihan S, Terho P, Helander M, Saikkonen K (2013) Efficient
analysis of ploidy levels in plant evolutionary ecology.
Caryologia 66:251-256. IF 0.6
2. Nelly Rahkonen: Regulation of self-renewal and detection of
karyotypic changes of pluripotent human embryonic stem
cells. University of Turku, p. 60.
7. Eerola K, Nordlund W, Virtanen S, Dickens AM, Mattila M,
Ruohonen ST, Chua SC, Jr., Wardlaw SL, Savontaus M,
Savontaus E (2013) Lentivirus-Mediated alpha-MelanocyteStimulating Hormone Overexpression in the Hypothalamus
Decreases Diet Induced Obesity in Mice. J Neuroendocrinol
25:1298-1307. IF 3.3
3. Minna Kyläniemi: Regulation of lymphocyte response in vitro
and in vivo. University of Turku, p. 78.
4. Gunilla Högnäs: Integrins in Tumorigenesis and Cancer Cell
Invasion. University of Turku, p. 104.
5. Antti Arjonen: Integrins on the move. University of Turku, p.
77.
6. Artur Padzik: JNK, a versatile regulator of kinesin-1 transport
and cytoskeleton dynamics. Åbo Akademi University, p.
119.
7. Anni Laine: The Role of an Oncoprotein CIP2A in Breast
Cancer, University of Turku, p. 138.
8. Saima E. Ferraris: Cellular responses to stress and kinase
signaling activation: apoptosis and differentiation, Åbo
Akademi University, p. 87.
9. Tomoko Asaoka: Regulation of cell fate by c-FLIP
phosphorylation. Åbo Akademi University, p. 108.
10.Björkman, Mari: Identification of Epigenetic Targets in
Prostate Cancer for Therapeutic Development. University of
Turku. p. 62.
Publications 2013
1. Abankwa D, Millard SM, Martel N, Choong CS, Yang M,
Butler LM, Buchanan G, Tilley WD, Ueki N, Hayman MJ,
Leong GM (2013) Ski-interacting protein (SKIP) interacts
with androgen receptor in the nucleus and modulates
androgen-dependent transcription. BMC Biochem.
14(1):10. IF 4.2
2. Battula P, Dubnovitsky AP, Papageorgiou AC (2013)
Structural basis of L-phosphoserine binding to Bacillus
alcalophilus
phosphoserine
aminotransferase.
Acta
Crystallogr Sect D-Biol Crystallogr 69:804-811. IF 14.1
3. Bouvard D, Pouwels J, De Franceschi N, Ivaska J (2013)
Integrin inactivators: balancing cellular functions in vitro and
in vivo. Nat Rev Mol Cell Biol 14:430-442. IF 37.2
4. Chen Z, Lonnberg T, Lahesmaa R (2013) Holistic Systems
Biology Approaches to Molecular Mechanisms of Human
Helper T Cell Differentiation to Functionally Distinct Subsets.
Scand J Immunol 78:172-180. IF 2.2
12
5. Costa P, Scales TME, Ivaska J, Parsons M (2013) IntegrinSpecific Control of Focal Adhesion Kinase and RhoA
Regulates Membrane Protrusion and Invasion. PLoS One
8:e74659. IF 3.7
8. Gardberg M, Kaipio K, Lehtinen L, Mikkonen P, Heuser VD,
Talvinen K, Iljin K, Kampf C, Uhlen M, Grenman R, Koivisto
M, Carpen O (2013) FHOD1, a Formin Upregulated in
Epithelial-Mesenchymal Transition, Participates in Cancer
Cell Migration and Invasion. PLoS One 8:e74923. IF 3.7
9. Haikarainen T, Frioux C, Zhnag LQ, Li DC, Papageorgiou AC
(2013) Crystal structure and biochemical characterization
of a manganese superoxide dismutase from Chaetomium
thermophilum. Biochim Biophys Acta 1844:422-429. IF
3.8
10.Haikarainen T, Loimaranta V, Prieto-Lopez C, Battula P,
Finne J, Papageorgiou AC (2013) Expression, purification
and crystallization of the C-terminal LRR domain of
Streptococcus pyogenes protein 0843. Acta Crystallogr
F-Struct Biol Cryst Commun 69:559-561. IF 0.5
11.Hamalisto S, Pouwels J, de Franceschi N, Saari M,
Ivarsson Y, Zimmermann P, Brech A, Stenmark H, Ivaska J
(2013) A ZO-1/alpha 5 beta 1-Integrin Complex Regulates
Cytokinesis Downstream of PKC epsilon in NCI-H460 Cells
Plated on Fibronectin. PLoS One 8:e70696. IF 3.7
12.Hawkins RD, Larjo A, Tripathi SK, Wagner U, Luu Y, Lönnberg
T, Raghav SK, Lee LK, Lund R, Ren B, Lähdesmäki H,
Lahesmaa R. Global Chromatin State Analysis Reveals
Lineage-Specific Enhancers during the Initiation of Human
T helper 1 and T helper 2 Cell Polarization. Immunity. 2013,
38:1271-84. IF 19.8
13.Hognas G, Hamalisto S, Rilla K, Laine JO, Vilkki V, Murumagi
A, Edgren H, Kallioniemi O, Ivaska J (2013) Aneuploidy
facilitates oncogenic transformation via specific genetic
alterations, including Twist2 upregulation. Carcinogenesis
34:2000-2009. IF 5.6
14.Jaakkola PM, Rantanen K (2013) The regulation, localization,
and functions of oxygen-sensing prolyl hydroxylase PHD3.
Biol Chem 394:449-457. IF 2.7
15.Jaaskelainen AE, Seppala S, Kakko T, Jaakkola U, Kallio
J (2013) Systemic treatment with neuropeptide Y receptor
Y1-antagonist enhances atherosclerosis and stimulates IL12 expression in ApoE deficient mice. Neuropeptides 47:6773. IF 2.1
13
16.Jin S, Mutvei AP, Chivukula IV, Andersson ER, Ramskold
D, Sandberg R, Lee KL, Kronqvist P, Mamaeva V, Ostling P,
Mpindi J, Kallioniemi O, Screpanti I, Poellinger L, Sahlgren C,
Lendahl U (2013) Non-canonical Notch signaling activates
IL-6/JAK/STAT signaling in breast tumor cells and is
controlled by p53 and IKK alpha/IKKb. Oncogene 32:48924902. IF 7.3
17.Junttila S, Laiho A, Gyenesei A, Rudd S (2013) Whole
transcriptome characterization of the effects of dehydration
and rehydration on Cladonia rangiferina, the grey reindeer
lichen. BMC Genomics 14:870-2164-14-870. IF 4.4
18.Kahara J, Lahdesmaki H (2013) Evaluating a linear k-mer
model for protein-DNA interactions using high-throughput
SELEX data. BMC Bioinformatics 14:S2. IF 3.0
19.Kalhori V, Kemppainen K, Asghar MY, Bergelin N, Jaakkola
P, Tornquist K (2013) Sphingosine-1-Phosphate as a
Regulator of Hypoxia-Induced Factor-1 alpha in Thyroid
Follicular Carcinoma Cells. PLoS One 8:e66189. IF 3.7
20.Kallio A, Elo LL (2013) Optimizing Detection of Transcription
Factor-Binding Sites in ChIP-seq Experiments. Methods Mol
Biol 1038:181-91. IF 1.3
21.Kamalainen A, Viswanathan J, Natunen T, Helisalmi S,
Kauppinen T, Pikkarainen M, Pursiheimo J, Alafuzoff I,
Kivipelto M, Haapasalo A, Soininen H, Herukka S, Hiltunen
M (2013) GRN Variant rs5848 Reduces Plasma and Brain
Levels of Granulin in Alzheimer’s Disease Patients. J
Alzheimers Dis 33:23-27. IF 4.2
22.Khanna A, Kauko O, Bockelman C, Laine A, Schreck I,
Partanen JI, Szwajda A, Bormann S, Bilgen T, Helenius M,
Pokharel YR, Pimanda J, Russel MR, Haglund C, Cole KA,
Klefstrom J, Aittokallio T, Weiss C, Ristimaki A, Visakorpi T,
Westermarck J (2013) Chk1 Targeting Reactivates PP2A
Tumor Suppressor Activity in Cancer Cells. Cancer Res
73:6757-6769. IF 8.6
23.Khanna A, Pimanda JE, Westermarck J (2013) Cancerous
Inhibitor of Protein Phosphatase 2A, an Emerging Human
Oncoprotein and a Potential Cancer Therapy Target. Cancer
Res 73:6548-6553. IF 8.6
24.Knuuti J, Saraste A, Kallio M, Minn H. (2013) Is cardiac
magnetic resonance imaging causing DNA damage? Eur
Heart J. 34(30):2337-9. IF 14.1
25.Koch S, Scifo E, Rokka A, Trippner P, Lindfors M, Korhonen
R, Corthals GL, Virtanen I, Lalowski M, Tyynela J (2013)
Cathepsin D deficiency induces cytoskeletal changes and
affects cell migration pathways in the brain. Neurobiol Dis
50:107-119. IF 5.6
26.Kong L, Aho K, Granberg K, Lund R, Jarvenpaa L, Seppala
J, Gokhale P, Leinonen K, Hahne L, Makela J, Laurila K,
Pukkila H, Narva E, Yli-Harja O, Andrews PW, Nykter M,
Lahesmaa R, Roos C, Autio R (2013) ESTOOLS Data@
Hand: human stem cell gene expression resource. Nat
Methods 10:814-815. IF 23.6
14
27.Kong L, Tuomela S, Hahne L, Ahlfors H, Yli-Harja O, Fadeel
B, Lahesmaa R, Autio R (2013) NanoMiner - Integrative
Human Transcriptomics Data Resource for Nanoparticle
Research. PLoS One 8:e68414. IF 3.7
28.Korhonen JT, Olkkonen VM, Lahesmaa R, Puolakkainen M
(2013) ABC-cassette transporter 1 (ABCA1) expression in
epithelial cells in Chlamydia pneumoniae infection. Microb
Pathog 61-62:57-61. IF 2.0
29.Lahti L, Torrente A, Elo LL, Brazma A, Rung J (2013) A
fully scalable online pre-processing algorithm for short
oligonucleotide microarray atlases. Nucleic Acids Res
41:e110 IF 8.3
30.Laiho A, Kotaja N, Gyenesei A, Sironen A (2013)
Transcriptome Profiling of the Murine Testis during the First
Wave of Spermatogenesis. PLoS One 8:e61558. IF 3.7
31.Laine A, Sihto H, Come C, Rosenfeldt MT, Zwolinska A,
Niemela M, Khanna A, Chan EK, Kahari V, KellokumpuLehtinen P, Sansom OJ, Evan GI, Junttila MR, Ryan KM,
Marine J, Joensuu H, Westermarck J (2013) Senescence
Sensitivity of Breast Cancer Cells Is Defined by Positive
Feedback Loop between CIP2A and E2F1. Cancer Discov
3:182-197. IF 10.1
32.Lehtimaki S, Lahesmaa R (2013) Regulatory T Cells Control
Immune Responses through Their Non-Redundant Tissue
Specific Features. Front Immunol 4:294.
33.Lehtinen L, Ketola K, Makela R, Mpindi J, Viitala M,
Kallioniemi O, Iljin K (2013) High-throughput RNAi screening
for novel modulators of vimentin expression identifies
MTHFD2 as a regulator of breast cancer cell migration and
invasion. Oncotarget 4:48-63. IF 6.6
34.Li L, Ginet V, Liu X, Vergun O, Tuittila M, Mathieu M, Bonny
C, Puyal J, Truttmann AC, Courtney MJ (2013) The nNOSp38MAPK Pathway Is Mediated by NOS1AP during
Neuronal Death. J Neurosci 33:8185-8201. IF 6.9
35.Lonnberg T, Chen Z, Lahesmaa R (2013) From a genecentric to whole-proteome view of differentiation of T helper
cell subsets. Brief Funct Genomics 12:471-482. IF 4.2
36.Lonnberg T, Yetukuri L, Seppanen-Laakso T, Lahesmaa R,
Oresic M (2013) T-cell activation induces selective changes
of cellular lipidome. Front Biosci (Elite Ed) 5:558-573. IF
3.5
37.Lund RJ, Emani MR, Barbaric I, Kivinen V, Jones M, Baker
D, Gokhale P, Nykter M, Lahesmaa R, Andrews PW (2013)
Karyotypically abnormal human ESCs are sensitive to HDAC
inhibitors and show altered regulation of genes linked to
cancers and neurological diseases. Stem Cell Res 11:10221036. IF 4.5
38.Mamaeva V, Sahlgren C, Linden M (2013) Mesoporous silica
nanoparticles in medicine-Recent advances. Adv Drug Deliv
Rev 65:689-702. IF 12.9
15
39.Mohazab L, Koivisto L, Jiang G, Kytomaki L, Haapasalo
M, Owen GR, Wiebe C, Xie Y, Heikinheimo K, Yoshida T,
Smith CE, Heino J, Haekkinen L, McKee MD, Larjava H
(2013) Critical role for alpha v beta 6 integrin in enamel
biomineralization. J Cell Sci 126:732-744. IF 5.9
49.Pouwels J, De Franceschi N, Rantakari P, Auvinen K,
Karikoski M, Mattila E, Potter C, Sundberg JP, Hogg
N, Gahmberg CG, Salmi M, Ivaska J (2013) SHARPIN
Regulates Uropod Detachment in Migrating Lymphocytes.
Cell Reports 5:619-628. IF 7.3
40.Najumudeen AK, Kohnke M, Solman M, Alexandrov K,
Abankwa D (2013) Cellular FRET-Biosensors to Detect
Membrane Targeting Inhibitors of N-Myristoylated Proteins.
PLoS One 8:e66425. IF 3.7
50.Prabhakar N, Nareoja T, von Haartman E, Sen Karaman
D, Jiang H, Koho S, Dolenko TA, Hanninen PE, Vlasov DI,
Ralchenko VG, Hosomi S, Vlasov II, Sahlgren C, Rosenholm
JM (2013) Core-shell designs of photoluminescent
nanodiamonds with porous silica coatings for bioimaging
and drug delivery II: application. Nanoscale 5:3713-3722. IF
6.2
41.Narva E, Pursiheimo J, Laiho A, Rahkonen N, Emani MR,
Viitala M, Laurila K, Sahla R, Lund R, Lahdesmaki H, Jaakkola
P, Lahesmaa R (2013) Continuous Hypoxic Culturing of
Human Embryonic Stem Cells Enhances SSEA-3 and MYC
Levels. PLoS One 8:e78847. IF 3.7
42.Narvi E, Jaakkola K, Winsel S, Oetken-Lindholm C, Halonen
P, Kallio L, Kallio MJ (2013) Altered TUBB3 expression
contributes to the epothilone response of mitotic cells. Br J
Cancer 108:82-90. IF 5.3
43.Natunen T, Martiskainen H, Sarajarvi T, Helisalmi S,
Pursiheimo J, Viswanathan J, Laitinen M, Makinen P,
Kauppinen T, Rauramaa T, Leinonen V, Alafuzoff I, Haapasalo
A, Soininen H, Hiltunen M (2013) Effects of NR1H3 Genetic
Variation on the Expression of Liver X Receptor alpha and the
Progression of Alzheimer’s Disease. PLoS One 8:e80700. IF
3.7
44.Natunen T, Parrado AR, Helisalmi S, Pursiheimo J, Sarajarvi
T, Makinen P, Kurkinen KMA, Mullin K, Alafuzoff I, Haapasalo
A, Bertram L, Soininen H, Tanzi RE, Hiltunen M (2013)
Elucidation of the BACE1 Regulating Factor GGA3 in
Alzheimer’s Disease. J Alzheimers Dis 37:217-232. IF 4.2
45.Nikula T, Mykkanen J, Simell O, Lahesmaa R (2013)
Genome-wide comparison of two RNA-stabilizing reagents
for transcriptional profiling of peripheral blood. Transl Res
161:181-188. IF 3.5
46.Nwaru BI, Takkinen H, Niemela O, Kaila M, Erkkola M,
Ahonen S, Haapala A, Kenward MG, Pekkanen J, Lahesmaa
R, Kere J, Simell O, Veijola R, Ilonen J, Hyoty H, Knip M,
Virtanen SM (2013) Timing of infant feeding in relation to
childhood asthma and allergic diseases. J Allergy Clin
Immunol 131:78-86. IF 12.0
47.Nwaru BI, Takkinen H-, Niemela O, Kaila M, Erkkola M,
Ahonen S, Tuomi H, Haapala A-, Kenward MG, Pekkanen J,
Lahesmaa R, Kere J, Simell O, Veijola R, Ilonen J, Hyoty H,
Knip M, Virtanen SM (2013) Introduction of complementary
foods in infancy and atopic sensitization at the age of 5
years: timing and food diversity in a Finnish birth cohort.
Allergy 68:507-516. IF 5.9
48.Peuhu E, Paul P, Remes M, Holmbom T, Eklund P, Sjoholm
R, Eriksson JE (2013) The antitumor lignan Nortrachelogenin
sensitizes prostate cancer cells to TRAIL-induced cell death
by inhibition of the Akt pathway and growth factor signaling.
Biochem Pharmacol 86:571-583. IF 4.6
16
51.Rantanen K, Pursiheimo J, Hogel H, Miikkulainen P,
Sundstrom J, Jaakkola PM (2013) p62/SQSTM1 regulates
cellular oxygen sensing by attenuating PHD3 activity through
aggregate sequestration and enhanced degradation. J Cell
Sci 126:1144-1154. IF 5.9
52.Sainio A, Nyman M, Lund R, Vuorikoski S, Bostrom P,
Laato M, Bostrom PJ, Jarvelainen H (2013) Lack of Decorin
Expression by Human Bladder Cancer Cells Offers New
Tools in the Therapy of Urothelial Malignancies. PLoS One
8:e76190. IF 3.7
53.Salmela A, Pouwels J, Maki-Jouppila J, Kohonen P,
Toivonen P, Kallio L, Kallio M (2013) Novel pyrimidine-2,4diamine derivative suppresses the cell viability and spindle
assembly checkpoint activity by targeting Aurora kinases.
Carcinogenesis 34:436-445. IF 5.6
54.Santos HM, Kouvonen P, Capelo J, Corthals GL (2013) Ontarget ultrasonic digestion of proteins. Proteomics 13:14231427. IF 4.1
55.Sarek G, Ma L, Enback J, Jarviluoma A, Moreau P, Haas
J, Gessain A, Koskinen PJ, Laakkonen P, Ojala PM (2013)
Kaposi’s sarcoma herpesvirus lytic replication compromises
apoptotic response to p53 reactivation in virus-induced
lymphomas. Oncogene 32:1091-1098. IF 7.3
56.Tahvanainen J, Kylaniemi MK, Kanduri K, Gupta B,
Lahteenmaki H, Kallonen T, Rajavuori A, Rasool O, Koskinen
PJ, Rao KVS, Lahdesmaki H, Lahesmaa R (2013) Proviral
Integration Site for Moloney Murine Leukemia Virus (PIM)
Kinases Promote Human T Helper 1 Cell Differentiation. J
Biol Chem 288:3048-3058. IF 4.6
57.Teittinen KJ, Laiho A, Uusimaki A, Pursiheimo J, Gyenesei
A, Lohi O (2013) Expression of small nucleolar RNAs in
leukemic cells. Cell Oncol 36:55-63. IF 2.4
58.Tuomela J, Sandholm J, Kauppila JH, Lehenkari P, Harris
KW, Selander KS (2013) Chloroquine has tumor-inhibitory
and tumor-promoting effects in triple-negative breast cancer.
Oncol Lett. Dec;6(6):1665-1672. IF 0.2
59.Tuomela S, Autio R, Buerki-Thurnherr T, Arslan O, Kunzmann
A, Andersson-Willman B, Wick P, Mathur S, Scheynius A,
Krug HF, Fadeel B, Lahesmaa R (2013) Gene Expression
Profiling of Immune-Competent Human Cells Exposed to
17
Engineered Zinc Oxide or Titanium Dioxide Nanoparticles.
PLoS One 8:e68415. IF 3.7
60.Tuomela S, Lahesmaa R (2013) Early T helper cell
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61.Tyagarajan SK, Ghosh H, Yevenes GE, Imanishi SY, Zeilhofer
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Gephyrin Postsynaptic Aggregation and GABAergic
Synaptic Function in a Calpain-dependent Mechanism. J
Biol Chem 288:9634-9647. IF 4.8
62.Velasquez EV, Rios M, Elena Ortiz M, Lizama C, Nunez E,
Abramovich D, Orge F, Oliva B, Orellana R, Villalon M, Moreno
RD, Tesone M, Rokka A, Corthals G, Croxatto HB, Parborell
F, Owen GI (2013) Concanavalin-A Induces Granulosa
Cell Death and Inhibits FSH-Mediated Follicular Growth
and Ovarian Maturation in Female Rats. Endocrinology
154:1885-1896. IF 4.7
63.Vihervaara A, Sergelius C, Vasara J, Blom MAH, Elsing AN,
Roos-Mattjus P, Sistonen L (2013) Transcriptional response
to stress in the dynamic chromatin environment of cycling and
mitotic cells. Proc Natl Acad Sci U S A 110:E3388-E3397.
IF 9.7
64.Vuoristo S, Toivonen S, Weltner J, Mikkola M, Ustinov J,
Trokovic R, Palgi J, Lund R, Tuuri T, Otonkoski T (2013) A
Novel Feeder-Free Culture System for Human Pluripotent
Stem Cell Culture and Induced Pluripotent Stem Cell
Derivation. PLoS One 8. IF 3.7
65.Wei W, Gyenesei A, Semple CAM, Haley CS (2013)
Properties of Local Interactions and Their Potential Value in
Complementing Genome-Wide Association Studies. PLoS
One 8:e71203. IF 3.7
66.Westermarck J, Ivaska J, Corthals GL (2013) Identification
of Protein Interactions Involved in Cellular Signaling. Mol Cell
Proteomics 12:1752-1763. IF 7.2
67.Wittig R, Rosenholm JM, von Haartman E, Hemming J,
Genze F, Bergman L, Simmet T, Lindén M, Sahlgren C.
Active targeting of mesoporous silica drug carriers enhances
gamma-secretase inhibitor efficacy in an in vivo model for
breast cancer. Nanomedicine (Lond) (2013). IF 5.3
68.Ylilauri M, Mattila E, Nurminen EM, Kapyla J, Niinivehmas SP,
Maatta JA, Pentikainen U, Ivaska J, Pentikainen OT (2013)
Molecular mechanism of T-cell protein tyrosine phosphatase
(TCPTP) activation by mitoxantrone. BBAProteins and
Proteomics 1834:1988-1997. IF 3.7
PERSONNEL 2013
Administration
LAHESMAA Riitta, Director, Professor,
Group Leader
COFFEY Eleanor, Vice-Director, Adjunct
Professor, Group Leader
ALANKO Satu, Coordinator
GRÖNROOS Sirkku, Administrative
Planning Officer
HIRVENSALO Eva, Clerical Official (on
leave)
JASMAVAARA Aila, Clerical Official
LAHDENPERÄ Anne, Coordinator
LUMMEVUO Tiina, Clerical Official
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, Head of
bioinformatics
GHIMIRE Bishwa, IT Designer
HAWKINS David, Group Leader
LUND Riikka, Head of Laboratory
PURSIHEIMO Juha-Pekka, Senior
Scientist
JUNNI Päivi, Laboratory Technician
JUNTTILA Sini, Project Engineer
KAUKO Leni, Researcher
KONKI Mikko, Research Assistant
KYTÖMÄKI Leena, Project Engineer
LAIHO Asta, Acting head of
bioinformatics
MÄKELÄ Ville-Veikko, Research
Technician
NURMI Miina, Laboratory Technician
PIETILÄ Sami, IT-designer
RISSANEN Oso, Laboratory Technician
SOIDINSALO Pasi, Undergraduate
student
VENHO Reija, Laboratory Technician
VIRTANEN Eveliina, Project Engineer
VUORIKOSKI Sanna, Researcher
Cell Imaging Core
COFFEY Eleanor, Adjunct Professor,
Head of the Cell Imaging Core
KANKAANPÄÄ Pasi, Coordinator of the
Cell Imaging Core (January–June)
ADEL Ketlin, Project Engineer
18
SANDHOLM Jouko, Research
Coordinator
SAARI Markku, Research Coordinator
PALANI Senthil, CIC Part-time
Technical Support
Proteomics Facility
CORTHALS Garry, Group Leader, Head
of Proteomics
HAAPANIEMI Pekka, Laboratory
Technician
HEINONEN Arttu, Laboratory Engineer
IMANISHI Susumu, Senior Scientist
KOUVONEN Petri, Senior Scientist
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
JUNTTILA Sini, Graduate Student
KYTÖMÄKI Leena, Project Engineer
LAIHO Asta, Project Engineer
PIETILÄ Sami, Technical Team Officer
Virus Vector facility
COFFEY Eleanor, Group Leader,
Coordinator
ADEL Ketlin, Laboratory Technician
LINKO Linnéa, Quality Assurance
Officer
Mechanisms and Biosensors of
GTPases
ABANKWA Daniel, Group Leader,
Academy of Finland Research Fellow
BLAZEVICS Olga, Post-doctoral Fellow
GUZMAN Camilo, Post-doctoral Fellow
LIGABUE Alessio, Post-doctoral Fellow
NAJUMUDEEN Arafath, Graduate
Student
OETKEN-LINDHOLM Christina, Postdoctoral Fellow
SILJAMÄKI Elina, Post-doctoral Fellow
SOLMAN Maja, Graduate Student
Lymphocyts and Inflammation
CHEN Zhi Jane, MD, PhD, Group
Leader, Academy of Finland Research
Fellow
CSENDES Brigitta, Graduate Student
KHAN Mohd Moin, Graduate Student
MOHAMMAD Imran Ahammad,
Undergraduate Student
19
Protein Kinase Regulation of Brain
Development and Disease
COFFEY Eleanor, Group Leader,
DESHPANDE Prasannakumar,
Graduate Student
FLINKMAN Dani, Graduate Student
FREEMANTLE Erika, Post-Doctoral
Fellow
HOLLOS Patrik, Graduate Student
KOMULAINEN Emilia, Graduate
Student
MARCHISELLA, Francesca, Graduate
Student
MISIN Olavi, Undergraduate Student
MOHAMMAD Hasan, Graduate
Student
PADZIK Artur, Post-Doctoral Fellow
PYÖKÄRI Susanna, Laboratory
Manager
VARIDAKI, Artemis, Graduate Student
ZDROJEWSKA Justyna, Graduate
Student
Translational Proteomics
CORTHALS Garry, Group Leader, Head
of Proteomics
HAAPANIEMI Pekka, Laboratory
Technician
HEINONEN Arttu, Laboratory Engineer
IMANISHI Susumu, Senior Scientist
KOTTAHACHCHI Darshana, Graduate
Student
KOUVONEN Petri, Senior Scientist
LUKASH Tanya, Senior Scientist
MUTH-PAWLAK Dorotha, Senior
Scientist
NEES Susanne, Coordinator
NGUYEN Mimi, Senior Scientist
ROKKA Anne, Senior Scientist
SUNI Veronika, Graduate Student
VEHMAS Anni, Graduate Student
Organisation of Neuronal Signaling
Pathways
COURTNEY Michael, Group Leader,
Professor
LI Lili, Graduate Student
MARTINSSON Peter, Post-doctoral
Fellow
MELERO FERNANDEZ-DE MERA
Raquel
NÄRVÄINEN Jarkko, Integration
Specialist
SEPPÄNEN Aila, Laboratory Technician
VERGUN Olga, Post-doctoral Fellow
WANG Xijun, Graduate Student
Computational Biomedicine
ELO Laura, Group Leader, Adjunct
Professor
AFZAL Saira, Graduate Student
CHAKROBORTY Deepankar,
Undergraduate student
GHIMIRE Bishwa, Graduate Student
JAAKKOLA Maria, Graduate Student
KOSKINEN Anna, Undergraduate
Student
LAAJALA Teemu Daniel, Graduate
Student
LAIHO Asta, Graduate Student
LE THI THANH An, Post-doctoral
Fellow
20
LEHTINEN Oona, Undergraduate
student
MAHMOUDIAN Mehrad,
Undergraduate student
PURSIHEIMO Anna, Graduate Student
RANNIKKO Sami, Undergraduate
Student
SANTOS Rafael, Undergraduate
student
SEYEDNASROLLAH Fatemehsadat,
SINGARAVELU Kalaimathy, Graduate
Student
SUOMI Tomi, Graduate Student
Cytoskeletal and Survival Signaling
ERIKSSON John, Group Leader,
Professor
CHENG Fang, Post-doctoral Fellow
GULLMETS Josef, Graduate Student
HYDER Claire, Post-doctoral Fellow
JOKO Alia, Graduate Student
LINDQVIST Julia, Graduate Student
LINDSTRÖM Michelle, Undergraduate
Student
MOGOLLON Isabel, Undergraduate
Student
MOHANASUNDARAM Ponnuswamy,
Graduate Student
NIEMELÄ Erik, Graduate Student
ISONIEMI Kimmo, Graduate Student
JOKO Alia, Graduate Student
PAUL Preethy, Post-doctoral Fellow
PYLVÄNÄINEN Joanna, Graduate
Student
RAJENDRAN Senthil Kumar, Postdoctoral Fellow
SAARENTO Helena, Research
Associate
TORVALDSON Elin, Graduate student
WIKSTRÖM Vilhelm, Undergraduate
Student
WISTBACKA Num, Undergraduate
Student
ÖRN Fanny, Undergraduate Student
Epigenomics
HAWKINS David, Group Leader
PASUMARTHY Kalyan Kumar, Postdoctoral Fellow
VALENSISI Cristina, Post-doctoral
Fellow
Cell Adhesion and Cancer
IVASKA Johanna, Professor, Group
Leader
ALANKO Jonna, Graduate Student
ARJONEN Antti, Post-doctoral Fellow
DE FRANCESCHI Nicola, Graduate
Student
GEORGIADOU Maria, Post-doctoral
Fellow
KAUKONEN Riina, Graduate Student
LAASOLA Petra, Technician
LILJA Johanna, Undergraduate
Student
NÄRVÄ Elisa, Post-doctoral Fellow
PEUHU Emilia, Post-doctoral Fellow
SAARI Markku, Research assistant
SAHGAL Pranshu, Graduate Student
SIIVONEN Jenni, Technician
VIRTAKOIVU Reetta, Graduate Student
Hypoxia in Cell Survival
JAAKKOLA Panu, Group Leader
HEIKKINEN Pekka, Graduate Student
HÖGEL Heidi, Graduate Student
KALEVO-MATTILA Taina, Technician
MIIKKULAINEN Petra, Graduate
Student
RANTANEN Krista, Post-doctoral
Fellow
SILÉN Jonna, Graduate Student
Mitosis and drug discovery
KALLIO Marko, Group Leader, Adjunct
Professor
LAINE Leena, Post-doctoral Fellow
MÄKI-JOUPPILA Jenni, Graduate
Student
NARVI Elli, Post-doctoral Fellow
PRUIKKONEN, Sofia, Graduate
Student
TAMBE Mahesh, Graduate Student
Molecular Systems Immunology
and Stem Cell Biology
LAHESMAA Riitta, Director, Professor,
Group Leader
BHOSALE Santosh, Graduate Student
DIRASANTHA Obaiah, Undergraduate
Student
EDELMAN Sanna, Post-doctoral Fellow
GODLETT David R., Visiting Professor
HAKKARAINEN Marjo, Laboratory
Technician
HEINONEN Mirkka, Graduate Student
HEINONEN Sarita, Laboratory
Technician
HURME Antti, Undergraduate Student
HÄMÄLISTÖ Saara, Post-doctoral
Fellow
JALONEN Jussi, Undergraduate
Student
JUNNI Päivi, Laboratory Technician
KALLIONPÄÄ Henna, Graduate
Student
KANDURI Kartiek, Graduate Student
KHAN MOHN Moin, Graduate Student
KOSOLA Sakari, Undergraduate
Student
LAAJALA Essi, Graduate Student
LAHDENPERÄ Anne, Laboratory
Manager
LEHTIMÄKI Sari, Post-doctoral Fellow
LIETZEN Niina, Post-doctoral Fellow
LUND Riikka, Senior Scientist
MOULDER Robert, Senior Scientist
NGYEN Elizabeth, Post-doctoral Fellow
PIETILÄ Elina, Laboratory Technician
RAHKONEN Nelly, Post-doctoral Fellow
RAO Anjana, Visiting Professor
RAO Kanury, Visiting Professor
RASOOL Omid, Adjunct Professor,
Senior Scientist
REDDY Maheswara Emani, Postdoctoral Fellow
SALMI Jussi, Senior scientist
SALO Verna, Graduate Student
STOCKINGER Brigitta, Visiting
Professor
STUBB Aki, Undergraduate Student
TRIPATHI Subhash, Graduate Student
TUOMELA Soile, Post-doctoral Fellow
ULLAH Ubaid, Post-doctoral Fellow
VIITALA Miro, Undergraduate Student
WIJMENGA Cisca, Visiting Professor
ÖLING Viveka, Post-doctoral Fellow
Quality Assurance Unit
LINKO Linnéa, Group Leader, Adjunct
Professor
Computational Systems Biology
LÄHDESMÄKI Harri, Group Leader,
Professor
BANAFSHEH Khakipoor,
BASAK Eraslan, Undergraduate
Student
GÖKCEN Eraslan, Undergraduate
Student
INTOSALMI Jukka, Post-doctoral
Fellow
KANDURI Kartiek, Graduate Student
KÄHÄRÄ Juhani, Undergraduate
Student
LAAJALA Essi, Graduate Student
LARJO Antti, Graduate Student
MALONZO Maia, Graduate Student
MANNERSTRÖM Henrik, Graduate
Student
NOUSIAINEN Kari, Graduate Student
OSMALA Maria, Graduate Student
RAUTIO Sini, Graduate Student
SOMANI Juhi, Graduate Student
VATANEN Tommi, Graduate Student
ÄIJÖ Tarmo, Graduate Student
Cell Culture Models For Tumor Cell
Invasion and Epithelial Platicity
NEES Matthias, Group Leader
AHONEN Ilmari, Graduate Student
HÄRMÄ Ville, Post-doctoral Fellow
MISHRA Mrinal, Undergraduate
Student
ROBINSON Sean, Graduate Student
SCHUKOV Hannu-Pekka,
TOIVONEN Pauliina, Laboratory
technician
TORISEVA Mervi, Post-doctoral Fellow
VIRTANEN Johannes, Laboratory
technician
ÅKERFELT Malin, Post-doctoral Fellow
Computational Biology
NYKTER Matti, Group Leader
ANNALA Matti, Graduate Student
GRANBERG Kirsi, Post-doctoral Fellow
HÄYRYNEN Sergei, Undergraduate
Student
KESSELI Juha, Post-doctoral Fellow
KIVINUMMI Kati, Post-doctoral Fellow
KYTÖLÄ Ville,Undergraduate Student
LAAKSONEN Maria, Undergraduate
Student
LEHTINEN Birgitta, Undergraduate
Student
LIUKSIALA Thomas, Undergraduate
Student
RANTAPERO Tommi, Graduate
Student
RUUSUVUORI Pekka, Post-doctoral
Fellow
TABARO Francesco, Graduate Student
YLIPÄÄ Antti, Graduate Student
21
Systems Medicine
OREŠIČ Matej, Group Leader
Tuulia Hyötyläinen, Senior Scientist
Protein Crystallography
PAPAGEORGIOU Tassos, Group
Leader, Adjunct Professor
AMODA Adeleke, Undergraduate
Student
BATTULA Pradeep, Graduate Student
BHADARI Sagar, MSc Student
LASCORZ Marta, Visiting Scientist
MULETA Abdi, Graduate Student
POUDEL Nirmal, MSc Student
SEID Amin, MSc Student
SONKAR Kirti, Visiting Scientist
SUBEDI Bishwa, Graduate Student
Integrin activity in disease
POUWELS Jeroen, Group Leader,
Adjunct Professor
KHAN Meraj Hasan, Graduate Student
SKALDIN Maksym, Graduate Student
Cell fate
SAHLGREN Cecilia, Group Leader
ANTFOLK Daniel, Graduate Student
ANTILA Christian, Graduate Student
LANDOR Sebastian, Graduate Student
LERCHE Martina, Undergraduate
Student
MAMAEVA Veronika, Post-doctoral
Fellow
NIEMI Rasmus, Graduate Student
NIINIMAKI Jenni, Undergraduate
Student
PARAMANOV Valeriy, Graduate
Student
PRABHAKAR Neeraj, Graduate
Student
RÅTTS Natalie, Laboratory Technician
SJÖQVIST Marika, Graduate Student
Regulation and Function of Heat
Shock Transcription Factors
SISTONEN Lea, Group Leader,
Professor
ASPELIN Camilla, Graduate Student
BERGMAN Heidi, Graduate Student
BJÖRK Johanna, Post-doctoral Fellow
BLOM Malin, Undergraduate Student
BUDZYNSKI Marek, Graduate Student
DA SILVA Alejandro, Undergraduate
Student
ELSING Alexandra, Graduate Student
ESTRADA Marianna, Undergraduate
Student
HENRIKSSON Eva, Senior Scientist
HIMANEN Samu, Undergraduate
Student
JENSEN Maria, Undergraduate Student
JOUTSEN Jenny, Graduate Student
LUNDSTEN Emine, Graduate Student
LUOTO Jens, Undergraduate Student
LUSTIG Heidi, Undergraduate Student
ORASNIEMI Satu, Undergraduate
Student
PUUSTINEN Mikael, Undergraduate
Student
ROOS-MATTJUS Pia, Senior Scientist
SAARENTO Helena, Research
Assistant
SANDQVIST Anton, Post-doctoral
Fellow
VAINIO Petra, Graduate Student
VIHERVAARA Anniina, Graduate
Student
Cancer Cell Signaling
WESTERMARCK Jukka, Group Leader,
Professor
ARSIOLA Tiina, Head of Laboratory
KALEVO-MATTILA Taina, Laboratory
Technician
KAUKO Otto, Graduate Student
KAUR Amanpreet, Graduate Student
LAINE Anni, Post-doctoral Fellow
LIPSANEN Anna, Post-doctoral Fellow
OKKERI Juha, Post-doctoral Fellow
PUKONEN Inga, Laboratory Technician
RUPP Christian, Post-doctoral Fellow
SITTIG Eleonora, Graduate Student
QIAO Xi, Graduate Student
Adenosine Deaminases
ZAVIALOV Andrey, Group Leader,
LIU Chengquian, Graduate Student
MUKIIENKO Yuliia, Graduate Student
RAI Balwant, Graduate Student
SKALDIN Maksym, Graduate Student
THE FINNISH MICROARRAY AND
SEQUENCING CENTRE
http://fmsc.btk.fi
Contact details:
Turku Centre for Biotechnology, BioCity,
Tykistökatu 6A, P.O. Box 123, FIN-2050 Turku, Finland.
Tel. +358-2-333 7697 Fax +358-2-251 8808.
Email: fmsc@btk.fi
Heads/Coordinator
Prof. Riitta Lahesmaa
Dr. Attila Gyenesei (Head of bioinformatics)
MSc Asta Laiho (Acting head of bioinformatics)
Dr. Riikka Lund (Head of laboratory)
Dr. Juha-Pekka Pursiheimo
Technical Team
Bishwa Ghimire, Bogata Fezazi, Päivi Junni, Sini Junttila, Leni
Kauko, Leena Kytömäki, Ville-Veikko Mäkelä, Miina Nurmi, Sami
Pietilä, Oso Rissanen, Reija Venho, Eveliina Virtanen, Sanna
Vuorikoski, Pasi Soidinsalo (undergraduate student), Mikko Konki
(undergraduate student)
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 data analysis. The Centre also regularly
organizes courses, symposia and training for its users. Seminars
and practical courses are held frequently to facilitate knowledge
transfer within the field. Since 2010 FMSC has been a key member
in the Biocenter Finland national infrastructure program. According
to the division of tasks
within the Genome-Wide Methods network, our Centre focuses
on developing technologies in the areas of gene expression and
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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
Academy of 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 2013 the Centre carried out 87 projects on NGS
and microarray platforms from 49 research groups and analysed
more than 2000 samples. The QPCR service ran 1256 plates
and was used by 41 research groups. The Centre’s Sanger
sequencing service analysed 4827 samples for 88 research
projects. With our contribution, many papers were published
last year in high-quality journals, such as Nature Immunology
and Nature Methods.
Publications with FMSC contributions and co-authors in 20112013
Publications
FMSC contributions
FMSC co-authors
2013
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12
2012
46
13
2011
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2
From left to right. Front row: Päivi Junni, Eveliina Virtanen, Miina Nurmi, Bishwa
Ghimire, Leena Kytömäki and Sini Junttila. Back row: Mikko Konki, Ville-Veikko
Mäkelä, Asta Laiho, Riikka Lund, Sanna Vuorikoski, Pasi Soidinsalo and Oso
Rissanen.
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CELL IMAGING CORE
http://www.btk.fi/cell-imaging/
Cell Imaging Core Personnel:
Director: Eleanor Coffey, PhD (Pasi Kankaanpää, MSc., stand-in
January-June 2013)
Address: Turku Centre for Biotechnology
BioCity, Tykistokatu 6, P.O. Box 123, FI-20520 Turku, Finland.
Tel: +358-2-3338605
Email: ecoffey@btk.fi
Personnel:
Research Coordinators: Jouko Sandholm, MSc, Markku Saari,
MSc
Project engineer: Ketlin Adel
CIC technical support: Senthil Palani, MSc
CIC partner technical support at Åbo Akademi: Jari Korhonen, MSc
Steering Committee:
Prof. Olli Carpén, MD, PhD, University of Turku; Prof. John
Eriksson, PhD, Åbo Akademi University; Prof. Jyrki Heino, MD,
PhD, University of Turku; Prof. Pekka Hänninen, PhD, University
of Turku; Prof. Sirpa Jalkanen, MD, PhD, University of Turku; Prof.
Riitta Lahesmaa, MD, PhD, University of Turku; Prof. Olli Lassila,
MD, PhD; Prof. Matti Poutanen, PhD, University of Turku; Prof. Lea
Sistonen, PhD, Åbo Akademi University; Prof. Kid Törnquist, PhD,
Åbo Akademi University.
The Cell Imaging Core (CIC) provides state-of-the-art cell imaging
and flow cytometry instruments and services to researchers
nation-wide, our customer base deriving largely from the Biocity
Turku campus area. We provide open access services that benefit
academic and industrial users alike. Our technology platform hosts
state-of-the-art instruments for microscopy and flow cytometry,
with expertise covering a broad range of imaging and flow
cytometry modalities.
From left to right, back row: Senthil Palani, Jari Korhonen, Ketlin Adel, Jouko
Sandholm, Markku Saari. front row: Pasi Kankaanpää and Eleanor Coffey.
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The Cell Imaging Core offers one-to-one training and consultation
on instrument operation, experimental design and image analysis.
We contribute to ongoing formal education by organizing
training courses and workshops, while at once evaluating new
advances in hardware and software tools. During 2013, our
teaching efforts totaled more than 100 hours, including teaching
at the Turku Bioimaging summer school. In addition, the Lost
in Imaging webinar series continued for the third consecutive
year. Our goal is to provide instrumentation and know-how that
supports the research efforts of the BioCity Turku campus, while
at once we broaden the scope of this research by introducing
new technological and analysis solutions to the community.
CIC staff have developed free-access Flowing Software for flow
cytometry (www.flowingsoftware.com), and BioImageXD (www.
bioimagexd.net) for high-end optical image data visualization and
analysis. Areas of special expertise include fluorescence lifetime
imaging microscopy (FLIM), live cell imaging, high-sensitivity
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confocal imaging, fluorescence correlation spectroscopy (FCS),
laser-capture microdissection, fluorescence assisted cell sorting
(FACS), automated high-throughput flow cytometry and atomic
force microscopy.
PROTEOMICS FACILITY
During 2013, CIC acquired a total internal reflection (TIRF)
microscope (TIRF 3, Carl Zeiss) for high resolution imaging. We
continued our collaboration agreements with other major owners
of light microscopes in BioCity Turku, providing reservation
infrastructure and centralized advertising for bio-imaging
instruments campus-wide through cooperation agreements.
These include multi-photon super-resolution imaging devices,
slide scanning, live content imaging, atomic force microscopy and
calcium imaging. This cooperation has enabled us to broaden the
range of services that can be made available to researchers in a
centralized manner.
Director:
Garry Corthals, PhD (2005 – July 2014).
Turku Centre for Biotechnology,
BioCity, Tykistökatu 6A, 20520 Turku, Finland.
Tel. +358-2-333 8604, Fax. +358-2-2158808.
E-mail: ptoteomics_service@btk.fi
During 2013, CIC 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 and flow cytometry unit in Finland. In 2013,
our services (including collaboration instruments) were used
by approximately 300 people from 100 research groups, 12%
of whom were “external users” (from outside of the University
of Turku and Åbo Akademi University). We look forward to
continued expansion of infrastructure and services available in
the coming years, in anticipation of the successful completion
of the EuroBioimaging
The cell imaging core is best contacted by our designated email
addresses and phone numbers: microscopy@btk.fi (044-923 1356)
and flow@btk.fi (044-923 1322). We warmly thank our funders,
users and collaborators for a most productive 2013.
Major Instrumentation:
• Microscopy: Zeiss LSM-780, Zeiss-510-META, StereoLumar V12, Lambert FLIM, Zeiss P.A.L.M. LCM, TIRF 3
Zeiss, Leica TCS SP5 Matrix.
• Flow cytometry: BD-FACS Aria II Cell Sorter, BD-LSRII,
BD-FACS Caliber, BD-FACScan.
Funding:
Biocenter Finland, the University of Turku, Åbo Akademi University,
the Ministry of Social Affairs and Health.
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http://www.btk.fi/proteomics
Personnel:
Senior scientists: Anne Rokka, PhD; Dorota Muth-Pawlak, PhD;
Susumu Imanishi, PhD; Petri Kouvonen, PhD, Laboratory Engineer:
Arttu Heinonen, MSc; Technician: Pekka Haapaniemi, MSc
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. The Facility has developed a wide
basis of operation and expertise in quantitative proteomics, posttranslational modification analysis, biological mass spectrometry
and allied bioinformatic procedures.
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, post-doctoral 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 and nationally from Biocentre Finland. Nationally, the
facility spearheads mass spectrometric services and training
and in quantitative analysis of proteins and proteomes, and
analyses of PTMs. Consequently major focuses for the facility
have been the development of cutting-edge implementation
of emerging technologies and methods in these fields.
Furthermore the facility has developed a suite of methods
specifically aimed at the analysis of tissues and proximal fluids,
and is currently ideally suited to engage in clinical research
collaborations and ongoing developments with the national
and local Biobanks.
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Analytical services:
The facility provides mass spectrometry-based analytical services
and offers researches access to sophisticated instrumentation
that enables high-content proteome measurements. Moreover the
facility encourages its users to learn and co-develop MS methods,
thereby increasing the ocal knowledge base, users and community
of scientists versed in proteomics and mass spectrometry.
A full representation of our services in 2013 were as
follows:
• Proteome-wide 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
labelling with reagents such as iTRAQ, or using our in-house
developed workflows for label-free analysis using MS1 or
MS2 data.
• Label-free quantitation for clinical studies – we have
established a framework for label-free quantitative analysis,
particularly useful for large-scale clinical studies.
• Targeted quantitation by selected reaction monitoring (M/
SRM) – sensitive quantitative measurements of specific sets
of proteins (up to 100) from complex samples. useful for
HTP validation and large cohort studies.
• Post-translational modifications – a long standing history
with phosphorylation analysis, both in terms of enrichment
and validation.
• Biological mass spectrometry – various analytical
measurements for protein, peptide and small molecules,
mass determination and peptide and protein purity
determination are offered.
• Bioinformatics – in all areas of proteomics. Additionally ties
have been strengthened with the group of Laura Elo who
assists in computational and statistical analyses.
Major mass spectrometry instrumentation:
1. LTQ Orbitrap Velos Pro with ETD; 2. Q Exactive; 3. TSQ Vantage;
and 4. Q-Star Elite
Funding:
University of Turku, Åbo Akademi University, Biocenter Finland,
the Systems Biology Research Program, European Cooperation
in Science and Technology (e-COST) and 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: Anne Rokka, Pekka Haapaniemi, Dorota Muth-Pawlak, Susumu
Imanishi and Garry Corthals.
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PROTEIN CRYSTALLOGRAPHY
CORE FACILITY
http://www.btk.fi/crystallography/
Head:
Anastassios C. Papageorgiou, PhD,
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
Technical Team:
Technical support: Juha Strandén, Pasi Viljakainen. Computational
support: Petri Vahakoski, Mårten Hedman
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 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.
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 University; 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. There is regular access to synchrotrons (e.g.
ESRF, DIAMOND, DESY) and we have recently started to explore in
situ diffraction options. 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
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The X-ray generator and imaging plate detector.
Diffraction image recorded in the facility.
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BIOINFORMATICS CORE
http://www.btk.fi/bioinformatics
Contact information:
Tykistökatu 6B, FI-20521 Turku, Finland.
Tel. +358-2-333 8634, Fax +358-2-251 8808.
Email: bioinfo@btk.fi
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.
Heads/Coordinators
Dr. Konstantin Denessiouk (Structural Bioinformatics) Dr. Attila
Gyenesei (Head of Bioinformatics), MSc Asta Laiho (Acting Head
of Bioinformatics)
Technical Team:
Bhanupratap Singh Chouhan, Sini Junttila, Asta Laiho, Leena
Kytömäki, Bishwa Ghimire, Sami Pietilä
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 facility is to apply
methods and techniques of bioinformatics to study biological
macromolecules, their interactions and function. We work in
close co-operation 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 facility complements experimental
genomics and transcriptomics by storing, analysing and integrating
data. The core provides services in the analysis of microarray and
deep sequencing data. The team takes advantage of in-house
robust super-computing facility 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 the Bioinformatics Core are:
• Experimental design consultation
• Data analysis of various microarray and deep sequencing
data types
• Data analysis education and training
• Computer-based analysis of protein-protein and proteinligand interactions
• Computer-aided prediction and intelligent molecular
modeling and design
• Computer-based ligand docking Analysis and prediction of
effects of molecular recognition and mutations on protein
function
From left to right: Sami Pietilä, Asta Laiho, Leena Kytömäki, Bishwa Ghimire and
Sini Junttila.
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VIRUS VECTOR FACILITY
http://www.btk.fi/viral-vectors
Head of the Unit
Eleanor Coffey, PhD,
Turku Center for Biotechnology
BioCity, Tykistokatu 6, P.O. Box 123, FI-20520, Turku, Finland.
Consultant on Retroviruses: Jukka Westermarck, MD, PhD
Consultant on Adenoviruses: Mikko Savantaus, MD, PhD
Consultant on Lenti Vectors: Jari Heikkilä
Consultant on Herpes Simplex Virus: Veijo Hukkanen
Personnel
Laboratory Technician: Ketlin Adel
Quality Assurance: Linnéa Linko
The Virus Vector Facility has over ten years of experience
producing viral vectors for local and national research groups. We
have participated since 2010 in the national infrastructure network
on Viral Gene Transfer, funded by Biocenter Finland. 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 expressing genes of interest, as a
research service for customers
• produces high-titer lenti vectors using customer plasmids
• provides a range of quality assurance checks of viral prep
yield and activity as a service
•maintains a fully equipped bio-safety level-2 lab for
researchers wishing to produce their own vectors
• supplies working protocols and one-to-one training on
production and safe handling of adeno and lenti vectors as
a service to customers
•coordinates a network of local experts from whom
consultation on design of viral vectors can be sought
The virus vector facility has a national, long-standing customer
base providing services to researchers in the universities of Turku,
Oulu and Helsinki and to a lesser degree to biotech companies. In
addition to customer service, our infrastructure is used by 50 local
researchers that produce adenoviruses, adeno-associated virus,
retroviruses and lentiviral vectors for their research. These vector
tools are used to obtain high efficiency gene transfer in difficult
to transfect cells such as primary cultures of T lymphocytes and
neurons and for in vivo cancer studies. Use of viral gene transfer
for gene knockdown including stable knockdown studies is also
popular.
To build on local expertise in gene transfer technologies, the
Virus Vector Facility networks with experts in viral vector design.
Thus a number of local experts on retroviruses and alpha-viruses
are available for consultation on vector design, production and
concentration. Turku Viral Vector Facility follows without exception
the safety guidelines of the Geenitekniikan Lautakunta.
From left to right: Anna Lipsanen, Ketlin Adel, Eleanor Coffey and Linnéa Linko.
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MECHANISMS AND BIOSENSORS
OF GTPASES
http://www.btk.fi/research/research-groups/abankwa/
Principal investigator:
Daniel Abankwa, PhD, Docent (Adjunct Professor) at Åbo Akademi
University, Academy of Finland Research Fellow.
Tel. +358-2-3336969, Fax. +358-2-3338000.
Email: daniel.abankwa@btk.fi
Biography:
Daniel Abankwa (b. 1972) graduated in Chemistry (Dipl. Chem.) from
the Georg-August University in Göttingen in 1997 and received his
PhD in Molecular Neurobiology from the Heinrich-Heine University
Düsseldorf (2001). In 2002, he joined Prof. Horst Vogel at the EPFL
in Lausanne as a postdoc working with fluorescence methods to
study membrane proteins. In 2006, he went to the Institute for
Molecular Bioscience in Brisbane, Australia with an advanced
research fellowship from the Swiss National Science Foundation to
join the group of Prof. John Hancock. Since then his work is focused
on mechanisms of the nanoscale organisation (nanoclustering) of
small GTPases in the plasma membrane and its critical impact on
signalling. He discovered a novel switch III-region in H-ras, which
directs the reorientation of the protein on the membrane. In 2008
he joined Prof. Kirill Alexandrov as a junior group leader at the same
institute, heading projects on Rho protein membrane anchorage,
Rab nanoclustering and a chemical screening project to identify
nanoclustering and lipid transferase inhibitors. In July 2010, Daniel
joined the Turku Centre for Biotechnology. In June 2011 he became
docent/ adjunct professor at Åbo Akademi University and since
September 2011 he is holding an Academy of Finland Research
Fellowship.
Our research focuses on understanding the nanoscale organisation
of small GTPases, in particular oncogenic Ras. Like many
signalling proteins, Ras is cytoplasmically anchored to the plasma
membrane, where it is highly concentrated within nanometer
regions (nanocluster). Nanoclustering renders the associated
signalling system more efficient. We aim at understanding and
targeting this signalling architecture, by studying the determinants
in the structure of Ras (e.g. the orientation-switch III) and of
nanocluster modulating proteins. We employ quantitative
fluorescence microscopic techniques, computational modelling,
tailored fluorescence biosensor assays for compound and siRNA
screening, molecular cell biological approaches, as well as
tumour models to identify new nanocluster modulators as cancer
biomarkers and targets.
Research Questions:
• Which are the molecular and structural determinants of the
GTPase nanoscale organisation (nanoclustering) on the
membrane?
• Can we pharmacologically interfere with specific nanoclusters
or nanocluster modulatory proteins?
•In which physiological processes is nanoclustering
particularly significant?
• Do other membrane anchored signalling proteins also exploit
nanoclustering for robust signal transmission?
Personnel:
Post-doctoral Fellows: Olga Blazevics, PhD; Camilo Guzman,
PhD; Alessio Ligabue, PhD; Christina Oetken-Lindholm, PhD; Elina
Siljamäki, PhD; Graduate students: Arafath Kaja Najumudeen,
MSc; Maja Solman, MSc
Description of the project
Cancer is among the most common causes of deaths in humans.
It is caused by the accumulation of mutations in genes, which
ultimately lead to uncontrolled cell growth and spreading. The
small GTPase Ras is highly mutated in human cancers, where
it drives as a constitutively active protein cell transformation.
However, several approaches to block oncogenic Ras have
failed in the past 25 years, which earned it the premature
status of an undrugable protein. In the wake of personalized
medicine, which aims at targeting several components that are
misregulated, interest in inhibiting oncogenic Ras as one of the
cancer hallmarks has recently been reprioritized. Major funding
bodies (e.g. NIH-NCI oncogene initiative) and companies
worldwide currently support intensive research programs for
anti-Ras drugs.
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Ras orientation-switch III mutations affect nanoclustering and signalling.
(i) A conformational equilibrium of Ras on the membrane is guided by a novel
switch III. (ii) We showed that orientation-switch III mutants differentially interact with
galectin-1, a nanocluster modulator. This leads to specific nanoclustering responses
(Guzman C 2014, JBC). Nanoclusters, not free Ras, are sites of effector recruitment.
Thus signalling output follows nanoclustering. This critical mechanism has escaped
classical biochemical studies.
Funding:
The Academy of Finland, EU 7th framework (Marie-Curie grant),
Cancer Society Finland, Biocenter Finland, Sigrid-Juselius
Foundation
39
From left to right: Daniel Abankwa, Olga Blaževitš, Rounik Mazumdar, Camillo Guzman, Mideksa Yonatan Gebremariam, Christina Oetken-Lindholm, Arafath Najumudeen, Alessio Ligabue, Maja Solman and
Elina Siljamäki.
Collaborators:
Dr. Christian Eggeling (Max-Planck Institute Göttingen, Germany),
Dr. Harri Härmä (University of Turku), Dr. Jessica Rosenholm (Åbo
Akademi University), Prof. Jukka Westermarck (Turku Centre
for Biotechnology), Prof. Mike Waters (Institute for Molecular
Bioscience, Australia), Prof. Alemayehu Gorfe and Prof. John
Hancock (UT Medical School Houston, USA), Prof. Kirill Alexandrov
(Institute for Molecular Bioscience, Australia), Prof. Johanna Ivaska
(VTT, Turku Centre for Biotechnology), Prof. Robert Parton (Institute
for Molecular Bioscience, Australia), Dr. Krishnaraj Rajalingam
(University of Frankfurt, Germany), Katarzyna Blazewska (Lodz
University of Technology, Poland)
Selected Publications:
Guzmán, C., Bagga, M., Kaur, A., Westermarck, J., and Abankwa,
D. (2014) ColonyArea: An ImageJ Plugin to Automatically
Quantify Colony Formation in Clonogenic Assays. PLoS ONE
9, e92444
Guzmán, C., Solman, M., Ligabue, A., Blazevitš, O., Andrade, D.
M., Reymond, L., Eggeling, C., and Abankwa, D. (2014) The
efficacy of Raf kinase recruitment to the GTPase H-ras depends
on H-ras membrane conformer specific nanoclustering. Journal
of Biological Chemistry [EPub ahead of print]
Najumudeen, A. K., Köhnke, M., Solman, M., Alexandrov, K.,
and Abankwa, D. (2013) Cellular FRET-Biosensors to Detect
Membrane Targeting Inhibitors of N-Myristoylated Proteins.
PLoS ONE 8, e66425
Köhnke, M., Schmitt, S., Ariotti, N., Piggott, A. M., Parton, R. G.,
Lacey, E., Capon, R. J., Alexandrov, K., and Abankwa, D. (2012)
Design and Application of In Vivo FRET Biosensors to Identify
Protein Prenylation and Nanoclustering Inhibitors. Chemistry &
Biology 19, 866–874
Sinha, B., Köster, D., Ruez, R., Gonnord, P., Bastiani, M., Abankwa,
D., Stan, R. V., Butler-Browne, G., Vedie, B., Johannes, L.,
Morone, N., Parton, R. G., Raposo, G., Sens, P., Lamaze, C.,
and Nassoy, P. (2011) Cells respond to mechanical stress by
rapid disassembly of caveolae. Cell 144, 402–413
Abankwa, D., Gorfe, A. A., Inder, K., and Hancock, J. F. (2010) Ras
membrane orientation and nanodomain localization generate
isoform diversity. Proceedings of the National Academy of
Sciences 107, 1130–1135
Abankwa, D., Hanzal-Bayer, M. F., Ariotti, N., Plowman, S. J.,
Gorfe, A. A., Parton, R. G., McCammon, J. A., and Hancock,
J. F. (2008) A novel switch region regulates H-ras membrane
orientation and signal output. EMBO J 27, 727–735
Hill, M. M., Bastiani, M., Luetterforst, R., Kirkham, M., Kirkham,
A., Nixon, S. J., Walser, P. J., Abankwa, D., Oorschot, V. M. J.,
Martin, S., Hancock, J. F., and Parton, R. G. (2008) PTRF-Cavin,
a conserved cytoplasmic protein required for caveola formation
and function. Cell 132, 113–124
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41
LYMPHOCYTES AND INFLAMMATION
Zhi Jane Chen, MD; PhD, Academy of Finland Research Fellow.
Åbo Akademi and University of Turku,
Tykistökatu 6, FI-20520, Turku, Finland,
Tel. +358-2-3338028.
Email: zhi.chen@btk.fi or zhi.chen@utu.fi
Biography:
Zhi Jane Chen graduated from Beijing Medical University (Collage
of Medicine, Peking University), China. She carried out her Ph.D
study at the Turku Centre for Biotechnology and received Ph.D from
Faculty of Medicine, University of Turku in 2004. During 2005-2007,
she was a post-doctoral fellow in Dr. John O’Shea’s laboratory
at the NIH, USA. She received a Post-doctoral Fellowship from
the Academy of Finland and worked in the Department of Cell
Biology and Anatomy, Faculty of Medicine, University of Turku in
2008-2010. In 2011, she joined Prof. Riitta Lahesmaa’s laboratory
as a senior scientist. Since September 2012, she is holding an
Academy of Finland Research Fellow position.
Personnel:
Graduate students: Khan Mohd Moin, MSc (co-supervision with
Prof. Riitta Lahesmaa), Csendes Brigitta, MSc, Undergraduate
student: Mohammad Imran Ahammad
Inflammatory and autoimmune diseases underlie a vast variety
of human diseases. The immune system is often involved with
these disorders. We focus on understanding the role of the
relatively newly identified subsets of CD4+ T cells, Th17 and iTreg
in regulating the inflammatory/auto-immune axis. We study Th17
and iTreg differentiation at multiple levels from mouse and human
and integrate the results to build a comprehensive view of the
processes.
We are particularly interested in the study of the regulation and
interactions between the immune and hormonal responses and
how the interactions contribute to pathogenesis of immunemediated diseases.
The results of our studies are expected to gain new insight into the
molecular mechanisms of lymphocyte differentiation to Th17 and
iTreg lineages. This in turn will be important for the development
therapeutic strategies that will facilitate rational modulation of the
immune response.
Funding:
The Academy of Finland
From left to right: Brigitta Csendes, Zhi Jane Chen and Imran Ahammad Mohammad.
42
Collaborators:
Prof. Riitta Lahesmaa: Director, Turku Centre for Biotechnology.
Dr. John O’Shea: Scientific Director, Intramural Research Program,
43
NIAMS, NIH, USA. Dr. Wendy Watford: Assistant Professor,
University of Georgia, College of Veterinary Medicine, USA. Dr. Diana
Toivola: Docent, Åbo Akademi University. Dr. Harri Lähdesmäki,
Professor, Aalto University
PROTEIN KINASE REGULATION OF
BRAIN DEVELOPMENT AND DISEASE
http://www.btk.fi/research/research-groups/coffey/
Lönnberg T, Chen Z, Lahesmaa R. From a gene-centric to wholeproteome view of differentiation of T helper cell subsets. Brief
Funct Genomics. 2013 Nov;12(6):471-82.
Chen Z, Lönnberg T, Lahesmaa R. Holistic systems biology
approaches to molecular mechanisms of human helper T cell
differentiation to functionally distinct subsets. Scand J Immunol.
2013 Aug;78(2):172-80.
Tuomela S, Salo V, Tripathi SK, Chen Z, Laurila K, Gupta B,
Aijö T, Oikari L, Stockinger B, Lähdesmäki H, Lahesmaa R.
Identification of early gene expression changes during human
Th17 cell differentiation. Blood. 2012 Jun 7;119(23):e151-60.
Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C,
Yoshimura A, Hennighausen L, O’Shea JJ.: Selective regulatory
function of Socs3 in the formation of IL-17-secreting T cells.
Proc Natl Acad Sci U S A. 2006 May 23;103(21):8137-42.
Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank
RB, Meylan F, Siegel R, Hennighausen L, Shevach EM, O’shea
JJ. Interleukin-2 signaling via STAT5 constrains T helper 17 cell
generation. Immunity. 2007 Mar;26(3):371-81.
Chen Z, Tato CM, Muul L, Laurence A, O’Shea JJ. Distinct
regulation of interleukin-17 in human T helper lymphocytes.
Arthritis Rheum. 2007 Sep;56(9):2936-46.
Chen Z, Buki K, Vääräniemi J, Gu G, Väänänen H.K., The critical
role of IL-34 in osteoclastogenesis. PLoS One. 2011 Apr
8;6(4):e18689.
Chen Z, Laurence A, O’Shea JJ. Signal transduction pathways and
transcriptional regulation in the control of Th17 differentiation.
Semin Immunol. 2007 Dec;19(6):400-8.
Chen Z, O’Shea JJ. Regulation of IL-17 production in human
lymphocytes. Cytokine. 2008 Feb;41(2):71-8.
Chen Z, O’Shea JJ. Th17 cells: a new fate for differentiating helper
T cells. Immunol Res. 2008;41(2):87-102
Jiang JK, Ghoreschi K, Deflorian F, Chen Z, Perreira M, Pesu M, Smith
J, Nguyen DT, Liu EH, Leister W, Costanzi S, O’Shea JJ, Thomas
CJ. Examining the chirality, conformation and selective kinase
inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]
pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile
(CP690,550). J Med Chem. 2008 Dec 25;51(24):8012-8.
Chen Z, Lund R, Aittokallio T, Kosonen M, Nevalainen O, Lahesmaa
R. Identification of novel IL-4/Stat6-regulated genes in T
lymphocytes. J Immunol. 2003 Oct 1;171(7):3627-35.
44
Eleanor Coffey, PhD, Adjunct Prof.,
Åbo Akademi and Turku University,
BioCity, Tykistokatu 6B, FI-20521 Turku, Finland.
Tel. +358-2-3338605,
Fax. +358-2-3338000.
Email: ecoffey@btk.fi
Biography:
Eleanor Coffey graduated from Trinity College Dublin in 1990 and
received her PhD from the University of Dundee in 1994. She was
awarded a Wellcome Trust fellowship to carry out post-doctoral
research in Prof. Karl Åkerman’s laboratory from 1994-1997. In
1997 she founded the Neuronal Signalling group at Åbo Akademi
University 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 and Viral Vector
Facility at the Center. She coordinates a Marie Curie International
Training Network r´BIRTH; Brain Imaging Return to Health, involving
9 academic and industrial partners around Europe.
Personnel:
Graduate students: Justyna Zdrojewska, MSc, Emilia Komulainen,
MSc, Hasan Mohammed, MSc., Prasannakumar Deshpande,
MSc, Patrik Hollos, MSc., Dani Flinkman, Francesca Marchisella,
MSc., Artemis Varidaki, MSc. Undergraduate student: Olavi Misin.
Lab Manager: Susanna Pyökari.
Neurodegenerative disorders such as Alzheimer’s and Parkinson’s
disease as well as stroke are characterised by the irreversible loss
of nerve cell function. These diseases for which no cure is known
are among the most costly to society. The protein kinase JNK is
recognised as a critical player in stroke and neurodegeneration.
However exactly how this family of kinases mediates cell death in
the brain remains largely unknown. Although targeting of JNK for
drug-based therapy is already underway, our understanding of the
physiological function of JNK in the brain is in its infancy.
A major challenge for signal transduction therapy is to selectively
target the pathological function of signalling molecules without
interfering with important physiological roles. To achieve this, our
lab established a proteomics-based screen to identify protein
kinase substrates and thereby broaden our understanding of kinase
function. While we have used this methodology to successfully
identify both novel and known substrates for JNK, p38 and
PIM kinases (collaboration with Päivi Koskinen), among others
(collaboration Erwin Wagner), the main focus of our research is to
elucidate the molecular mechanism of JNK and JNK targets in the
brain. Identification of novel JNK targets such as SCG10 and MAP2,
45
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 compartmenttargeted 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 utilizing targeted inhibitors of JNK (prepared in our lab) and
targeted FRET reporters of compartmental JNK activity, modified in
our lab to investigate the potential therapeutic benefit of targeted
kinase inhibition for treatment of excitotoxicity. 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.
As an extension of this study on brain development, we are now
examining regulation of neurogenesis in brain in the context of
depressive disorders and anxiety. This is as a part of Marie Curie
International Training Network, involving molecular neuroscience,
patient imaging and imaging tool development.
We have in recent years switched attention to Parkinson’s disease
kinases LRRK2 and PINK1. To gain better understanding of the
molecular underpinnings of Parkinson’s disease, we are carrying
out phosphoproteomcis screens in collaboration with Peter James’s
lab. Gain of function mutations in LRRK2 are the most common
cause of familial Parkinson’s disease. Yet, substrates for LRRK2
have remained elusive and the disease mechanism is unknown. In
collaboration with Peter James’s lab, we are searching for LRRK2
targets in brain using a shot-gun approach. We hope that in the long
run this will enhance our understanding of Parkinson’s pathology
and contribute tools that can be used for earlier clinical diagnosis.
Funding:
Åbo Akademi University, EU FP7 Marie Curie, The Academy of
Finland, Biocenter Finland, Turku University Biomedical Sciences
Graduate School.
46
Collaborators:
Peter James (University of Lund), Kristen Verhey (University of
Michigan), Casper Hoogenraad (University of Utrecht).
1. Coffey, E.T. (2014) Nuclear and cytosolic JNK signalling. Nature
Reviews Neuroscience. in press
2. Zdrojewska, J., Coffey, E.T. (2014) The impact of JNK on
neuronal migration. Adv Exp Med Biol. 2014;800:37-57.
3. Jonsdottir, K., Zhang, H., Jhagroe, D., Skaland, I., Slewa, A.,
Björkblom, B., Coffey, E. T., Gudlaugsson, E., Smaaland, R.,
Janssen, E. A., and Baak, J. P. (2012) The prognostic value of
MARCKS-like 1 in lymph node-negative breast cancer. Breast
Cancer Res Treat 135, 381-390
4. Bjorkblom, 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., Magard,
M., James, P., and Coffey, E. T. (2012) c-Jun N-terminal kinase
phosphorylation of MARCKSL1 determines actin stability. Mol
Cell Biol 32, 3513-3526
5. Westerlund, N., Zdrojewska, J., Padzik, A., Komulainen, E.,
Björkblom, B., Rannikko, E., Tararuk, T., Garcia-Frigola, C.,
Sandholm, J., Nguyen, L., Kallunki, T., Courtney, M. J., and
Coffey, E. T. (2011) Phosphorylation of SCG10/stathmin-2
determines multipolar stage exit and neuronal migration rate.
Nat Neurosci 14, 305-313
6. Mai, A., Veltel, S., Pellinen, T., Padzik, A., Coffey, E., Marjomäki,
V., and Ivaska, J. (2011) Competitive binding of Rab21 and
p120RasGAP to integrins regulates receptor traffic and
migration. J Cell Biol 194, 291-306
7. Matlawska-Wasowska, K., Finn, R., Mustel, A., O’Byrne, C.
P., Baird, A. W., Coffey, E. T., and Boyd, A. (2010) The Vibrio
parahaemolyticus Type III Secretion Systems manipulate host
cell MAPK for critical steps in pathogenesis. BMC Microbiol 10,
329
8. Uusi-Oukari, M., Kontturi, L. S., Coffey, E. T., and Kallinen, S.
A. (2010) AMPAR signaling mediating GABA(A)R delta subunit
up-regulation in cultured mouse cerebellar granule cells.
Neurochem Int 57, 136-142
9. Podkowa, M., Zhao, X., Chow, C. W., Coffey, E. T., Davis, R.
J., and Attisano, L. (2010) Microtubule stabilization by bone
morphogenetic protein receptor-mediated scaffolding of c-Jun
N-terminal kinase promotes dendrite formation. Mol Cell Biol
30, 2241-2250
10. Morfini, G. A., You, Y. M., Pollema, S. L., Kaminska, A., Liu,
K., Yoshioka, K., Björkblom, B., Coffey, E. T., Bagnato, C.,
Han, D., Huang, C. F., Banker, G., Pigino, G., and Brady, S. T.
(2009) Pathogenic huntingtin inhibits fast axonal transport by
activating JNK3 and phosphorylating kinesin. Nat Neurosci 12,
864-871
11. Waetzig, V., Wacker, U., Haeusgen, W., Björkblom, B., Courtney,
M. J., Coffey, E. T., and Herdegen, T. (2009) Concurrent
47
protective and destructive signaling of JNK2 in neuroblastoma
cells. Cell Signal 21, 873-880
13. Naumanen, T., Johansen, L. D., Coffey, E. T., and Kallunki, T.
(2008) Loss-of-function of IKAP/ELP1: could neuronal migration
defect underlie familial dysautonomia? Cell Adh Migr 2, 236-239
From left to right: Hasan Mohammad, Susanna Pyökäri, Patrik Hollós, Eleanor Coffey, Prasanna Kumar Desphande, Erika Freemantle, Dani Flinkman, Justyna Zdrojewska and Artur Padzik.
14. 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
15. Hongisto, V., Vainio, J. C., Thompson, R., Courtney, M. J., and
Coffey, E. T. (2008) The Wnt pool of glycogen synthase kinase
3beta is critical for trophic-deprivation-induced neuronal death.
Mol Cell Biol 28, 1515-1527
16. Johansen, L. D., Naumanen, T., Knudsen, A., Westerlund, N.,
Gromova, I., Junttila, M., Nielsen, C., Bøttzauw, T., Tolkovsky,
A., Westermarck, J., Coffey, E. T., Jäättelä, M., and Kallunki, T.
(2008) IKAP localizes to membrane ruffles with filamin A and
regulates actin cytoskeleton organization and cell migration. J
Cell Sci 121, 854-864
17. Westerlund, N., Zdrojewska, J., Courtney, M. J., and Coffey,
E. T. (2008) Superior cervical ganglion-10 protein as a
molecular effector of c-Jun N-terminal kinase 1: implications
for the therapeutic targeting of Jun N-terminal kinase in nerve
regeneration. Expert Opin Ther Targets 12, 31-43
18. Semenova, M. M., Mäki-Hokkonen, A. M., Cao, J., Komarovski,
V., Forsberg, K. M., Koistinaho, M., Coffey, E. T., and Courtney, M.
J. (2007) Rho mediates calcium-dependent activation of p38alpha
and subsequent excitotoxic cell death. Nat Neurosci 10, 436-443
19. Tararuk, T., Ostman, 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
20. Björkblom, B., Ostman, N., Hongisto, V., Komarovski, V., Filén,
J. J., Nyman, T. A., Kallunki, T., Courtney, M. J., and Coffey, E. T.
(2005) Constitutively active cytoplasmic c-Jun N-terminal kinase 1
is a dominant regulator of dendritic architecture: role of microtubuleassociated protein 2 as an effector. J Neurosci 25, 6350-6361
21. Ha, H. Y., Cho, I. H., Lee, K. W., Song, J. Y., Kim, K. S., Yu, Y.
M., Lee, J. K., Song, J. S., Yang, S. D., Shin, H. S., and Han,
P. L. (2005) The axon guidance defect of the telencephalic
commissures of the JSAP1-deficient brain was partially rescued
by the transgenic expression of JIP1. Dev Biol 277, 184-199
22. Cao, J., Semenova, M. M., Solovyan, V. T., Han, J., Coffey,
E. T., and Courtney, M. J. (2004) Distinct requirements for
p38alpha and c-Jun N-terminal kinase stress-activated protein
kinases in different forms of apoptotic neuronal death. J Biol
Chem 279, 35903-35913
23. Hongisto, V., Smeds, N., Brecht, S., Herdegen, T., Courtney,
M. J., and Coffey, E. T. (2003) Lithium blocks the c-Jun stress
response and protects neurons via its action on glycogen
synthase kinase 3. Mol Cell Biol 23, 6027-6036
48
49
TRANSLATIONAL PROTEOMICS
http://www.btk.fi/research/research-groups/corthals/
Garry Corthals, PhD
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, Veronika Suni, Darshana Kottahachchi
(visiting); Laboratory engineer: Arttu Heinonen; Technician: Pekka
Haapaniemi; Coordinator: Susanne Nees. Apprentice: Nikolai Huwa.
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
method of choice to discover, measure and characterize proteins
and protein networks in biological systems.
Left to right: Dorotha Muth-Pawlak, Eeva Rainio, Anne Rokka, Garry Corthals,
Pekka Haapaniemi, Nikolai Huwa, Susumu Imanishi, Susanne Nees and Elisabeth
Nguyen.
50
For the analysis of tissues we are interested in defining and measuring
changes of proteins and peptides, which of these have an impact on
51
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.
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 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, Thomas Kietzmann and
Hannu Larjava.
Westermarck J, Ivaska J, Corthals GL. (2013) Identification of Protein
Interactions Involved in Cellular Signalling. Mol Cell Proteomics.
12(7):1752-63
Santos HM, Kouvonen P, Capelo JL, Corthals GL. (2013) On-target
ultrasonic digestion of proteins. Proteomics. 13(9):1423-7
Velasquez EV, Ríos M, Ortiz ME, Lizama C, Nuñez E, Abramovich
D, Orge F, Oliva B, Orellana R, Villalon M, Moreno RD, Tesone M,
Rokka A, Corthals G, Croxatto HB, Parborell F, Owen GI. (2013)
Concanavalin-A induces granulosa cell death and inhibits FSH
mediated follicular growth and ovarian maturation in female rats.
Endocrinology. 154(5):1885-96.
Tyagarajan SK, Ghosh H, Yevenes GE, Imanishi SY, Zeilhofer HU,
Gerrits B, Fritschy JM. (2013) Extracellular Signal-regulated
Kinase and Glycogen Synthase Kinase 3β Regulate Gephyrin
Postsynaptic Aggregation and GABAergic Synaptic Function in
a Calpain-dependent Mechanism. J Biol Chem. 288(14):9634-47
Koch S, Scifo E, Rokka A, Trippner P, Lindfors M, Korhonen
R, Corthals G, Virtanen I, Lalowski M and Tyynelä J. (2013)
Cathepsin D deficiency induces cytoskeletal changes and affects
cell migration pathways in the brain. Neurobiol Dis. 50:107-119
52
ORGANISATION OF NEURONAL
SIGNALING PATHWAYS
www.uef.fi/aivi/neuro/signalling
Michael Courtney, PhD, Affiliated Group Leader at BTK, Professor
of Cell Signaling at UEF.
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
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 University,
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 Fellows: Peter Martinsson, PhD, Raquel MeleroFernandez de Mera, PhD, Olga Vergun, PhD; Graduate students:
Lili Li, MSc, Uma Thanigaiarasu, MSc, Xijun Wang, MSc Technician
Aila Seppänen; MUIC (Imaging Facility) Integration Specialist Jarkko
Närväinen, MSc
Disease states place cells under stressful conditions. Signaling
pathways involving protein kinases p38MAPK, JNK and others
are widely accepted to play a significant role in cell death in and
outside the nervous system, they also contribute to development,
differentiation, and even survival and proliferation. Thus drugs
developed to directly target stress activated protein kinases may
be of only limited use. To exploit the pathways for the development
of novel neuroprotective drugs, we must elucidate the mechanisms
that organise these pathways into pools with neurodegenerative
or physiological functions within the complex architecture of
neuronal cells. Only then can we begin to elective eliminate
neurodegenerative activities of these pathways, which have been
implicated neurodegenerative disease such as in Alzheimer’s
disease and conditions such as cerebral ischaemia or stroke,
increasingly major causes of death, disability and socioeconomic
impact in society.
53
In recent years we focused on signaling pathways downstream of
the NMDA receptor as they have immense translational potential,
being implicated in chronic pain, depression and psychosis in
addition to the neurodegenerative conditions mentioned above.
The NMDA receptor GluN subunits form complexes with receptor
scaffold PSD95 and nNOS leading to activation of neuronal p38
MAPK. These pathways have now demonstrated clinical potential
as a drug targeting the GluN:PSD95 interaction is the first to
succeed in a clinical trial for stroke. We showed that the interaction
between PSD95 and nNOS is targetable by a peptide-competition
approach, which can limit neurodegeneration via p38MAPK
signaling in ex vivo cell culture models (Cao et al., 2005). The Lai
lab and others developed small molecule inhibitors targeting this
interaction and demonstrated in vivo efficacy using models of both
neuropathic pain and cerebral ischaemia.
A systematic analysis of the neuroprotective nNOS sequence we
derived earlier (Cao et al., 2005) has now revealed an unexpected
requirement for recruitment by nNOS of the protein NOS1AP
(Li et al., 12013), which is encoded by a gene implicated in
schizophrenia, sudden cardiac death and diabetic complications.
We found this recruitment is also druggable. Furthermore
NOS1AP binds MKK3, an activator of p38, the MAPK already
implicated in neurodegeneration, depression and chronic pain.
We have therefore embarked on a new project that combines
the mapping of interaction surfaces, molecular modelling and in
silico screening, systematic RNAi screens, cell-based interaction
screens and high-throughput microscopy and other approaches.
The aims are, amongst others, to develop a panel of inhibitory
strategies for consideration in the wide range of NMDA receptorassociated disorders as well as derive genome-wide relevance
of novel functional interactions. To this end we have established
new collaborations to better address the translational value of this
approach in the possible treatment of neuropathic pain, depression
and schizophrenia as well as neurodegeneration (collaborations
with Andrea Hohmann, Yvonne Lai, Andrew Harkin, Jari Tiihonen,
Jari Koistinaho).
To assist in these investigations we have continued to develop
genetically-encoded optical reporters and actuators (optogenetics
tools), in part via consortium projects of the Academy of Finland
photonics programme. Previous activity in this area led to the
development of novel imaging probes of cell death signalling (e.g.
Hellwig et al., 2008; D’Orsi et al., 2012) and we have participated
in the ROSIm consortium (coordinator Rashid Giniatullin, UEF)
to facilitate the generation of new imaging reporters of reactiveoxygen species. Meanwhile, we coordinate the PhotoON
consortium to develop a new optogenetic cassette compatible
with regulatory peptide sequences we have been developing
(see above), to facilitate the light-driven modulation of signaling
pathways. As proof of principle we have initially selected the JNK
pathway for optogenetic regulation (reported in Melero et al., 2013,
SFN abstract 676.20; Hollos et al., 2013, SFN abstract 873.15),
using the high affinity JNK-interacting sequence “JBD”, derived
from the JIP class of MAPK scaffold proteins which can be used as
a selective targetable inhibitor to discriminate the roles of distinct
compartmentalized pools of kinase (e.g. Björkblom et al., 2005,
2008; Tararuk et al., 2006; Westerlund et al., 2011).
54
In addition we continue to maintain and develop the Multimodal
Imaging Core facility at the University of Eastern Finland (www.uef.
fi/aivi/muic), an open-access facility which provides instrumentation
including widefield, confocal and TIRF microscopy as well as highthroughput microscopy and sample preparation facilities. Recent
activities have focused on integration between 8/96/384 channel
pipetting robot and plate reader/automated microscope, addition of
high-speed sCMOS/LED-based imaging options and repair of the
exisiting BD pathway 855-TwisterII-Cytomat Cell incubator system.
Funding:
The Photonics Programme of the Academy of Finland, the EU
th
7 framework project “MEMOLOAD”, The University of Eastern
Finland Innovative Research Initiatives, The Doctoral Programme in
Molecular Medicine and the European Union 7th Framework Initial
Training Network “ReBIRTH”.
Collaborators:
Andrea Hohmann and Yvonne Lai (University of Indiana
Bloomington), Tibor Harkany and Jari Tiihonen (Karolinska Institute,
Sweden), Jochen Prehn and Andrew Harkin (Trinity College Dublin),
Eleanor Coffey and Tassos Papageorgiou (BTK, Åbo Akademi
and University of Turku), Antti Poso, Jari Koistinaho and Rashid
Giniatullin (University of Eastern Finland) and Anita Truttmann
(University of Lausanne).
Tortoriello G, Morris CV, Alpar A, Fuzik J, Shirran SL, Calvigioni D,
Keimpema E, Botting CH, Reinecke K, Herdegen T, Courtney
M, Hurd YL, Harkany T. (2014) Miswiring the brain: Δ9tetrahydrocannabinol disrupts cortical development by inducing an
SCG10/stathmin-2 degradation pathway. EMBO J. 33(7):668-85.
Li L-L, Ginet V, Liu X, Vergun O, Tuittila M, Mathieu M, Bonny
C, Puyal J, Truttmann AC, Courtney MJ. (2013) The nNOSp38MAPK pathway is mediated by NOS1AP during neuronal
death. J Neurosci. 33(19):8185-201.
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.
(2012) c-Jun N-terminal kinase phosphorylation of MARCKSL1
determines actin stability and migration in neurons and in cancer
cells. Mol Cell Biol. 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. 32:1847-58.
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 (2011) Phosphorylation
of SCG10/stathmin-2 determines multipolar stage exit and
neuronal migration rate. Nat Neurosci. 14:305-13.
Yang H, Courtney MJ, 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.
55
Hellwig CT, Kohler BF, Lehtivarjo AK, Dussmann H, Courtney MJ,
Prehn JH, Rehm M (2008) Real-time analysis of TRAIL/ CHXinduced caspase activities during apoptosis initiation. J Biol
Chem. 283, 21676-85.
COMPUTATIONAL BIOMEDICINE
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. J Biol Chem. 283, 19704-19713.
Laura Elo, PhD, Adjunct Professor in Biomathematics,
Turku Centre for Biotechnology, and Department of Mathematics
and Statistics, University of Turku,
Tykistökatu 6A, FI-20521 Turku, Finland.
Tel. +358-2-3338009, Fax. +358-2-2518808.
E-mail: laura.elo@utu.fi.
Hongisto V, Vainio JC, Thompson R, Courtney MJ, Coffey ET
(2008) The Wnt pool of GSK-3β is critical for trophic deprivation
induced neuronal death. Mol Cell Biol. 28, 1515-1527.
Westerlund N, Zdrojewska J, Courtney MJ, Coffey ET (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 MM, Mäki-Hokkonen AM, Cao J, Komarovski V,
Forsberg KM, Koistinaho M, Coffey ET, Courtney MJ (2007) Rho
mediates calcium-dependent activation of p38α and subsequent
excitotoxic cell death. Nat Neurosci. 10, 436-443.
Tararuk T, Ostman N, Li W, Björkblom B, Padzik A, Zdrojewska J,
Hongisto V, Herdegen T, Konopka W, Courtney MJ, Coffey ET
(2006) JNK1 phosphorylation of SCG10 determines microtubule
dynamics and axodendritic length. J Cell Biol. 173, 265-277.
Björkblom B, Ostman N, Hongisto V, Komarovski V, Filén JJ, Nyman
TA, Kallunki T, Courtney MJ, Coffey ET (2005) Constitutively
active cytoplasmic JNK1 is a dominant regulator of dendritic
architecture; role of MAP2 as an effector. J Neurosci. 25, 63506361.
Cao J, Viholainen JI, Dart C, Warwick HK, Leyland ML, Courtney
MJ (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 MM, Solovyan VT, Han J, Coffey ET, Courtney MJ
(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 VT, Bezvenyuk ZA, Salminen A, Austin CA, Courtney
MJ (2002) The role of topoisomerase II beta in the excision of
DNA loop domains during apoptosis. J Biol Chem. 277, 2145821467.
Coffey ET, Smiciene G, Hongisto V, Cao J, Brecht S, Herdegen T,
Courtney MJ (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 ET, Hongisto V, Dickens M, Davis RJ, Courtney MJ (2000)
Dual Roles for c-Jun N-terminal kinase in developmental and
stress responses in cerebellar granule neurons. J Neurosci. 20,
7602-7613.
Courtney MJ, Åkerman KEO, Coffey ET (1997) Neurotrophins
protect cultured cerebellar granule neurons against the early
phase of cell death by a two-component mechanism. J Neurosci.
17, 4201-4211.
56
http://www.btk.fi/research/research-groups/elo/
Biography:
Laura Elo received her PhD in Applied Mathematics from the
University of Turku in 2007. In 2008 she received a Post-doctoral
Fellowship from the Academy of Finland. During that time, she
did post-doctoral work with Prof. Riitta Lahesmaa, Molecular
Immunology Group, Turku Centre for Biotechnology, and with Prof.
Benno Schwikowski, Systems Biology Unit, Institut Pasteur, Paris,
France. In 2009, she became also a principal investigator in the
Data Mining and Modelling Group at University of Turku. Since
2011 she is an Adjunct Professor in Biomathematics at University
of Turku. In 2013, she was awarded the highly competitive 5-year
Career Development Award from the Juvenile Diabetes Research
Foundation JDRF from the US and established an independent
research group of Computational Biomedicine at University of
Turku.
Personnel:
Post-doctoral Fellows: An Le Thi Thanh, PhD Graduate students:
Saira Afzal, MSc, Bishwa Ghimire, MSc, Maria Jaakkola, MSc,
Teemu Daniel Laajala, MSc, Asta Laiho, MSc, Anna Pursiheimo,
MSc, Kalaimathy Singaravelu, MSc, Tomi Suomi, MSc
Undergraduate students: Deepankar Chakroborty, B.Sc., Anna
Koskinen, B.Sc., Oona Lehtinen, B.Sc., Mehrad Mahmoudian,
B.Sc., Sami Rannikko, B.Sc., Rafael Santos, B.Sc., Fatemehsadat
Seyednasrollah, B.Sc.
We develop computational data analysis tools and
mathematical modelling methods for biomedical research in
close collaboration with experimental and clinical groups. A
specific focus is on transforming high-dimensional molecular
and clinical data into biomedical knowledge. While modern
high-throughput biotechnologies, such as deep sequencing
and mass-spectrometry-based proteomics, enable large-scale
measurements of molecular events in health and disease, the
experimental data alone are not sufficient for understanding the
complex disease processes. Therefore, the goal of our research
is to enable robust and reproducible interpretation of the data.
Building on our previous computational, statistical and networkbased studies, we aim at establishing a computational framework
that allows optimized integration and analysis of large-scale clinical
and molecular data at multiple levels as well as heterogeneity
between individuals. The ultimate goal is to improve the diagnosis,
prognosis and treatment of complex diseases, such as diabetes
57
and cancer, by combining computational, experimental and
clinical expertise.
Funding:
JDRF, The Academy of Finland, Päivikki and Sakari Sohlberg
Foundation, Yrjö Jahnsson Foundation, The Finnish Cultural
Foundation, The Finnish Cancer Foundation, The Finnish Funding
Agency for Technology and Innovation (Tekes), University of Turku
Graduate School (UTUGS), Turku Systems Biology Research
Programme, Turku University Foundation
Selected collaborators:
Garry Corthals (Turku Centre for Biotechnology), David Goodlett
(University of Maryland School of Pharmacy, Baltimore and Turku
Centre for Biotechnology), Heikki Hyöty (University of Tampere),
Panu Jaakkola (Turku University Hospital), Eija Korpelainen
(CSC), Riitta Lahesmaa (Turku Centre for Biotechnology), Tarja
Laitinen (Turku University Hospital and University of Turku), Olli
Nevalainen (University of Turku), Howard Petrie (Scripps Florida),
Tapio Salakoski (University of Turku), Benno Schwikowski (Institut
Pasteur, Paris), Olli Simell (DIPP), Lucy Walker (University College
London)
pathways characterizes children with prediabetes in genomewide gene expression profiling. J Autoimmun. 35: 70-76. [IF
8.145]
8. Elo LL, Järvenpää H, Tuomela S, Raghav S, Ahlfors H, Laurila
K, Gupta B, Lund RJ, Tahvanainen J, Hawkins RD, Oresic M,
Lähdesmäki H, Rasool O, Rao KV, Aittokallio T, Lahesmaa
R (2010). Genome-wide profiling of interleukin-4 and STAT6
transcription factor regulation of human Th2 cell programming.
Immunity 32: 852-862. [IF 19.795]
9. Laajala E, Aittokallio T, Lahesmaa R, Elo LL (2009). Probelevel estimation improves the detection of differential splicing
in Affymetrix exon array studies. Genome Biol. 10: R77. [IF
10.288]
10.Laajala TD, Raghav S, Tuomela S, Lahesmaa R, Aittokallio T,
Elo LL (2009). A practical comparison of methods for detecting
transcription factor binding sites in ChIP-seq experiments.
BMC Genomics 10:618. [IF 4.397]
1. Kallionpää H*, Elo LL*, Laajala E*, Mykkänen J, RicañoPonce I, Vaarma M, Laajala TD, Hyöty H, Ilonen J, Veijola
R, Simell T, Wijmenga C, Knip M, Lähdesmäki H, Simell O
and Lahesmaa R. Innate immune activity is detected prior
to seroconversion in children with HLA-conferred type
1 diabetes susceptibility. To appear in Diabetes. (*equal
contribution) [IF 7.895]
2. Seyednasrollah F, Laiho A, Elo LL. Comparison of methods for
detecting differential expression in RNA-seq studies. To appear
in Briefings in Bioinformatics. [IF 5.298]
3. Elo LL and Schwikowski B (2013) Analysis of Time-Resolved
Gene Expression Measurements Across Individuals. PLoS
ONE 8(12): e82340. [IF 3.730]
4. Lahti L, Torrente A, Elo LL, Brazma A, Rung J (2013). A
fully scalable online pre-processing algorithm for short
oligonucleotide microarray atlases. Nucleic Acids Res. 41:
e110. [IF 8.278]
5. Elo LL, Schwikowski B (2012). Mining proteomic data for
biomedical research. Invited review. WIREs Data Mining Knowl
Discov. 2: 1-13. [IF 1.422]
6. 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:
e1. [IF 8.278]
7. Elo LL, Mykkänen J, Nikula T, Järvenpää H, Simell S, Aittokallio
T, Hyöty H, Ilonen J, Veijola R, Simell T, Knip M, Simell O,
Lahesmaa R (2010). Early suppression of immune response
58
From left to right: Maria Jaakkola, Deepankar Chakroborty, Fatemehsadat
Seyednasrollah, Laura Elo, Teemu Daniel Laajala, Tomi Suomi, Anna Pursiheimo
and An Le Thi Thanh.
59
CYTOSKELETAL AND SURVIVAL
SIGNALING
Principal Investigator:
John E. Eriksson, PhD, Professor.
Deptartment 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 PhD 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
and Chair of the Biocenter Finland Imaging Infrastructure Network.
Personnel:
Post-doctoral Fellows: Fang Cheng, MD-PhD, Claire Hyder, PhD,
Senthil Kumar, PhD, Preethy Paul, PhD, Graduate students: Josef
Gullmets, MSc, Kimmo Isoniemi, MSc, Julia Lindqvist, MSc,
Ponnuswamy Mohanasundaram, MSc, Erik Niemelä, MSc, Elin
Torvaldson, MSc, Joanna Pylvänäinen, MSc, MSc, Alia Joko, MSc,
Undegraduate students: Isabelle Mogollon, Michelle Lindström,
Vilhelm Wikström, Num Wistbacka, Fanny Örn. Laboratory
Technician: Helena Saarento.
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
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 differentiationrelated processes.
Intermediate filaments (IFs) are major cytoskeletal proteins
important for ultrastructural organization and protection against
various mechanical and other types of stresses. We have
established that intermediate filaments are important signaling
determinants, a question that relates to how the organization
of the cytoskeleton will affect different signaling modules.
By employing the interactions of different IFs (keratin 8/18,
vimentin, nestin) with their signaling partners as models, we have
elucidated the relationship between the cytoskeletal structure
and the signaling state of the cell, and how this relationship will
affect cell differentiation, growth, and survival. We observed
that IFs act as general scaffolds for signaling proteins, and
have focused on the association of IFs with JNKs, Cdk5,
PKC isoforms, 14-3-3, and surface adhesion molecules. Our
findings include vimentin and nestin as regulators of adhesion,
migration and invasion, showing that the IFs are form highly
dynamic anchoring structures that are involved in organizing the
surface molecules crucial for migration and invasion. Another
topical highlight includes the discovery of nestin as regulator of
Cdk5 signaling, forming a scaffold and rheostat for the Cdk5/
p35 signaling complex during the differentiation of muscle cells
and in apoptosis of neuronal cells. We have also determined
the roles of specific PTMs on nuclear lamins in regulating their
turnover and organization.
Collaborators:
The studies on apoptosis-related signaling are done in collaboration
with Ralph Budd (Univ. of Vermont), Marion McFarlane (Univ. of
Leicester) and Lea Sistonen (Turku Centre for Biotechnology).
The studies on IF-related signaling functions are carried out as a
collaboration with Robert Goldman and Karen Ridge (Northwestern
Univ., Chicago, USA), Johanna Ivaska (Univ. of Turku), and Thomas
Magin (Univ. of Leipzig, German).
61
Funding:
The Academy of Finland, TEKES, the European Union, the Finnish
Cancer Organizations, the Sigrid Jusélius Foundation, the W. M.
Keck Foundation, and the Åbo Akademi Foundation.
Hyder C.L., Lazaro G., Pylvänäinen J.W., Roberts M.W.,
Rosenberg S.M. & Eriksson J.E. (2014) Nestin regulates
prostate cancer cell invasion by influencing FAK and integrin
localisation and functions. J. Cell Sci., in press (Epub Mar 7,
2014).
Kochin V., Shimi T., Torvaldson E., Adam S.A., Goldman A., Pack
C.G., Melo-Cardenas J., Imanishi S.Y., Goldman R.D. & Eriksson
J.E. (2014) Interphase phosphorylation of lamin A. J. Cell Sci., in
press (Epub Apr 16, 2014).
Paul P., Rajendran S.K., Peuhu E., Alshatwi A.A., Akbarsha M.A.,
Hietanen S. & Eriksson J.E. (2014) Novel action modality of
the diterpenoid anisomelic acid causes depletion of E6 and E7
viral oncoproteins in HPV-transformed cervical carcinoma cells.
Biochem. Pharmacol. 89:171-84.
Peuhu E., Paul P., Remes M., Holmbom T., Eklund P., Sjöholm
R., Eriksson J.E. (2013) The antitumor lignan Nortrachelogenin
sensitizes prostate cancer cells to TRAIL-induced cell death
by inhibition of the Akt pathway and growth factor signaling.
Biochem. Pharmacol. 86:571-83.
Ferraris S.E., Isoniemi K., Torvaldson E., Anckar J., Westermarck
J. & Eriksson J.E. (2012). Nucleolar AATF regulates c-Junmediated apoptosis. Mol. Biol. Cell. 23: 4323-32.
Karaman D.S., Desai D., Senthilkumar R., Johansson E.M.,
Råtts N., Odén M., Eriksson J.E., Sahlgren C., Toivola D.M.
& Rosenholm J.M. (2012). Shape engineering vs organic
modification of inorganic nanoparticles as a tool for enhancing
cellular internalization. Nanoscale Res Lett. 7: 358
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: 11547-52.
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: 1539-49.
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: 18375-82.
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.
62
Asaoka T., Kaunisto A. & Eriksson J.E. (2011). Regulation of cell
death by c-FLIP phosphorylation. Adv. Exp. Med. Biol. 691:
625-30.
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. 285:19324-9
de Thonel A., Ferraris S.E., Pallari H.M., Imanishi S.Y., Kochin V.,
Hosokawa T., Hisanaga S., Sahlgren C. & Eriksson J.E. (2010).
Protein kinase Czeta regulates Cdk5/p25 signaling during
myogenesis. Mol. Biol. Cell 21:1423-1434.
Shen W.J., Patel S., Eriksson J.E., Kraemer F.B. (2010). Vimentin
is a functional partner of hormone sensitive lipase and facilitates
lipolysis. J. Proteome Res. 9:1786-1794.
Peuhu E., Rivero-Müller A., Stykki H., Torvaldson E., Holmbom
T., Eklund P., Unkila M., Sjöholm R. & Eriksson J.E. (2010).
Inhibition of Akt signaling by the lignan matairesinol sensitizes
prostate cancer cells to TRAIL-induced apoptosis. Oncogene
29:898-908.
Imanishi S.Y., Kouvonen P., Smått J.H., Heikkilä M., Peuhu E.,
Mikhailov A., Ritala M., Lindén M., Corthals G.L. & Eriksson
J.E. (2009). Phosphopeptide enrichment with stable spatial
coordination on a titanium dioxide coated glass slide. Rapid
Commun. Mass Spectrom. 23:3661-3667.
Rosenholm J.M., Peuhu E., Eriksson J.E., Sahlgren C. & Lindén
M. (2009). Targeted intracellular delivery of hydrophobic agents
using mesoporous hybrid silica nanoparticles as carrier systems.
Nano Lett. 9:3308-3311.
Eriksson J.E., Dechat T., Grin B., Helfand B., Mendez M., Pallari
H.M., Goldman R.D. (2009). Introducing intermediate filaments:
from discovery to disease. J. Clin. Invest. 119:1763-1771
(review).
Rosenholm J., Meinander A. Peuhu E., Niemi R., Eriksson J.E.,
Sahlgren C. & Lindén M. (2009). Selective uptake of porous silica
nanoparticles by cancer cells. Amer. Chem. Soc. 27:197-206.
Kaunisto A, Kochin V, Asaoka T, Mikhailov A, Poukkula
M, Meinander A. & Eriksson JE. (2009). PKC-mediated
phosphorylation regulates c-FLIP ubiquitylation and stability. Cell
Death Differ.16:1215-26.
63
From left to right: Michelle Lindström, Carolyn Alia Joko, Fanny Örn, Senthil Rajendran, Ponnuswamy Mohana Sundaram, Kimmo Isoniemi, Fang Chen, Erik Niemelä, Helena Saarento, Claire Hyder, Vilhelm
Wikström, Preethy Paul, Num Wistbacka, Elnaz Fazeli, Josef Gulmets and John Eriksson.
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: 464-75.
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: 3944-53.
Imanishi S.Y., Kochin V., Ferraris S.E., deThonel A., Pallari H-M.,
Corthals G.L. & Eriksson J.E. (2007). Reference-facilitated
phosphoproteomics: fast and reliable phosphopeptide validation
by mikro-LC-ESI-Q-TOF MS/MS. Mol. Cell. Proteomics 6: 13801391.
Nieminen, M., Henttinen, T., Merinen, M., Marttila-Ichihara, F.,
Eriksson, J.E. and Jalkanen S. (2006) Vimentin function in
lymphocyte adhesion and transcellular migration. Nat. Cell Biol.
8: 156-162.
Kochin, V., Imanishi S.Y. and Eriksson, J.E. (2006) Fast track
to a phosphoprotein sketch – MALDI-TOF characterization
of TLCbased tryptic phosphopeptide maps at femtomolar
detection sensitivity. Proteomics 6: 5676-82.
Sahlgren, C.M., Pallari, H-P., He, T., Chou, Y-H., Goldman, R.D.
and Eriksson, J.E. (2006) An essential role of a nestin scaffold
for regulation of Cdk5/p35 signaling in oxidant-induced death of
neuronal progenitor cells. EMBO J. 25: 4808-4819.
Imanishi, S.Y., Kochin, V. and Eriksson, J.E. (2006) Optimization of
phosphopeptide elution conditions in immobilized Fe(III) affinity
chromatography. Proteomics 7: 174-176.
Pallari, H.M. and Eriksson, J.E. (2006) Intermediate filaments as
signaling platforms. Science STKE. 19: pe53 (review).
Söderström, T.S., Nyberg, S., Nieminen, M.I. and Eriksson, J.E.
(2005) CD95 capping is ROCK-dependent and dispensable for
apoptosis. J. Cell Sci. 118: 2211-2223.
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.
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. (2005) 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. 117:919-32.
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65
EPIGENOMICS
http://www.btk.fi/research/research-groups/hawkins/
David Hawkins, PhD,
Biocity, 5th floor, Tykistökatu 6A, FI-20520, Finland.
Tel. +358-2-3338094, Fax. +358-2-3338000.
Email: dhawkins@btk.fi.
Personnel:
Post-doctoral Fellows: Kalyan Kumar Pasumarthy, PhD, Cristina
Valensisi, PhD
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:
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. Timo Otonkoski,
University of Helsinki
Hawkins RD*, Larjo A, Tripathi SK, Wagner U, Luu Y, Lonneberg T, Raghav
S, Lee LK, Lund R, Ren B, Lähdesmäki H*, Lahesmaa R*. (2013).
Global Chromatin State Analysis Reveals Lineage-Specific Enhancers
During the Initiation of Human T helper 1 and T helper 2 Polarization.
Immunity. 38(6):1271-1284. *Co-Corresponding Author.
Xie W, Schultz MD, Lister R, Hou Z, Rajagopal N, Ray P, Whitaker
JW, Tian S, Hawkins RD, Leung D, et al. (2013). Epigenomic
Analysis of Multilineage Differentiation of Human Embryonic
Stem Cells. Cell. 153(5):1134-1148.
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.
Left to right: Cristina Valensisi and Kalyan Pasumarthy.
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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.
Lister R†., Pelizzola M†., Kida Y.S., Hawkins R.D., Nery J.R., Hon
G., Antosiewicz-Bourget J., O’Malley R., Castanon R., Klugman
S., Downes M., Yu R., Stewart R., Ren B., Thomas J.A., Evans
R.M. and Ecker JR. (2011) Hotspots of aberrant epigenomic
reprogramming in human induced pluripotent stem cells. Nature.
471: 68-73. †Equal contribution of work.
Egelhofer T.A†., Minoda A†., Klugman S., Kolasinska-Zwierz P.,
Alekseyenko A.A., Gadel S., Gorchakov A.A., Gu T., Kharchenko
P.V., Kuan S., Latorre I., Linder-Basso D., Luu Y., Ngo Q.,
Rechtsteiner A., Riddle N.C., Schwartz Y.B., Vielle A., Elgin S.C.R.,
Kuroda M.I., Park P.J., Pirrotta V., Ren B., Ahringer J., Strome S.,
Karpen G^., Hawkins R.D^. and Lieb J.D^. (2011) Assessment
of histone-modification antibody quality. Nat. Struct. Mol. Biol. 18:
91-93. †Equal contribution of work; ^Co-corresponding Authors.
Harris R.A., Wang T., Coarfa C., Nagarajan R.P., Hong C., Downey
S.L., Johnson B.E., Fouse S.D., Delaney A., Zhao Y., Olshen A.,
Ballinger T., Zhou X., Forsberg K.J., Gu J., Echipare L., O’Geen H.,
Lister R., Pelizzola M., Xi Y., Epstein C.B., Bernstein B.E., Hawkins
R.D., Ren B., Chung W.Y., Gu H., Bock C., Gnirke A., Zhang M.Q.,
Haussler D., Ecker J.R., Li W., Farnham P.J., Waterland R.A.,
Meissner A., Marra M.A., Hirst M., Milosavljevic A. and Costello
J.F. (2010) Comparison of sequencing-based methods to profile
DNA methylation and identification of monoallelic epigenetic
modifications. Nat. Biotechnology. 28(10), 852-862.
Elo L.L†., Järvenpää H†., Tuomela S†., Raghav S†., Ahlfors H.,
Laurila K., Gupta B., Lund R,J., Tahvanainen J., Hawkins R,D.,
Oresic M., Lähdesmäki H., Rasool O., Rao K,V., Aittokallio T.
and Lahesmaa R. (2010) Genome-wide profiling of interleukin-4
and STAT6 transcription factor regulation of human Th2 cell
programming. Immunity. 32: 852-862.
Hawkins R.D†., Hon G.C†. and Ren B. (2010) Next-Generation
Genomics: An Integrative Approach. Nat. Rev. Genetics. 11: 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
http://www.btk.fi/research/research-groups/ivaska/
Johanna Ivaska, Professor, PhD,
Tykistökatu 6, FI-20520 Turku, Finland;
Phone: + 358 2 333 7954;
FAX: + 358 2 2518808,
email: johanna.ivaska@utu.fi
Biography:
Johanna Ivaska (b. 1972) received her MSc in Biochemistry in
1995 and PhD in 2000 from the University of Turku. In 2000
she received a Post-doctoral Fellowship from the Academy of
Finland. In 2001 she received the EMBO Long Term Fellowship.
She was a post-doctoral fellow at Cancer Research UK 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.
Personnel:
Post-doctoral Fellows: Antti Arjonen, PhD, Maria Georgiadou PhD,
Elisa Närvä, PhD, Emilia Peuhu, PhD, Graduate students: Jonna
Alanko, MSc, Nicola De Franceschi, MSc, Riina Kaukonen, MSc,
Pranshu Sahgal, B.Sc., Reetta Virtakoivu, MSc, Undergraduate
students: Johanna Lilja, Research assistant: Markku Saari, M.Sc
(CIC, part-time), Technicians: Jenni Siivonen, Petra Laasola
We investigate the relationship between cell adhesion and
cancer. 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. To unravel the cellular
pathways regulated by integrins and to begin to understand the
mechanisms involved 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) Cooperation 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.
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Funding:
ERC Starting Grant, Academy of Finland, Sigrid Juselius Foundation,
Finnish Cancer Organizations, EMBO
Pouwels, J., De Franceschi, N., Rantakari, P., Auvinen, K.,
Karikoski, M., Mattila, E., Potter, C., Sundberg, J.P., Hogg, N.,
Gahmberg, C.G., Salmi, M. and Ivaska, J. (2013) SHARPIN
regulates uropod detachment in migrating lymphocytes. Cell
Rep. 2013 5:619-628.
Bouvard, D., Pouwels, J., De Franceschi, N. and Ivaska, J. (2013)
Integrin inactivators: balancing cellular functions in vitro and in
vivo. Nat. Rev. Mol. Cell Biol. 14:430-442.
Högnäs, G., Hämälistö, S., Rilla, K., Laine, J.O., Vilkki, V., Murumägi,
A., Edgren, H., Kallioniemi, O. and Ivaska J. (2013) Aneuploidy
facilitates oncogenic transformation via specific genetic
alterations, including Twist2 upregulation. Carcinogenesis.
34:2000-2009.
PKCε Regulation of an α5 Integrin-ZO-1 Complex Controls
Lamellae Formation in Migrating Cancer Cells. Sci. Sign., 2
(77): ra32.
Pellinen T., Tuomi, S., Arjonen, A., Wolf, M., Edgren, H., Meyer,
H., Grosse, R., Kitzing, T., Rantala, JK., Kallioniemi O., Fässler,
R., Kallio, M., and Ivaska, J. (2008) Integrin traffic regulated
by Rab21 is necessary for cytokinesis. Dev. Cell, 15:371-385.
Pellinen T, Arjonen A, Vuoriluoto K, Kallio K, Fransen JA, Ivaska
J. (2006) Small GTPase Rab21 regulates cell adhesion and
controls endosomal traffic of beta1-integrins. J. Cell Biol. 2006
173:767-80.
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.
Arjonen, A., Alanko, J., Veltel, S., Ivaska, J. (2012) Distinct Recycling
of Active and Inactive β1 Integrins. Traffic 13:610-625.
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.
Tuomi, S., Mai, A., Nevo, J., Laine, JO, Vilkki, V., Öhman,
TJ., Gahmberg, CG., Parker, PJ. and Ivaska, J. (2009)
70
From left to right. Back row: Ghaffar Muharram, Riina Kaukonen, Maria Georgiadou,
Markku Saari, Nicola De Franceschi, Elisa Närvä, Reetta Virtakoivu, Antti Arjonen
and Pranshu Sahgal, Lilja. Front row: Jonna Alanko, Petra Laasola and Johanna
Ivaska.
71
HYPOXIA IN CELL SURVIVAL
Panu Jaakkola, MD, PhD,
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 MD in 1992 and PhD in 1998
at the University of Turku. In 1999 he received a Junior Fellowship
from the Academy of Finland. He was a post-doctoral 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, (MSc), Petra Miikkulainen, (MSc), Jonna Silen, (MSc),
Pekka Heikkinen, (MSc), Undergraduate student: Olli Metsälä,
Technician: 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 cancer progression.
The reduced oxygen is sensed by a family of enzymes called the
HIF prolyl hydroxylases (PHD1-3). Under normoxia the hypoxiainducible factor (HIF) is hydroxylated by PHDs at critical proline
residues. This leads to ubiquitylation and proteosomal destruction
of HIF by von Hippel-Lindau tumour suppressor (pVHL). 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. HIF however, can only
partially explain the effects of hypoxia on cell survival and cancer
progression
From left to right: Panu Jaakkola, Petra Miikkulainen, Krista Rantanen, Heidi Högel,
Meraj Khan and Taina Kalevo-Mattila.
72
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
73
under hypoxia by regulating the expression of p27kip1, a
cell cycle controlling kinase inhibitor. 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:
Sigrid Juselius Foundation, Finnish Cancer Unions. Turku University
Hospital (EVO), Turku University Foundation
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.
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; 4354.
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
Jokilehto T., Jaakkola P.M. (2010) The role of HIF prolyl hydroxylases
in tumor growth. J Cell Mol Med. 14(4):758-70.
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.
Jokilehto T., Högel H., Heikkinen, P., Rantanen K., Elenius,
K., Sundström J., Jaakkola P.M. (2010). Retention of prolyl
hydroxylase PHD2 in the cytoplasm prevents PHD2-induced
anchorage-independent carcinoma cell growth. Exp. Cell Res.
316(7):1169-78
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
Oxygen-dependent 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
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75
MITOSIS AND DRUG DISCOVERY
Marko Kallio, PhD 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
Turku Centre for Biotechnology, BioCity, Tykistökatu 6B, FI-20521
Turku, Finland.
Tel. +358-(50)-4097725, Fax +358(0)20-7222840,
E-mail: marko.kallio@vtt.fi, marko.kallio@btk.fi
Biography:
Marko Kallio (b. 1967) graduated in Genetics from University of Turku
in 1992 and received his PhD 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), 19982000 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. 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 Fellows: Leena Laine, PhD, Elli Narvi, PhD, Graduate
students: Jenni Mäki-Jouppila, MSc, MSc, Mahesh Tambe, MSc
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:
The Academy of Finland, VTT Technical Research Centre of Finland,
DRDP and TuDMM Graduate Schools, Bayer Schering Pharma
AG, The Finnish Cancer Organisations, The Cultural Foundation
of Finland
From left to right: Leena Laine, Elli Narvi, Mahesh Tambe, Jenni Mäki-Jouppila and
Marko Kallio.
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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),
Klaus Elenius (Univ. Turku).
MOLECULAR SYSTEMS
IMMUNOLOGY AND STEM CELL
BIOLOGY
http://www.btk.fi/research/research-groups/lahesmaa/
Salmela AL, Pouwels J, Mäki-Jouppila J, Kohonen P, Toivonen
P, Kallio L, and Kallio M. (2013) Novel pyrimidine-2,4-diamine
derivative suppresses the cell viability and spindle assembly
checkpoint activity by targeting Aurora kinases. Carcinogenesis
34: 436-45.
Narvi E, Jaakkola K, Winsel S, Oetken-Lindholm C, Halonen P,
Kallio L, Kallio MJ. (2013) Altered TUBB3 expression contributes
to the epothilone response of mitotic cells. Br. J. Cancer 108:
82-90.
Salmela AL, Kallio MJ. (2013) Mitosis as an anti-cancer drug target.
Chromosoma 122: 431-49.
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.
Riitta Lahesmaa, Professor, Director.
Tel +358-2-333 8601, Fax +358-2-2518808.
E-mail: riitta.lahesmaa [at] btk.fi.
Biography:
Riitta Lahesmaa received her MD in 1984 and PhD in 1987 from
the University of Turku, and was appointed Docent in Immunology
in 1990. She was a post-doctoral 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:
Laboratory Manager: Anne Lahdenperä, PhD
Visiting Professors/Scientists: Professor David Goodlett, Finland
Distinguished Professor, University of Baltimore, U.S., Professor
Anjana Rao, La Jolla Institute for Allergy & Immunology, La Jolla,
U.S., Dr. Kanury Rao, International Centre for Genetic Engineering
and Biotechnology, New Delhi, India, Dr. Brigitta Stockinger,
National Institute for Medical Research, London, U.K., Professor
Cisca Wijmenga, University of Groningen, The Netherlands
Senior Scientists: Riikka Lund, PhD, Adjunct Professor, Robert
Moulder, PhD, Omid Rasool, PhD, Adjunct Professor, Jussi Salmi,
PhD
Post-doctoral Fellows: Sanna Edelman, PhD, Maheswara Reddy
Emani, PhD, Saara Hämälistö, PhD, Sari Lehtimäki, PhD, Niina
Lietzen, PhD, Elizabeth Ngyen, PhD, Nelly Rahkonen, PhD, Soile
Tuomela, PhD, Ubaid Ullah, PhD, Viveka Öling, PhD
Graduate students: Santosh Bhosale, MSc, Mirkka Heinonen,
MSc, Henna Kallionpää, MSc, Kartiek Kanduri, MSc, Mohd Moin
Khan, MSc, Essi Laajala, MSc (tech), Verna Salo, MSc, Subhash
Tripathi, M.Tech, MSc
Technicians: Marjo Hakkarainen, Sarita Heinonen, Päivi Junni, Elina
Pietilä
Undergraduate students: Obaiah Dirasantha, Antti Hurme, Jussi
Jalonen, Sakari Kosola, Aki Stubb, Miro Viitala
78
79
Molecular mechanisms of T cell activation and differentiation to
functionally distinct subsets. These studies are carried out in the
Academy of Finland Centre of Excellence on Molecular Systems
Immunology and Physiology, where we are responsible for Molecular
Systems Immunology research.
Immune-mediated diseases such as type 1 diabetes, rheumatoid
arthritis, asthma and allergies result from abnormal immune response.
T lymphocytes that orchestrate the immune response can differentiate
into functionally distinct lineages to combat infection and disease. The
correct response to cytokines and a controlled balance of T lymphocyte
populations are critical for the immune system and for the avoidance of
autoimmune disorders. Dissecting pathways and regulatory networks
leading to the development of T helper 1 (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.
The research highlight of the year was to discover a novel mechanism
regulating the immune response that can contribute to the susceptibility
for autoimmune diseases (Hawkins et al. 2013). By combining state-ofthe art techniques, next-generation deep sequencing and computational
data mining we found new epigenetic factors that regulate lymphocyte
function. Regulatory regions of the genes studied displayed variations
(single nucleotide polymorphisms or SNPs) that have been associated
with predisposition to autoimmune diseases such as type 1 diabetes,
rheumatoid arthritis and inflammatory bowel disease. Such variations
were able to influence the binding of transcription factors that regulate
gene expression. These discoveries provide new insights into and basis
for the study of emergent mechanisms of immune-mediated diseases.
Our results have led to novel hypotheses on the key factors involved in
human Th cell differentiation (reviewed in Chen et al. 2013, Lehtimäki
& Lahesmaa 2013, Lönnberg et al. 2013 and Tuomela & Lahesmaa
2013). Our key goal is to elucidate their functions further and to
understand how human T cell response can be modulated.
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 a substantial proportion of
the β cells have been destroyed or impaired in their function. 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.
To investigate the genes and molecular pathways in the pathogenesis
of T1D we performed genome-wide transcriptomics analysis on a
unique series of prospective whole-blood RNA samples from atrisk children collected in the Finnish Type 1 Diabetes Prediction and
Prevention (DIPP) study Kallionpää et al, Diabetes, 2014). We studied
28 autoantibody-positive children, out of which 22 progressed to
clinical disease. Collectively the samples covered the time span from
before the development of autoantibodies (seroconversion) through the
80
diagnosis of diabetes. Healthy controls matched for date and place of
birth, gender and HLA-DQB1 susceptibility were selected for each case.
Additionally, we genotyped the study subjects to identify potential genetic
variants associated with the observed transcriptional signatures. Genes
and pathways related to innate immunity functions, such as the type 1
interferon response, were active and interferon response factors (IRFs)
were identified as central mediators of the interferon-related transcriptional
changes. Importantly, this signature was detected already before the type
1 diabetes associated autoantibodies were detected. Together, the data
provide a unique starting point for new hypotheses explaining type 1
diabetes biology.
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. 2012). Our results indicate that
it is essential to monitor stem cell lines carefully to minimize the risk of
malignancies in stem cell therapies. (Närvä et al. 2010, Hussein S, et
al. 2011).
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) and a data base (Kong et al. 2013) to facilitate stem cell
research. We also aim at understanding the role of L1TD1 and its regulatory
network in human cancer.
Funding:
The Academy of Finland – including Academy of Finland Centre
of Excellence in Molecular Systems Immunology and Physiology
Research, The National Technology Agency of Finland (TEKES), JDRF,
The Sigrid Jusélius Foundation, The Finnish Cancer Organizations,
Turku University Hospital Fund, Graduate Schools (TuBS, ISB, Turku
Doctoral Programme of Molecular Medicine), University of Turku, Åbo
Akademi University, European Research Council, EU 7th framework
projects “SYBILLA”, “DIABIMMUNE”, “NANOMMUNE”, “PEVNET”,
“Nanosolutions”, EraSysBioPlus.
Key Collaborators:
Ruedi Aebersold & Matthias Gstaiger (ETZ, Zürich, Swizerland), Reija
Autio (Tampere University of Technology ), Christopher Burge (MIT,
Cambridge, MA, USA), Sanjeev Galande (IISER, Pune, India), Heikki
Hyöty (U. Tampere), Mikael Knip (U. Helsinki), Harri Lähdesmäki
(Aalto University, CBT), David Goodlett (University of Washington,
Seattle, WA, USA and a FiDiPro in CBT) , Matej Oresic (CBT and
Steno Diabetes Center), 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), Jorma Toppari and Olli Simell (U. Turku),
Brigitta Stockinger (NIMR, London, UK and visiting professor at CBT),
Thomas Tushl (Rockefeller University, New York, NY, USA), Cisca
Wijmenga (University of Groningen, The Netherlands and visiting
professor at CBT)
Selected Recent Publications:
Ahlfors H, Limaye A, Elo LL, Tuomela S, Burute M, Gottimukkala K, Notani
D, Rasool O, Galande S, Lahesmaa R. SATB1 dictates expression
of multiple genes including IL-5 involved in human T helper cell
differentiation. Blood. 2010 Sep 2;116(9):1443-53.
81
82
From left to right. Front row: Essi Laajala, Moin Mohd Khan, Robert Moulder, Elina Pietilä, Henna Kallionpää, Sarita Heinonen, Riitta Lahesmaa, Maheswara Reddy Emani, Elizabeth Ngyen, Obaiah Dirasantha.
Second row: Anne Lahdenperä, Marjo Hakkarainen, Nelly Rahkonen, Sanna Edelman, Mirkka Heinonen, Kartiek Kanduri, Omid Rasool, Jussi Jalonen, Sari Lehtimäki, Ubaid Ullah, Subash Tripathi, Riikka Lund,
Jussi Salmi and Jane Chen Zhi. Third row: Verna Salo, Santosh Boshale and Miro Viitala.
Chen Z, Lönnberg T, Lahesmaa R. Holistic systems biology approaches
to molecular mechanisms of human helper T cell differentiation to
functionally distinct subsets. Scand J Immunol. 2013, 78:172-80.
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. Genome-wide
profiling of interleukin-4 and STAT6 transcription factor regulation of
human Th2 cell programming. Immunity. 2010 Jun 25;32(6):852-62. #,
* Equal contribution.
Hawkins, R. D., Larjo, A., Tripathi, S. K., Wagner, U., Luu, Y., Lönnberg,
T., Raghav, S. K., Lee, L. K., Lund, R., Ren, B., Lähdesmäki, H., and
Lahesmaa R. (2013) Global chromatin state analysis reveals lineagespecific enhancers during the initiation of human T helper 1 and T
helper 2 cell polarization. Immunity. 38, 1271-1284
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# Increased mutation
load is associated with reprogramming of human somatic cells
.#.Equal contribution. Nature, (2011) 471:58-62.
Kallionpää H, Elo LL, Laajala E, Mykkänen J, Ricaño-Ponce I, Vaarma M,
Laajala TD, Hyöty H, Ilonen J, Veijola R, Simell T, Wijmenga C, Knip
M, Lähdesmäki H, Simell O, Lahesmaa R. Innate immune activity is
detected prior to seroconversion in children with HLA-conferred type
1 diabetes susceptibility. Diabetes. 2014 Feb 18. [Epub ahead of print]
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. Tet1 and tet2 regulate 5-hydroxymethylcytosine
production and cell lineage specification in mouse embryonic stem cells.
Cell Stem Cell. 2011, 8:200-13.
Kong, L., Aho, K. L., Granberg, K., Lund, R., Järvenpää, L., Seppälä, J.,
Gokhale, P., Leinonen, K., Hahne, L., Mäkelä, J., Laurila, K., Pukkila,
H., Närvä, E., Yli-Harja, O., Andrews, P. W., Nykter, M., Lahesmaa, R.,
Roos, C., and Autio, R. (2013) ESTOOLS Data@Hand: human stem cell
gene expression resource. Nat Methods. 10, 814-815
Lehtimäki, S., and Lahesmaa, R. (2013) Regulatory T Cells Control Immune
Responses through Their Non-Redundant Tissue Specific Features.
Front Immunol. 4:294.
Lund RJ, Närvä E, Lahesmaa R. Genetic and epigenetic stability of human
pluripotent stem cells. Nat Rev Genet. 2012 Sep 11. doi: 10.1038/
nrg3271. Review.
Lönnberg, T., Chen, Z., and Lahesmaa, R. (2013) From a gene-centric to
whole-proteome view of differentiation of T helper cell subsets. Brief
Funct Genomics. 12, 471-482
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. High resolution genome wide
DNA analysis on a large panel of Human Embryonic Stem Cell lines
reveals novel genomic changes associated with cultureand affecting
gene expression. Nat Biotechnol. 2010 Apr;28(4):371-7.
O’Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic views
of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol.
2011 Apr;11(4):239-50. Review.
Roncagalli R, Hauri S, Fiore F, Liang Y, Chen Z, Sansoni A, Kanduri K, Joly R,
Malzac A, Lähdesmäki H, Lahesmaa R, Yamasaki S, Saito T, Malissen M,
Aebersold R, Gstaiger M, Malissen B. Quantitative proteomics analysis of
signalosome dynamics in primary T cells identifies the surface receptor
CD6 as a Lat adaptor-independent TCR signaling hub. Nat Immunol.
2014, 15:384-92.
Tahvanainen J, Kallonen T, Lähteenmäki H, Heiskanen KM, Westermarck
J, Rao KV, Lahesmaa R. PRELI is a mitochondrial regulator of human
primary T helper cell apoptosis, STAT6 and Th2 cell differentiation.
Blood. 2009 Feb 5;113(6):1268-77. Epub 2008 Oct 22
Tuomela S, Salo V, Tripathi SK, Chen Z, Laurila K, Gupta B, Äijö T, Oikari L,
Stockinger B, Lähdesmäki H, Lahesmaa R. Identification of early gene
expression changes during human Th17 celldifferentiation. Blood. 119:
e151-160, 2012.
Tuomela, S., and Lahesmaa, R. (2013) Early T helper cell programming of
gene expression in human. Semin Immunol. 25, 282-290
83
COMPUTATIONAL
SYSTEMS BIOLOGY
http://users.ics.aalto.fi/harrila/
Harri Lähdesmäki, D.Sc. (Tech), Assistant Professor (tenure track),
Academy Research Fellow
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.
Biography:
Harri Lähdesmäki (b. 1977) graduated in bionformatics from
Tampere University of Technology in 2005.
Personnel:
Post-doctoral Fellows: Jukka Intosalmi
Graduate students: Kartiek Kanduri, Laajala Essi, Antti Larjo, Maia
Malonzo, Henrik Mannerström, Kari Nousiainen, Maria Osmala,
Rautio Sini, Somani Juhi, Vatanen Tommi, Tarmo Äijö
Undergraduate students: Eraslan Basak, Eraslan Gökcen,
Khakipoor Banafsheh, Kähärä Juhani
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)
Selected publications from 2013:
Hawkins RD*, Larjo A*, Tripathi SK*, Wagner U, Luu Y, Lönnberg T,
Raghav SK, Lee LK, Lund R, Ren B, Lähdesmäki H, Lahesmaa
84
R, Global chromatin state analysis reveals lineage-specific
enhancers during the initiation of human T helper 1 and T helper
2 cell polarization, Immunity, Vol. 38, No. 6, pp. 1271-1284,
2013.
Närvä E, Pursiheimo J-P, Laiho A, Rahkonen N, Emania MR, Viitala
M, Laurila K, Sahla R, Lund R, Lähdesmäki H, Jaakkola P and
Lahesmaa R, Continuous hypoxic culturing of human embryonic
stem cells enhances Ssea-3 and Myc levels, PLoS ONE, Vol. 8,
No. 11, e78847, 2013.
Kähärä J, Lähdesmäki H, Evaluating a linear k-mer model for
protein-DNA interactions using high-throughput SELEX data,
BMC Bioinformatics, 14(Suppl 10):S2, 2013.
Ko M, An J, Bandukwala HS, Chavez L, Äijö T, Pastor WA, Segal
MF, Li H, Koh KP, Lähdesmäki, Hogan PG, Aravind L, Rao A,
Modulation of TET2 expression and 5-methylcytosine oxidation
by the CXXC domain protein IDAX,” Nature, Vol. 497, No. 7447,
pp. 122-126, 2013.
Äijö T, Granberg K, Lähdesmäki H, Sorad: A systems biology
approach to predict and modulate dynamic signaling pathway
response from phosphoproteome time-course measurements,
Bioinformatics, Vol. 29, No. 10, pp. 1283-1291, 2013.
Weirauch MT, Cote A, Norel R, Annala M, Zhao Y, Riley TJ, SaezRodriguez J, Cokelaer T, Vedenko A, Talukder S, DREAM5
consortium, Bussemaker HJ, Morris QD, Bulyk ML, Stolovitzky
G, Hughes TR, Evaluation of methods for modeling transcription
factor sequence specificity, Nature Biotechnology, Vol. 31, No.
2, pp. 126-134, 2013.
Tahvanainen J, Kyläniemi MK, Kanduri K, Gupta B, Lähteenmäki
H, Kallonen T, Rajavuori A, Rasool O, Koskinen PJ, Rao KVS,
Lähdesmäki H, Lahesmaa R, Proviral integration site for Moloney
murine leukemia virus (PIM) kinases promote human T helper 1
cell differentiation, The Journal of Biological Chemistry, Vol. 288,
No. 5, pp. 3048-3058, 2013.
Kanduri C, Ukkola-Vuoti L, Oikkonen J, Buck G, Blancher C,
Raijas P, Karma K, Lähdesmäki H, Järvelä I, The genome wide
landscape of copy number variations in the isolated Finnish
population: the MUSGEN study provides evidence for a founder
effect, European Journal of Human Genetics, Vol. 288, No. 5,
pp. 3048-3058, 2013.
Ukkola-Vuoti L, Kanduri C, Oikkonen J, Buck G, Blancher C,
Raijas P, Karma K, Lähdesmäki H, Järvelä I, Genome-wide copy
number variation analysis in extended families and unrelated
individuals characterized for musical aptitude and creativity in
music, PLoS ONE, Vol. 8, No. 2, e56356, 2013.
Lehmusvaara S, Erkkilä T, Urbanucci A, Jalava S, Seppälä J, Kaipia A,
Kujala P, Lähdesmäki H, Tammela TLJ and Visakorpi T, Goserelin
and bicalutamide treatments alter the expression of microRNAs in
prostate, The Prostate, Vol. 73, No. 1, pp. 101-112, 2013.
Larjo A, Lähdesmäki H, Active learning for Bayesian network
models of biological networks using structure priors, In IEEE
International Workshop on Genomic Signal Processing and
Statistics, Houston, TX, USA, November 17-19, 2013.
85
CELL CULTURE MODELS FOR
TUMOR CELL INVASION AND
EPITHELIAL PLASTICITY
Matthias Nees, PhD, Docent for Genetics
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 PhD 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 at VTT Medical Biotechnology, and a team leader at
CBT.
Personnel:
Post-doctoral Fellows: Ville Härmä, Malin Åkerfelt, Mervi
Toriseva. Graduate students: Ilmari Ahonen, Sean Robinson
(with CEA France). Technicians: Pauliina Toivonen, Johannes
Virtanen
Undergraduate students: Mrinal Mishra, Hannu-Pekka Schukov
Description of the projects:
Over the past years, our group (located at VTT, Pharmacity)
has systematically established a phenotypic platform that was
specifically designed for phenotypic drug discovery, based on
the morphology of multicellular organoid structures that form in
organotypic, three-dimensional (3D) cell- and tissue culture. We
focus mainly on prostate, breast, bladder and ovarian carcinomas,
and utilized these models in both academic and custom research
applications. In close collaboration with Turku University Hospital
(TYKS) and the Turku Prostate Cancer Consortium (TPCC),
we also establish primary cell cultures of urological cancers
for personalized medicine and patient-specific drug testing.
Furthermore, we have developed a novel 3D co-culture platform
that combines tumour cells with stromal and cancer-associated
fibroblasts (CAFs). These recapitulate critical aspects of complex
tumor biology.
Our goal is 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. This includes
tumor cell motility and invasion, parameters likely related to
metastasis and aggressive cancer progression. Our 3D culture
86
and co-culture platform is standardized and miniaturized,
allowing medium scale throughput for high content screens.
Assays can be performed in both 96- and 384-well plates, using
plate-based high-content readers (IncuCyte, PE Operetta) for
rapid biometric readout, or confocal spinning-disc microscopy
(Zeiss Axiovert) for more detailed imaging. Microscopic imaging
can be either performed in real-time, live cell settings (using
fluorochromes, stable markers like GFP and DsRed or reactive
dyes), or using endpoint markers (e.g. antibody stains, immune
fluorescence). In both cases, the readout is of morphometric
nature and utilizes the phenotypes of multicellular spheroid
structures as a basis for functional evaluation of anti-cancer
drugs, siRNAs, and other treatments. Morphological changes
in shape, size and texture of tumour organoids have been
demonstrated by us and others to correlate with tumour
histology, progression, and pathological grading. In particular,
dynamic phenotypic changes (such as tumour cell invasion)
are predictive for patient outcome. For this purpose, we have
developed the AMIDA automated image analysis software
package that allows rapid segmentation of large numbers of
confocal image stacks, together with statistical & machine
learning solutions for the subsequent data normalization and
interpretation.
Scientifically, we mainly address the mechanisms of tumour
cell plasticity, and the molecular pathways involved in the
loss of tissue organization versus epithelial differentiation.
Both the TME and ECM play decisive roles in the regulation
of tumour spheroid morphology, local invasion into the ECM,
and tumour cell motility. Even well-differentiated structures
are often of only metastable nature, and can spontaneously
progress to form highly invasive structures. 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 (amoeboid) patterns
of invasion, or epithelial versus mesenchymal invasion
processes.
Funding:
The Academy of Finland (consortium project with Medisiina
and FIMM Helsinki), 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
University), Pirkko Härkönen (U. Turku), Olli Kallioniemi and Tuomas
Mirtti (FIMM), Varda Rotter and Moshe Oren (Weizmann Institute
of Science, Rehovot/Israel), Markku Kallajoki, Pekka Taimen and
Peter Boström (University Hospital Turku), Julia Schueler (Oncotest
GmbH Heidelberg), and others.
87
Härmä V, Schukov HP, Happonen A, Ahonen I, Virtanen J, Siitari
H, Åkerfelt M, Lötjönen J, Nees M: Quantification of Dynamic
Morphological Drug Responses in 3D Organotypic Cell Cultures
by Automated Image Analysis PLOS ONE 08 May 2014 |
10.1371/journal.pone.0096426
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
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):207589.
From left to right: : Mrinal Mishra, Mervi Toriseva, Malin Åkerfelt, Pauliina Toivonen, XX, YY, Mathias Nees, ZZ and QQ.
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.
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89
COMPUTATIONAL BIOLOGY
http://www.uta.fi/ibt/institute/research/nykter/
Matti Nykter, D. Sc. (Tech), Professor. Affiliated Group Leader at CBT,
Institute of Biosciences and Medical Technology, University of
Tampere
Biokatu 8 (Finn-Medi 2), 33520 Tampere, Finland
Tel. +358-40-8490651.
Email: matti.nykter@uta.fi
Biography:
Matti Nykter (b. 1978) received the degree of Master of Science
(Engineering) with Distinction in information technology in 2002 and
the degree of Doctor of Science (Technology) in signal processing
in 2006 from Tampere University of Technology, Tampere, Finland.
He has worked as a visiting researcher at The University of Texas
M. D. Anderson Cancer Center in Houston, Texas, USA in 20042005, and as a post-doctoral research at the Institute for Systems
Biology, Seattle, USA during 2007-2009. 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 Biosciences and
Medical 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 Fellows: Kati Kivinummi, PhD, Kirsi Granberg, PhD,
Juha Kesseli, D.Sc., Pekka Ruusuvuori, D.Sc.
Graduate students: Antti Ylipää, Matti Annala, Tommi Rantapero,
Francesco Tabaro
Undergraduate students: Thomas Liuksiala, Sergei Häyrynen, Ville
Kytölä, Maria Laaksonen, Birgitta Lehtinen.
The Computational Biology groups 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.
90
Based on novel data integration and data analysis methodology,
we are studying the gene networks that give raise to different cell
types and apply computational approach to uncover recipes for
cell type reprogramming experiments.
Funding:
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 MD 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).
Liuksiala T, Teittinen KJ, Granberg K, Heinäniemi M, Annala M, Mäki
M, Nykter M, Lohi O. Overexpression of SNORD114-3 marks
acute promyelocytic leukemia. Leukemia 2014 ;28(1)233-6
Heinäniemi M, Nykter M, Kramer R, Wienecke-Baldacchino A,
Sinkkonen L, Zhou JX, Kreisberg R, Kauffman SA, Huang S,
Shmulevich I. Gene-pair expression signatures reveal lineage
control. Nat Methods 2013 ;10(6)577-83
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 229(3)449-59.
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.
91
SYSTEMS MEDICINE
http://www.btk.fi/research/affiliated-groups/oresic-matej-systemsbiology/
Matej Orešič, PhD, Steno Diabetes Center, Niels Steensens Vej 2,
2820 Gentofte, Denmark.
Phone: +358-44-972-6094
Email: mtjo@steno.dk
Biography:
Matej Orešič holds a PhD in biophysics from Cornell University.
Between 2003 and 2014 he led the research in domains of
quantitative biology and bioinformatics at VTT Technical Research
Centre of Finland (Espoo, Finland), where he was a Research
Professor in Systems Biology and Bioinformatics. In 2014 he
joined Steno Diabetes Center in Gentofte/Denmark as principal
investigator, where he leads a newly established department of
systems medicine. Prior to joining VTT, Dr. 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:
Seniors scientists: Tuulia Hyötyläinen, PhD (co-PI)
Our main research area is systems medicine, particularly
metabolomics applications in biomedical research and related
integrative bioinformatics. Specifically, we are particularly interested
in the identification of disease vulnerabilities associated with different
metabolic phenotypes and the underlying mechanisms linking
these vulnerabilities with the development of specific disorders or
their co-morbidities. Such in depth understanding of the metabolic
phenotypes in health and disease is crucial if one is to implement
personalized medicine. We also initiated the popular MZmine open
source project, leading to popular software for metabolomics data
processing.
Funding:
List sources of funding as follows: The Academy of Finland, EU 7th
framework, Juvenile Diabetes Research Foundation (JDRF), GENFL Head Health Challenge I.
Collaborators:
Mikael Knip (University of Helsinki), Riitta Lahesmaa (University
of Turku), Olli Simell (University of Turku), Harri Lähdesmäki
(Aalto University), Antonio Vidal-Puig (Cambridge University),
Fredrik Bäckhed (Gothenburg University), David Menon
(Cambridge University), Olli Tenovuo (University of Turku), Kirsi
Pietiläinen (University of Helsinki), Jaana Suvisaari (National
Institute for Health and Welfare), Jaakko Kaprio (University of
Helsinki).
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Bondia-Pons I, Maukonen J, Mattila I, Rissanen A, Saarela M,
Kaprio J, Hakkarainen A, Lundbom J, Lundbom N, Hyötyläinen
T, Pietiläinen KH, Orešič M , Metabolome and faecal microbiota
in monozygotic twin pairs discordant for weight- a Big Mac
challenge, FASEB J. (2014). doi: 10.1096/fj.14-250167
La Torre D, Seppänen-Laakso T, Larsson HE, Hyötyläinen T,
Ivarsson SA, Lernmark Å, Orešič M , the DiPiS study group,
Decreased cord-blood phospholipids in young age at onset type
1 diabetes, Diabetes 62, 3951-3956 (2013).
Orešič M , Hyötyläinen T, Kotronen A, Gopalacharyulu P, Nygren H,
Arola J, Castillo S, Mattila I, Hakkarainen A, Borra R JH, Honka
MJ, Verrijken A, Francque S, Iozzo P, Leivonen M, Jaser N, Juuti
A, Sørensen TIA, Nuutila P, Van Gaal L, Yki-Järvinen H, Prediction
of non-alcoholic fatty liver disease and liver fat content by serum
molecular lipids, Diabetologia 56, 2266-2274 (2013).
Orešič M , Gopalacharyulu P, Mykkänen J, Lietzen N, Mäkinen M,
Nygren H, Simell S, Simell V, Hyöty H, Veijola R, Ilonen J, SysiAho M, Knip M, Hyötyläinen T, Simell O, Cord serum lipidome in
prediction of islet autoimmunity and type 1 diabetes, Diabetes
62, 3268-3274 (2013).
Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall H-U, Bamberg K,
Angelin B, Hyötyläinen T, Orešič M , Bäckhed F, Gut microbiota
regulates bile acid metabolism by reducing the levels of
taurobetamuricholic acid, a naturally occurring FXR antagonist,
Cell Metab. 17, 225–235 (2013).
Hyötyläinen T, Mattila I, Wiedmer S, Koivuniemi A, Taskinen M-R,
Yki-Järvinen H, Orešič M , Metabolomic analysis of polar
metabolites in lipoprotein fractions identifies lipoprotein-specific
metabolic profiles and their association with insulin resistance,
Mol. Biosyst. 8, 2559-2565 (2012).
Orešič M , Seppänen-Laakso T, Sun D, Tang J, Therman S, Viehman
R, Mustonen U, van Erp TGM, Hyötyläinen T, Thompson P,
Toga AW, Huttunen MO, Suvisaari J, Kaprio J, Lönnqvist J,
Cannon TD, Phospholipids and insulin resistance in psychosis:
a lipidomics study of twin pairs discordant for schizophrenia,
Genome Med. 4, e1 (2012).
Orešič M , Hyötyläinen T, Herukka S-K, Sysi-Aho M, Mattila I,
Seppänan-Laakso T, Julkunen V, Gopalacharyulu PV, Hallikainen
M, Koikkalainen J, Kivipelto M, Helisalmi S, Lötjönen J, Soininen
H, Metabolome in progression to Alzheimer’s disease, Transl.
Psychiatry 1, e57 (2011). (Commentary in Alzheimer Research
Forum) (Commentary in Neurology Today)
Sysi-Aho M, Ermolov A, Gopalacharyulu PV, Tripathi A, SeppänenLaakso T, Maukonen J, Mattila I, Ruohonen ST, Vähätalo L,
Yetukuri L, Härkönen T, Lindfors E, Nikkilä J, Ilonen J, Simell O,
Saarela M, Knip M, Kaski S, Savontaus E, Orešič M , Metabolic
regulation in progression to autoimmune diabetes, PLoS Comp.
Biol. 7 (10), e1002257 (2011).
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
93
I, Vidal-Puig A, Orešič M , Association of lipidome remodeling
in the adipocyte membrane with acquired obesity in humans,
PLoS Biol. 9(6), e1000623 (2011).
Orešič M, Hänninen V, Vidal-Puig A, Lipidomics: a new window
to biomedical frontiers, Trends Biotechnol. 26(12), 647-652
(2008).
Orešič M , Tang J, Seppänen-Laakso T, Mattila I, Saarni SE,
Saarni SI, Lönnqvist J, Sysi-Aho M, Hyötyläinen T, Perälä J,
Suvisaari J, Metabolome in schizophrenia and other psychotic
disorders: a general population-based study, Genome Med. 3,
e19 (2011).
Nikkilä J, Sysi-Aho M, Ermolov A, Seppänen-Laakso T, Simell O,
Kaski S, Orešič M , Gender dependent progression of systemic
metabolic states in early childhood, Mol. Syst. Biol. 4, e197
(2008).
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 JL, Fiehn O, Loibl
S, Richter-Ehrenstein C, Radke C, Hyötyläinen T, Kallioniemi
O, Iljin K, Orešič M, Novel theranostic opportunities offered
by characterization of altered membrane lipid metabolism
in breast cancer progression, Cancer Res. 71, 3236-3245
(2011).
Pluskal T, Castillo S, Villar-Briones A, Orešič M , MZmine 2: Modular
framework for processing, visualizing, and analyzing mass
spectrometry-based molecular profile data, BMC Bioinformatics
11, 395 (2010).
Westerbacka J, Kotronen A, Fielding BA, Wahren J, Hodson L,
Perttilä J, Seppänen-Laakso T, Suortti T, Arola J, Hultcrantz R,
Castillo S, Olkkonen VM, Frayn KN, Orešič M , Yki-Järvinen H,
Splanchnic balance of free fatty acids, endocannabinoids and
lipids in subjects with NAFLD, Gastroenterology 139, 19611971 (2010).
Yetukuri L, Söderlund S, Koivuniemi A, Seppänen-Laakso
T, Niemelä PS, Hyvönen M, Taskinen M-R, Vattulainen I,
Jauhiainen M, Orešič M , Composition and lipid spatial
distribution of High Density Lipoprotein particles in subjects
with low and high HDL-cholesterol, J. Lipid Res. 51, 23412351 (2010).
Yetukuri L, Katajamaa M, Medina-Gomez G, Seppänen-Laakso
T, Vidal Puig A, M. Orešič M , Bioinformatics strategies for
lipidomics analysis: characterization of obesity related hepatic
steatosis, BMC Systems Biology 1, e12 (2007).
Laaksonen R, Katajamaa M, Päivä H, Sysi-Aho M, Saarinen L,
Junni P, Lütjohann D, Smet J, Van Coster R, Seppänen-Laakso
T, Lehtimäki T, Soini J, Orešič M , A systems biology strategy
reveals biological pathways and plasma biomarker candidates
for potentially toxic statin induced changes in muscle, PLoS
ONE 1(1): e97 (2006).
Katajamaa M, Orešič M , Processing methods for differential
analysis of LC/MS profile data, BMC Bioinformatics 6:179
(2005).
Orešič M , Shalloway D, Specific Correlations between Relative
Synonymous Codon Usage and Protein Secondary Structure,
J. Mol. Biol. 281, 31-48 (1998).
Orešič M , Shalloway D, Hierarchical characterization of energy
landscapes using Gaussian packet states, J. Chem. Phys. 101,
9844-9856 (1994).
Velagapudi VR, Hezaveh R, Reigstad CS, Gopalacharyulu PV,
Yetukuri L, Islam S, Felin J, Perkins R, Borén J, Orešič M,
Backhed F, The gut microbiota modulates host energy and lipid
metabolism in mice, J. Lipid Res. 51, 1101-1112 (2010).
Orešič M , Seppänen-Laakso T, Yetukuri L, Bäckhed F, Hänninen
V, Gut microbiota affects lens and retinal lipid composition, Exp.
Eye Res. 89, 604-607 (2009).
Kotronen A, Velagapudi VR, Yetukuri L, Westerbacka J, Bergholm
R, Ekroos K, Makkonen J, Taskinen M-R, Orešič M , Yki-Järvinen
H, Saturated fatty acids containing triacylglycerols are better
markers of insulin resistance than total serum triacylglycerol
concentrations, Diabetologia 52(4), 684-690 (2009).
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
R, Knip M, Simell O, Dysregulation of lipid and amino acid
metabolism precedes islet autoimmunity in children who later
progress to type 1 diabetes, J. Exp. Med. 205(13), 2975-2984
(2008).
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95
PROTEIN CRYSTALLOGRAPHY
Anastassios C. Papageorgiou, PhD, Adjunct Professor in
Biochemistry and Structural Biology
Tel. +358-2-3338012, Fax +358-2-3338000.
E-mail: tassos.papageorgiou@btk.fi
Biography:
Tassos Papageorgiou obtained his PhD from the University of Athens
in 1992. He was a post-doctoral 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, Pradeep
Battula, MSc students: Amin Seid, Nirmal Poudel, Sagar Bhadari,
Undergraduate students: Adeleke Amoda, Visiting scientist: Kirti
Sonkar, Marta Lascorz
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.
Work on several new Dps proteins continued in order to understand
better the iron core formation using X-ray crystallography,
microcalorimetry, EXAFS, magnetization measurements, and
Mössbauer spectroscopy. Small crystals of a Dps protein from the
Lyme disease pathogen Borrelia burgdorferi were grown but they
need further optimization.
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. Various data sets have been
collected and attempts to determine the structures are underway.
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. Small angle X-ray
experiments were carried out in ESRF Grenoble and revealed the
overall shape of the molecules. A third adhesin with galabiosebinding 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.
96
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. Using directed evolution approaches, new GSTs have
been generated with altered specificity. Structural studies are
currently in progress.
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. Binding of a tetramer analogue has
suggested a possible substrate binding binding . 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
2.15 Å. The structure is currently under rounds of refinement and
extensive rebuilding. Docking calculations have been carried out
to identify key residues for substrate binding.
Recent reports implicating phosphoserine aminotransferase
(PSAT), a vitamin B6 enzyme, in cancer and tuberculosis has
led us to investigate closer the substrate binding mechanism of
this enzyme for potential drug design efforts. In addition to the
phosphoserine-bound PSAT structure determined to 1.5 Å, new
structures in the presence of other substrates are currently being
determined to high/atomic resolution. These studies will reveal the
exact local conformational changes during the catalytic cycle of
the enzyme.
Funding
University of Turku, Biocenter Finland, EU FP7 (access to
synchrotrons), Biostruct-X, Cultural Foundation of Southwestern
Finland, CIMO
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), Xin Li (Ohio State university), Maria Fillat (University
of Zaragoza)
97
Haikarainen, T., Loimaranta, V., Prieto-Lopez, C., Battula, P., Finne,
J., and Papageorgiou, A. C. (2013) Expression, purification and
crystallization of the C-terminal LRR domain of Streptococcus
pyogenes protein 0843. Acta Crystallogr Sect F Struct Biol Cryst
Commun 69, 559–561
Battula, P., Dubnovitsky, A. P., and Papageorgiou, A. C. (2013)
Structural basis of L-phosphoserine binding to Bacillus
alcalophilus phosphoserine aminotransferase. Acta Crystallogr
D Biol Crystallogr 69, 804–811
Chronopoulou, E. G., Papageorgiou, A. C., Markoglou, A., and
Labrou, N. E. (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
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., and Coffey, E. T. (2012) c-Jun N-Terminal Kinase
Phosphorylation of MARCKSL1 Determines Actin Stability and
Migration in Neurons and in Cancer Cells. Mol. Cell. Biol. 32,
3513–3526
Skopelitou, K., Dhavala, P., Papageorgiou, A. C., and Labrou,
N. E. (2012) A glutathione transferase from Agrobacterium
tumefaciens reveals a novel class of bacterial GST superfamily.
PLoS ONE 7, e34263
Haikarainen, T., Paturi, P., Lindén, J., Haataja, S., Meyer-Klaucke,
W., Finne, J., and Papageorgiou, A. C. (2011) Magnetic properties
and structural characterization of iron oxide nanoparticles formed
by Streptococcus suis Dpr and four mutants. J Biol Inorg Chem
16, 799–807
Haikarainen, T., Thanassoulas, A., Stavros, P., Nounesis, G.,
Haataja, S., and Papageorgiou, A. C. (2011) Structural and
thermodynamic characterization of metal ion binding in
Streptococcus suis Dpr. J Mol Biol 405, 448–460
Li, D.-C., Li, A.-N., and Papageorgiou, A. C. (2011) Cellulases
from thermophilic fungi: Recent insights and biotechnological
potential. Enzyme Research 2011, 1–9 Article ID 308730
Selected publications:
Papageorgiou, A. C., and Mattsson, J. (2014) Protein structure
validation and analysis with x-ray crystallography. Methods Mol
Biol 1129, 397–421
Haikarainen, T., Frioux, C., Zhnag, L.-Q., Li, D.-C., and
Papageorgiou, A. C. (2014) Crystal structure and biochemical
characterization of a manganese superoxide dismutase from
Chaetomium thermophilum. Biochimica et Biophysica Acta
(BBA) - Proteins and Proteomics 1844, 422–429
Jendrossek, D., Hermawan, S., Subedi, B., and Papageorgiou,
A. C. (2013) Biochemical analysis and structure determination
of Paucimonas lemoignei poly(3-hydroxybutyrate) (PHB)
depolymerase PhaZ7 muteins reveal the PHB binding site and
details of substrate-enzyme interactions. Mol Microbiol 90, 649–
664
98
Wakadkar, S., Zhang, L.-Q., Li, D.-C., Haikarainen, T., Dhavala,
P., and Papageorgiou, A. C. (2010) Expression, purification and
crystallization of Chaetomium thermophilum Cu,Zn superoxide
dismutase. Acta Crystallogr Sect F Struct Biol Cryst Commun
66, 1089–1092
Haikarainen, T., Tsou, C.-C., Wu, J.-J., and Papageorgiou,
A. C. (2010) Structural characterization and biological
implications of di-zinc binding in the ferroxidase center
of Streptococcus pyogenes Dpr. Biochem Biophys Res
Commun 398, 361–365
Wakadkar, S., Hermawan, S., Jendrossek, D., and Papageorgiou,
A. C. (2010) The structure of PhaZ7 at atomic (1.2 Å) resolution
reveals details of the active site and suggests a substrate-binding
mode. Acta Crystallogr Sect F Struct Biol Cryst Commun 66,
648–654
99
Axarli, I., Georgiadou, C., Dhavala, P., Papageorgiou, A. C., and
Labrou, N. E. (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. Biochim
Biophys Acta 1804, 662–667
Labrou NE Papageorgiou AC Avramis VI (2010) Structure-function
relationships and clinical applications of L-asparaginases. Curr
Med Chem 17, 2183–2195
Haikarainen, T., and Papageorgiou, A. C. (2010) Dps-like proteins:
structural and functional insights into a versatile protein family.
Cell Mol Life Sci 67, 341–351
Haikarainen, T., Tsou, C.-C., Wu, J.-J., and 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
Melissis, S., Papageorgiou, A., Labrou, N. E., and Clonis, Y. D.
(2010) Purification of M-MLVH-RT on a 9-Aminoethyladenine(1,6-diamine-hexane)-triazine Selected from a Combinatorial
Library of dNTP-Mimetic Ligands. Journal of Chromatographic
Science 48, 496–502
Dhavala, P., and Papageorgiou, A. C. (2009) Structure of
Helicobacter pylori L-asparaginase at 1.4 A resolution. Acta
Crystallogr D Biol Crystallogr 65, 1253–1261
Mitsiki, E., Papageorgiou, A. C., Iyer, S., Thiyagarajan, N.,
Prior, S. H., Sleep, D., Finnis, C., and Acharya, K. R. (2009)
Structures of native human thymidine phosphorylase and in
complex with 5-iodouracil. Biochem Biophys Res Commun
386, 666–670
Axarli, I., Dhavala, P., Papageorgiou, A. C., and Labrou, N. E.
(2009) Crystal structure of Glycine max glutathione transferase
in complex with glutathione: investigation of the mechanism
operating by the Tau class glutathione transferases. Biochem J
422, 247–256
Axarli, I., Dhavala, P., Papageorgiou, A. C., and 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
From left to right. Back row: Amin Seid, Abdi Muleta,Tassos Papageorgiou and
Nirmal Poudel. Front row: Kirti Sonkar, Pradeep Battula and Sagar Bhadari.
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101
INTEGRIN ACTIVITY IN DISEASE
http://www.btk.fi/research/research-groups/pouwels/
Jeroen Pouwels, Ph.D., Adjunct Professor of Biochemistry,
Tykistökatu 6A
FIN-20521 Turku, Finland
phone: +358-440466088
Fax: +358-2-2158808.
email: jpouwels@btk.fi
Biography:
Jeroen Pouwels (b. 1976) graduated from Wageningen University
(The Netherlands) in 1999 (Molecular Sciences) and received
his PhD from Wageningen University in 2004 (Plant Molecular
Biology). He did one postdoc in the research team of Dr. Marko
Kallio at VTT Medical Biotechnology in Turku (2004-2008). In 2009
he received an Academy of Finland Post-doctoral Fellowship for
research in the team of Prof. Dr. Johanna Ivaska (Turku Centre for
Biotechnology, VTT Medical Biotechnology), which was continued
using a Finnish Cancer Institute Postdoc Grant. In 2013 he was
awarded the title of Adjunct Professor of Biochemistry and he
established the Integrin Activity in Disease research group at
the Turku Centre for Biotechnology as an Academy of Finland
Research Fellow.
Personnel:
Graduate students: Meraj Hasan Khan, MSc., Maksym Skaldin,
MSc.
Regulation of integrin activity is fundamentally important during
development and in many physiological processes in adults.
Impaired regulation of integrin activation has been linked to
bleeding disorders, skin blistering, immune-deficiencies, chronic
inflammation, thrombosis and cancer. Integrins usually switch
between an active and an inactive state. Activation of integrins, which
leads to enhanced integrin-dependent signalling and strengthened
local cell adhesion, can occur by outside-in or inside-out signalling.
Outside-in signalling is triggered by binding to extracellular ligands
like collagen or fibronectin, while inside-out signalling is mediated
by binding of proteins to the intracellular region, which propagates
conformational changes from the intracellular to the extracellular
domains leading to an increase in affinity for ligands. Currently,
members of two protein families, Kindlins and Talins, are known
to activate integrins by binding to the cytoplasmic tail of betaintegrins.
Even though molecules keeping integrins inactive or switching
activated integrins back to inactive conformation are likely to be
biologically as important as integrin activators for regulating the
dynamic nature of integrin function, such molecules are not well
characterized. Moreover, the cytoplasmic domains of integrin
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alpha subunits are important in maintaining the integrin in an
inactive conformation but the mechanisms involved have remained
enigmatic. Very recently, a few proteins were shown to inhibit
integrin activity by binding to the beta-integrin cytoplasmic tail and
competing with Talin and Kindlin (DOK1 and Filamin).
However, given the broad range of cellular functions regulated by
the 24 different alpha-beta integrin heterodimers, it is very likely
that more modulators of integrin activity remain to be discovered.
To identify novel regulators of integrin activity we have utilized
the cell spot microarray (CSMA), a high-throughput RNAi screen
developed at VTT Medical Biotechnology (Pellinen et al., J. Cell
Sc. 2012), and identified Sharpin as a novel inhibitor of integrin
activity in vivo and in vitro (Rantala, Pouwels et al., Nature Cell
Biology, 2011). This study opened a new paradigm in integrin
regulation by showing that the dynamic switching between the
inactive and active conformations is physiologically controlled in
vivo by a protein interacting with the alpha-subunit cytoplasmic
domain. Very recently we have also shown that Sharpin regulates
lymphocyte function associated antigen-1 (LFA-1), an integrin
present on leukocytes (Pouwels et al., Cell Reports, 2013). In
these cells Sharpin mediates release of the cell rear (uropod)
during cell migration and therefore plays an important role in
leukocyte transmigration and homing in vivo.
As Sharpin has oncogenic potential, Sharpin knockout mice
show a psoriasis-like phenotype with chronic inflammation
and proliferative dermatitis, and Sharpin plays a role in linear
ubiquitination and regulation of the NF-κB pathway, understanding
the exact mechanism of Sharpin-induced integrin inhibition is highly
important, as well as finding potential other roles for this protein.
The aim of the integrin activity in disease group is to characterize
Sharpin and its integrin-inhibiting characteristics in more detail, both
at the molecular level and how Sharpin could play a role in human
diseases. This includes functional posttranslational modifications
of Sharpin, as well as identification of proteins that functionally
interact with Sharpin.
Funding:
The Academy of Finland.
Collaborators:
Prof. Johanna Ivaska (Turku Centre for Biotechnology, Turku,
Finland), Dr. John Sundberg (The Jackson Laboratory, Bar Harbor,
USA), Dr. Maddy Parsons (King’s College London Guy’s Campus,
London, UK), Prof. Henning Walczak (University College London,
Cancer Research UK, London, UK), Prof Marko Salmi (MediCity
Research Laboratory, University of Turku, Turku, Finland).
Selected Publications († Equal Contribution):
Pouwels J†, De Franceschi N†, Rantakari P, Auvinen K, Karikoski M,
Mattila E, Potter C, Sundberg JP, Hogg N, Gahmberg CG, Salmi
M, Ivaska J. (2013) SHARPIN Regulates Uropod Detachment in
Migrating Lymphocytes. Cell Rep. 5(3): 619-28.
Hämälistö S†, Pouwels J†, De Franceschi N, Saari M, Ivarsson Y,
Zimmermann P, Brech A, Stenmark H, Ivaska J. (2013) A ZO-1/
α5β1-integrin complex regulates cytokinesis downstream of
103
PKCε in NCI-H460 cells plated on fibronectin. PLOS ONE. 8(8):
e70696.
Bouvard D†, Pouwels J†, De Francesci N, Ivaska J. (2013) Integrin
inactivators: balancing cellular functions in vitro and in vivo.
Nature Reviews Mol. Cell Biol. 14(7): 430-42.
Pouwels J, Nevo J, Pellinen T, Ylänne J and Ivaska J. (2012)
Negative regulators of integrin activity. J Cell Sci. 125(Pt 14):
3271-80.
Rantala JK†, Pouwels J†, Pellinen T, Veltel S, Mattila E, Laasola
P, Potter CS, Duffy T, Sundberg JP, Kallioniemi O, Askari
JA, Humphries M, Parsons M, Salmi M and Ivaska J. (2011)
SHARPIN is an endogenous inhibitor of beta1-integrin activation.
Nature Cell Biol. 13(11): 1315-1324.
From left to right: Johanna Lilja, Jeroen Pouwels and Maksym Skaldin
104
105
CELL FATE
Funding:
The Academy of Finland, Åbo Akademi University, Centre of
Excellence in Cell Stress and Molecular Aging, Abo Academi,
Doctoral Network of Molecular Biosciences, EU 7th NotchIT,
Turku Graduate school for Biomedical Sciences, Cancer
Society of Finland, Sigrid Juselius Foundation, Marie Curie CIG
FP7.
Cecilia Sahlgren, PhD, Academy Research Fellow,
Tykistökatu 6B, FI-20521 Turku, Finland.
Tel. 358-2-3338611, Fax. +358-2-251 8808
E-mail: cecilia.sahlgren@btk.fi
Associate professor in biomedical engineering,
University of Technology, The Netherlands,
E-mail:c.m.sahlgren@tue.nl
Eindhoven
Biography:
Cecilia Sahlgren received her PhD 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. She has an affiliated position at the
Eindhoven University of Technology as an associate professor in
biomedical engineering
Personnel:
Post-doctoral Fellows: Veronika Mamaeva, MD, PhD. Graduate
students: Marika Sjöqvist, M.Sc, Neeraj Prabhakar, MSc Sebastian
Landor, M.Sc, Christian Antila, M.Sc, Daniel Antfolk, M.Sc, Rasmus
Niemi, MSc, Valeriy Paramanov, MD. Laboratory Technician: Natalie
Ratts. Undergraduate students: Jenni Niinimaki, 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)
develop technology platforms to regulate Notch signaling in
cancer stem and regeernation and tools for bioimaging of
cellular functions in vivo.
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Collaborators:
Prof. Urban Lendahl (Karolinska Institute), Prof. John Eriksson
(Turku Centre for Biotechnology). Prof. Milos Pekny (Sahlgrenska
Academy at Göteborg University), Ph.D Susumu Imanishi (Turku
Centre for Biotechnology), Prof. Lea Sistonen (Turku Centre for Biotechnology). Dr.Tech Jessica Rosenholm (Laboratory for Physical
Chemistry, Åbo Akademi University, Turku), Prof. Mika Linden (Dept
of Chemistry, Ulm University, Germany), Prof Carlijn Bouten, Dept of
biomedical engineering, Eindhoven University of Technology, Ass.
Professor Patricia Dankers, Dept for Chemcial Biology, Eindhoven
University of Technology.
Sjöqvist M, Antfolk D, Ferraris S, Rraklli V, Granqvist C, Antila C,
Mutvei A, Imanishi SY, Holmberg J, Jin S, Eriksson JE, Lendahl
U, and Sahlgren C. aPKC regulates Notch receptor routing and
activity in a Notch signalling dependent manner. Cell Research,
in press
Böcking D, Wiltschka O, Niinimäki J, Shokry H, Brenner R,
Lindén M & Sahlgren C (2014) Mesoporous silica nanoparticlebased substrates for cell directed delivery of Notch signalling
modulators to control myoblast differentiation. Nanoscale 6:
1490–8
Mamaeva V, Sahlgren C* & Lindén M* (2013) Mesoporous silica
nanoparticles in medicine--recent advances. Adv. Drug Deliv.
Rev. 65: 689–702 *Equal contribution
Wittig R, Rosenholm JM, von Haartman E, Hemming J, Genze
F, Bergman L, Simmet T, Lindén M & Sahlgren C (2013)
Active targeting of mesoporous silica drug carriers enhances
γ-secretase inhibitor efficacy in an in vivo model for breast
cancer. Nanomedicine (Lond). Available at: http://www.ncbi.
nlm.nih.gov/pubmed/23898823
Jin S, Mutvei AP, Chivukula I V, Andersson ER, Ramsköld D,
Sandberg R, Lee KL, Kronqvist P, Mamaeva V, Ostling P, Mpindi
J-P, Kallioniemi O, Screpanti I, Poellinger L, Sahlgren C &
Lendahl U (2013) Non-canonical Notch signaling activates IL-6/
JAK/STAT signaling in breast tumor cells and is controlled by
p53 and IKKα/IKKβ. Oncogene 32: 4892–902
Prabhakar N, Näreoja T, von Haartman E, Karaman DŞ, Jiang H,
Koho S, Dolenko TA, Hänninen PE, Vlasov DI, Ralchenko VG,
Hosomi S, Vlasov II, Sahlgren C & Rosenholm JM* (2013) Coreshell designs of photoluminescent nanodiamonds with porous
silica coatings for bioimaging and drug delivery II: application.
Nanoscale 5: 3713–22
Wilhelmsson U, Faiz M, de Pablo Y*, Sjöqvist M,* Andersson D,
Widestrand A, Potokar M, Stenovec M, Smith PLP, Shinjyo N,
107
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: 2320–9
*Equal contribution
Rosenholm JM, Mamaeva V, Sahlgren C* & Lindén M* (2012)
Nanoparticles in targeted cancer therapy: mesoporous
silica nanoparticles entering preclinical development stage.
Nanomedicine (Lond) 7: 111–20. *Equal contribution
Landor SK-J, Mutvei AP, Mamaeva V, Jin S, Busk M, Borra R,
Grönroos TJ, Kronqvist P, Lendahl U & Sahlgren C (2011) Hypoand hyperactivated Notch signaling induce a glycolytic switch
through distinct mechanisms. Proc. Natl. Acad. Sci. U. S. A.
108: 18814–9
Mamaeva V, Rosenholm JM, Bate-Eya LT, Bergman L, Peuhu E,
Duchanoy A, Fortelius LE, Landor S, Toivola DM, Lindén M &
Sahlgren C (2011) Mesoporous silica nanoparticles as drug
delivery systems for targeted inhibition of Notch signaling in
cancer. Mol. Ther. 19: 1538–46
Rosenholm JM, Sahlgren C* & Lindén M* (2010b) Towards
multifunctional, targeted drug delivery systems using
mesoporous silica nanoparticles--opportunities & challenges.
Nanoscale 2: 1870–83 *Equal contribution
Rosenholm JM, Peuhu E, Bate-Eya LT, Eriksson JE, Sahlgren C*
& Lindén M* (2010a) Cancer-cell-specific induction of apoptosis
using mesoporous silica nanoparticles as drug-delivery vectors.
Small 6: 1234–41 *Equal contribution
Rosenholm JM, Peuhu E, Eriksson JE, Sahlgren C* & Lindén M*
(2009b) Targeted intracellular delivery of hydrophobic agents
using mesoporous hybrid silica nanoparticles as carrier systems.
Nano Lett. 9: 3308–11 *Equal contribution
Rosenholm JM, Meinander A, Peuhu E, Niemi R, Eriksson JE,
Sahlgren C* & Lindén M* (2009a) Targeting of porous hybrid
silica nanoparticles to cancer cells. ACS Nano 3: 197–206
*Equal contribution
Sahlgren C, Gustafsson M V, Jin S, Poellinger L & Lendahl U (2008)
Notch signaling mediates hypoxia-induced tumor cell migration
and invasion. Proc. Natl. Acad. Sci. U. S. A. 105: 6392–7
From left to right. Back row: Valeriy Paramonov, Ramsus Niemi, Martina Lerche and
Marika Sjöqvist. Front row: Daniel Antfolk, Christian Antila and Sebastian Landor
108
109
From left to right: Marianna Estrada, Satu Orasniemi, Maria Jensen, Malin Blom, Jens Luoto, Jenny Joutsen, Camillla Aspelin, Samu Himanen, Emine Lundsten, Eva Henriksson, Lea Sistonen, Mikael Puustinen,
Heidi Bergman and Alexandra Elsing.
110
REGULATION AND FUNCTION OF
HEAT SHOCK TRANSCRIPTION
FACTORS
Lea Sistonen, PhD, 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 PhD 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, PhD, Pia Roos-Mattjus, PhD
Post-doctoral Fellows: Johanna Björk, PhD, Anton Sandqvist, PhD
Graduate students: Camilla Aspelin, MSc, Heidi Bergman, MSc,
Marek Budzynski, MSc, Alexandra Elsing, MSc, Jenny Joutsen,
MSc, Emine Lundsten, MSc, Petra Vainio, MSc, Anniina Vihervaara,
MSc
Research assistant: Helena Saarento, MSc
Undergraduate students: Malin Blom, Alejandro Da Silva, Marianna
Estrada, Samu Himanen, Maria Jensen, Heidi Lustig, Jens Luoto,
Satu Orasniemi, Mikael Puustinen
Description of the Project:
The heat shock response is an evolutionarily well-conserved cellular
defense 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 expands well beyond the Hsps, and HSF functions
span from the heat shock response to development, metabolism,
111
lifespan and disease, especially cancer and neurodegenerative
disorders.
Our objective is to unravel 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
HSF1-HSF2 heterotrimers and their impact on various target
genes are designed to elucidate the roles of HSFs in proteinmisfolding 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.
Using mouse spermatogenesis as a model system, we
discovered an inverse correlation between the cell- and stagespecific wave-like expression patterns of HSF2 and a specific
microRNA, miR-18, which is a member of the Oncomir-1/miR17∼92 cluster. We found that miR-18 represses the expression
of HSF2 by directly targeting its 3’UTR, and using our in vivo
method T-GIST (Transfection of Germ cells in Intact Seminiferous
Tubules), we showed that inhibition of miR-18 in intact mouse
seminiferous tubules leads to increased HSF2 protein levels and
altered expression of HSF2 target genes. 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.
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.
Subsequently, we 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 exposure to acute heat
112
stress, highlight an orchestrated transcriptional program that
controls a multitude of cellular processes in stressed cycling cells.
Surprisingly, HSF1 was found to possess a limited capacity to
interact with the condensed chromatin and induce transcription
in mitotic cells, whereas HSF2 is capable of binding to several
targets, indicating a specific impact of HSF2 on transcription
throughout the cell cycle progression. Since HSF2 expression
declines during mitosis in many cell types, and the HSF2 levels
are further decreased in response to stress, we have now
addressed the functional relevance of HSF2 in the regulation of
cell survival in mitotic cells exposed to acute stress. Our results
indicate that in cells where HSF2 is downregulated, both HSF1
and RNA polymerase II that are normally displaced from mitotic
chromatin are able to access the target genes. Furthermore,
HSF2-deficient cells display diminished mitotic abnormalities
and increased survival upon acute heat stress, thereby providing
a protective mechanism to mitotic cells that are highly vulnerable
to stress.
Funding:
The Academy of Finland, the Sigrid Jusélius Foundation, the
Finnish Cancer Organizations, the Magnus Ehrnrooth Foundation,
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), Dennis Thiele (Duke
University, Durham, NC, USA), Laszlo Vigh (Biological Research
Center, Szeged, Hungary).
Elsing A.N., Aspelin C., Björk J.K., Bergman H.A., Himanen S.V.,
Kallio M.J., Roos-Mattjus P. and Sistonen L. (2014) Expression
of HSF2 decreases in mitosis to enable stress-inducible
transcription and cell survival. J. Cell Biol., in press.
Vihervaara A., Sergelius C., Vasara J., Blom M.A.H., Elsing
A.N., Roos-Mattjus P. and Sistonen L. (2013) Transcriptional
response to stress in the dynamic chromatin environment
of cycling and mitotic cells. Proc. Natl. Acad. Sci. USA 110:
E3388-E3397.
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: 2321623226.
113
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.
Björk J.K. and Sistonen L. (2010) Regulation of the members of the
mammalian heat shock factor family. FEBS J. 277: 4126-4139.
Ahlskog J.K., Björk J.K., Elsing A.N., Aspelin C., Kallio
M., Roos-Mattjus P. and Sistonen L. (2010) Anaphasepromoting complex/cyclosome participates in the acute
response to protein-damaging 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
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.
*equal contribution
114
CANCER CELL SIGNALING
http://www.btk.fi/research/research-groups/westermarck/
Jukka Westermarck, MD, PhD, Professor.
Address: Turku Centre for Biotechnology,
BioCity, Tykistökatu 6B, FIN-20251 Turku, Finland.
Tel. +358-2-3338621, Fax +358-2-2158808.
E-mail: jukwes@utu.fi.
Biography:
Jukka Westermarck (b. 1969) received his MD in 1996 and PhD in
1998 at the University of Turku. He was a post-doctoral fellow at
European Molecular Biology Laboratory in Heidelberg, Germany,
in Dr. Dirk Bohmann´s laboratory during 1999-2001. He was an
Academy of Finland senior scientist during 2002-2007. 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, MD, PhD Post-doctoral
Fellows: Anna Lipsanen, PhD, Juha Okkeri, PhD, Anni Laine,
PhD, Christian Rupp, PhD Graduate students: Otto Kauko, MD,
MSc, Amanpreet Kaur, MSc, Xi Qiao, MSc, Eleonora Sittig, MSc
Technicians: Taina Kalevo-Mattila, Lab.Tech., Inga Pukonen,
B.Eng. Head of Laboratory: Tiina Arsiola, PhD
The general goal of our research group is to explore regulation and
function of human tumor suppressor Protein Phosphatase 2A (PP2A)
in human malignancies. Various PP2A complexes regulate activity of
variety of critical signaling pathways in cancer by dephosphorylating
phosphorylated serine/threonine residues in kinases, transcription
factors and other signaling proteins. PP2A inhibition is one of
requirements of human cell transformation and thereby understanding
of the function and regulation of PP2A tumor suppressor activity is
a fundamentally important question in cancer biology. In addition
to genetic alterations in some of the PP2A complex components,
PP2A activity is inhibited in human cancers by endogenous inhibitor
proteins. Our laboratory recently identified CIP2A as a novel PP2A
inhibitor protein, and was first to demonstrate cancer-promoting
roles for both CIP2A and another PP2A inhibitor protein PME-1.
In addition, PP2A inhibitor protein SET promotes activity of several
oncogenic pathways and tumor growth. Expression of all of these
PP2A inhibitor proteins shows strong association with tumor
progression in several human cancer types and thus represents
novel potential targets for cancer therapy. Most of the projects in our
laboratory are focused on further understanding of CIP2A, PME-1
and SET as novel human oncoproteins, and their suitability as novel
drug targets for cancer therapies. Moreover, as there is a clear need
for novel genetic mouse models to study role of PP2A in cancer
development and progression, and to model potential PP2A re-
115
From left to right: Xi Qiao, Christian Rupp, Amanpreet Kaur, Juha Okkeri, Anna Lipsanen, Jukka Westermarck, Taina Kalevo-Mattila, Otto Kauko, Tiina Arsiola, Anni Laine, Eleonora Sittig and Inga Pukonen.
activating therapies, we are in the process of generating conditional
mouse models targeting endogenous PP2A inhibitors.
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), Heikki Joensuu
(Helsinki University Hospital), Tapio Visakorpi (University of Tampere),
Juha Klefström (University of Helsinki), Tero Aittokallio (FIMM, Helsinki)
Khanna, A., Kauko, O., Böckelman, C., Laine, A., Schreck, I., Partanen,
J.I., Szwadja, A., Bormann, S., Bilgen T, Helenius, M., Pokharel, Y.R.,
Pimanda, J., Russel, M.R., Haglund, C., Cole, K.A., Klefström, J.,
Aittokallio, T., Weiss, C., Ristimäki, A., Visakorpi, T. and Westermarck,
J. (2013). Chk1 targeting reactivates PP2A tumor suppressor activity in
cancer cells. Cancer Research 73(22): 6757-6769.
Laine, A., Sihto, H., Come, C., Rosenfeldt, M., Zwolinska, A., Niemelä,
M., Khanna, A., Chan, E.K., Kähäri, V.-M., Kellokumpu-Lehtinen, P.L., Sansom, O.J., Evan, G.I., Junttila, M.R., Ryan, K.M., Marine, J.-C.,
Joensuu, H. and Westermarck, J. (2013). Senescence sensitivity of breast
cancer cells is defined by positive feedback loop between CIP2A and
E2F1. Cancer Discovery 3: 182-197.
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 CIP2Aregulated phenotypes and its clinical association with breast cancer
subtypes. Oncogene 31: 4266-4278.
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.
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.
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.
116
117
ADENOSINE DEAMINASES
Andrey Zavialov, PhD, Finnish Academy Research Fellow (group
leader),
Turku Centre for Biotechnology, University of Turku,
Tykistökatu 6, FI-20520,Turku, Finland,
Tel. +358403776216, Fax. +358-2-3338000,
Email: azaviyal@btk.fi
Biography:
Andrey Zavialov (b. 1975) has obtained his M.S. in Biotechnology
from Russian Chemical Technology University (Moscow) and a PhD
in Molecular Biology from Uppsala University (Sweden). Between
2005-2010 Dr Zavialov received his post-doctoral 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.), Chengquian Liu (M.S.),
Yuliia Mukiienko (MD), Balwant Rai (MFO)
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.
The enzyme was purified and identified as a member of a new class
of adenosine deaminase related growth factors (ADGF). 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. 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 presence of
two different ADAs in humans and their interaction with adenosine
receptors, which may affect their function, has largely been ignored
due to a lack of knowledge and a dearth of research teams performing
systematic studies of adenosine receptors together with ADAs. At the
same time, clinical studies have shown that ADA2 is a very specific
biological marker for common and life-threatening diseases such as
HIV, tuberculosis and breast cancer. Recently, our collaborators from
the NIH and a group from Israel have identified patients with mutations
in the ADA2 gene. It was shown that ADA2 concentration in the
plasma of these patients is reduced more than 10-fold compared to
118
that in healthy subjects. Furthermore, these patients display multiple
health problems, including early onset systemic inflammation,
multiple ischemic strokes, and vasculitis. Interestingly, the symptoms
of the ADA2-deficient patients are distinct from SCID patients with
ADA1 deficiency. Although the absence of either functional ADA1
or ADA2 leads to disregulated immune function, the lack of one
functional enzyme is not compensated for by the presence of the
remaining enzyme, suggesting that ADA1 and ADA2 have distinct
roles. Strikingly, in both reports, the patients that were homozygous
for a common mutation in Gly47 had clear symptoms of polyarteritis
nodosa vasculopathy (PAN). Therefore, this type of mutation in ADA2
would be the first known and well-characterized cause of PAN. 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. Mikko Seppänen (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.)
van Montfrans J, Zavialov A, Zhou Q. Mutant ADA2 in Vasculopathies.
N Engl J Med. 371(5):478-481.
Zhou, Q., Yang, D., Ombrello, A.K., Zavialov, A.V. at al. (2014).
Intermittent Fever and Early-Onset Stroke Due to Mutations in
ADA2. N Engl. J Med. 370: 911-20.
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 374:1345-1358.
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.
119
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.
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.
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 codon-specific
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 107:115-124.
From left to right: Yuliia Mukiienko, Chengquian Liu and Andrey Zaviyalov.
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PhD DEFENCES
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LIFE OUTSIDE THE LAB
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TURKU CENTRE FOR BIOTECHNOLOGY REPORT 2013

Transcription

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