Report 2008

Transcription

Report 2008

www.i-med.ac.at/biocenter
REPORT
Adele Loidl | Alexander Hüttenhofer | Alexandra Lusser | Alexandra Pipal | Andrea Casari | Andrea Eigentler | Andreas
Ploner | Andreas Villunger | Anette Zeilner | Angela Klein-Wondrak | Angelika Walter | Anita Kofler | Anna Chirkova | Anna
Frenzel | Anna Wallner | Anto Nogalo | Arno Helmberg | Astrid Devich | Astrid Haara | Ayten Yigit | Barbara Gschirr |
Barbara Meissner | Bea Lechner | Beate Abt | Beatrix Fürst | Beatriz Campo-Fernández | Benedicte Sohm | Benedikt Koller |
Bernd Puschendorf Bernhard Halfinger | Bernhard Redl | Bernhard Rieder | Bettina Sarg | Bettina Thauerer (former Tomaselli) |
Bettina Unterberger | Birgit Fischer | Birgit Schraberger | Brigitte Andrä | Brigitte Andrä | Christian Ploner | Christian Eller |
Christian Kositz | Christina Weinl | Christine Bandtlow | Christine Mantinger | Christoph Dohmesen | Christoph Joechl | Cicek
Aydemir | Claudia Kragl | Claudia Manzl | Claudia Nagl | Claudia Ott | Claudia Ram | Claudia Sigl | Claudia Soratroi | Constanze
Nandy | Cornelia Thoeni | Cornelia Wandke | Daniel Wechselberger | Daniela Höller | David Teis | Diana Hilber | Dietmar Fuchs |
Divyavaradhi Varadarajan | Domagoj Cikes | Dorata Garczarczyk | Elena Ledjeff | Elisabeth Maier | Elisabeth Santer | Ernst R.
Werner | Fatma Dikmen | Florentine Marx | Florian Baumgartner | Florian Bock | Florian Kern | Florian Rechfeld | Florian Schwarze
| Florian Überall | Francesca Grespi | Gabriele Baier-Bitterlich | Gabriele Neurauter | Gabriele Scheran | Gabriele Stöckl | Gabriele
Werner-Felmayer | Georg Golderer | Georg Gruber | Georg Nikolaidis | Georg Wick | Gerald Brosch | Gerhard Krumschnabel |
Gernot Grissenaue | Gertrude Huber | Günther Böck | Heidelinde Jäkel | Hans Grunicke | Heribert Talasz | Hermann Krabichler |
Hildegard Wörle | Hubertus Haas | Igea Contarini | Ilenia Bertipaglia | Ilja Vietor | Ilona Lengenfelder | Ines Jaklitsch | Ines Peschel
| Ingo Bauer | Irene Gaggl | Irina Berger | Ivan Prokudin | Jan Mrazek | Jan Wiegers | Jasmina Sabiha | Joachim Meraner |
Johann Hofmann | Johannes Galehr | Johannes Rainer | Jonathan Vosper | Julia Scheffler | Julianna Leuenberger | Kamilla
Bakowska-Zywicka | Karin Ecker | Karin Lentsch | Karin Schluifer | Karl Maly | Karoline Hörtnagel | Katherin Patsch | Kathrin
Becker | Kathrin Rossi | Katja Jacob | Katrin Watschinger | Konstantinia Skreka | Krista Trappl | | Lára Hannesdottir | Leopold
Kremser | Levent Kaya | Linda Teufel | Lisa Kindler-Maly | Ludger Hengst | Lukas A. Hube | Lukas Sattler | Manuela VillungerGfreiner | Marcel Jenny | Marek Zywicki | Maren Fischer | Maria Ebner | Maria Gleinser | Maria Goralik-Schramel | Maria-Laura
Fluckinger | Mariana Eca Guimaraes de Araujo | Marin Barisic | Mario Gründlinger | Marion Mailänder | Markus Keller | Markus
Schrettl | Martin Eisendle | Martin Kerber | Martin Offterdinger | Martin Tribus | Martina Brunner | Mathieu Rederstorff | Matthias
Erlacher | Mayra Eduardoff | Melanie Amort | Melanie Heymann | Melanie Lukasser | Michael Blatzer | Michael C.Haffner |
Michael Keith Kullmann | Michael Rittinger | Michaela Pfister | Michela Carlet | Monika Hertscher | Muhammad Mansha |
Muhammad Saeed | Muhammad Wasim | Nadja Haas | Natalia Schiefermeier | Nicole Taub | Nikoletta Hegedüs | Nikos
Yannoutsos | Nina Clementi | Nina Madl | Nirmala Parajuli | Norbert Polacek | Oliver Wrulich | Paolo Piatt | Patrick Clemens | Peter
Gröbner | Peter Gruber | Peter Loidl | Petra Daum | Petra Loitzl | Petra Merschak | Petra Mikolcevic | Pia Müller | Przemyslaw
Filipek | Reinhard Kofler | Reinhard Sigl | Renate Gamper | Renate Weiler-Görz | Roland Hutzinger | osanna Nagele | Roswitha
Sgonc | Rüdiger Schweigreiter | Rudolf Schicho | Ruth Holzer | Ruth Pfeilschifter | Sabine Chwatal | Sandra Morandell | Sandra
Pittl | Sandra Trojer | Siegfried Schwarz | Silvio Podmirseg | Simon Schnaiter | Simone Barbara | Kreutmayer Simone | Stenico
Sonja | Philipp Stefan Ascher | Stefan Grässle | Stefan Steixner | Stefano Morettini | Stephan Geley | Susanne Lobenwein | Sylvia
Maurer | Taras Stasyk | Tarek Moussa | Traudl Erdel | Ulrike Binder | Valerie Podhraski | Verena Labi | Verena Melichar | Vinca
Ljesic | Walid Abu El-Soud | Wilhelm Sachsenmaier | Winfred Wunderlich | Wolfgang Doppler | Wolfgang Piendl | Yuuichi Soeno |
The People
REPORT
The Biocenter
The way and the goal: The view of the director
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We all hope that you enjoy the reading!
Lukas A. Huber
Director [email protected]
The Biocenter
History
The concept for the Innsbruck Biocenter was developed during my term as Rector of the Medical University. The
concept was based on the obvious fact that without first class basic medical science our medical university would
never be acknowledged appropriately as an internationally reputed research university. Basic medical research is a
core area within the life sciences. It is generally accepted that competitive research in this field should be
multidisciplinary. Furthermore, considering the extreme national and international competition in this area, the
corresponding institutions should be organized as efficiently as possible. Efficiency in this context means the
establishment of an organization which facilitates fast and uncomplicated interdisciplinary cooperation and,
especially, efficient use of limited funds.
The department called “Innsbruck Biocenter” was founded in order to achieve these goals. Five former “institutes”
were restructured into several “divisions”. These rather autonomous divisions form the backbone of the department.
The divisions were installed for a five year term after which their further fate would depend on the outcome of an
evaluation process. During these five years, the divisions are rather autonomous in order to avoid unnecessary
discussions over lab space, personnel and funds. The division heads form a conference which was intended to act
as the basis for interdisciplinary cooperation as well as the governing body for strategic decisions, i.e. planning of
common projects, design of the department budget and its distribution to the different divisions, establishment and
financing of core facilities, service units, commonly used expensive equipment and, last but not least, election of a
department director who should act as a speaker of the department, e.g. in negotiating the department budget with
the rector of the university.
With great pleasure I could observe that a great deal of this concept could be realized. The Innsbruck Biocenter
turned out to be a success and a model for similar institutions on our campus. This is to a large extent due to the
hard and dedicated work of the first department director, Professor Lukas Huber, who deserves our gratitude for this
extraordinary, altruistic engagement.
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As Professor emeritus, I am now focussing my work on reviewing, writing and
consulting. I am pleased that there is still some demand for my advice which I
am happy to give to anybody asking for it. I am convinced that the Innsbruck
Biocenter will continue its successful development to an internationally reputed
centre of basic medical research. My expertise is at the disposal of the
department whenever it is desired.
Hans Grunicke
Professor emeritus
f. Medical Chemistry
and Biochemistry
The Biocenter
Division & Groups
Division of Medical Biochemistry
Cell Cycle and Cell proliferation
Signal Transduction in Mammary Gland
Biochemical Pharmacology
Ribsosomal Proteins and RNA
Bioinformatics
Ludger HENGST
Ludger HENGST
Wolfgang DOPPLER
Johann HOFMANN
Wolfgang PIENDL
Florian ÜBERALL
Division of Clinical Biochemistry
Protein Analysis
Herbert LINDNER
Division of Biological Chemistry
Peter GRÖBNER
Division of Neurobiochemistry
Christine BANDTLOW
Dietmar FUCHS, Ernst WERNER, Gabriele WERNER-FELMAYR, Georg GOLDERER
Cell Death
Division of Cell Biology
Gabriele BAIER-BITTERLICH
Lukas A. HUBER
Signal Transduction & Proteomics
Cell Differentiation
Nuclear Receptor Tyrosine Kinases
Gene Regulation & Molecular Immunology
Lukas A. HUBER
Ilja VIETOR
Martin OFFTERDINGER
Nikis YANNOUTSOS
Membrane Traffic & Signalling
David TEIS
Division of Genomics and RNomics
Non-coding RNAs
Ribonucleoprotein complexes
Division of Molecular Biology
Chromatin and Epigenetics
Molecular Microbiology
Applied Mycology
Lipocalins
Alexander HÜTTENHOFER
Alexander HÜTTENHOFER
Norbert POLACEK
Peter LOIDL
Peter LOIDL, Gerald BROSCH, Stefan GRÄSSLE, Alexandra LUSSER
Hubertus HAAS
Florentine MARX
Bernhard REDL
Division of Exper. Pathophysiology & Immunol.
Exper. Rheumatology
Biophysics/Biooptics
Molecular Endocrinology
Division of Molecular Pathophysiology
Leukemia – Apoptosis
Molecular Oncology
Cell Cycle Control
Roswitha SGONC
Günther BÖCK
Siegfried SCHWARZ
Reinhard KOFLER
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Reinhard KOFLER
Arno HELMBERG
Stephan GELEY
Division of Developmental Immunology Andreas VILLUNGER
Apoptosis Group
Immunoendocrinology
Andreas VILLUNGER
Jan WIEGERS
The Biocenter
Facts
The BIOCENTER engages alltogether
200 collaborators
among these are
7 full professors
21 associate professors
77 post docs financed by public grants
12 technicians financed by public grants
Thus, almost 50% of the entire personell is presently financed by external funding
external funding
2006
2007
FWF, EU, GE-NAU
3.3
3.5
Mio Euro
Others
1.1
1.8
Mio Euro
Total
4.4
5.3
Mio Euro
Public & private support
Since the founding of the BIOCENTER, several hundred diploma and doctoral theses by
students enrolled in the PhD and MD programmes of the University of Innsbruck and the
Innsbruck Medical University have been successfully elaborated.
BIOCENTER SEMINARS
Every Friday afternoon, one of our postdocs or Ph.D. students gives a lecture of her/his
recent scientific achievements.
Therafter, HAPPY HOUR is on, which is deemed important for relaxation as well as for the
establishment of possible scientific cooperations.
INNSBRUCK MEDICAL UNIVERSITY MENTORING PROGRAMME
An „established“ person accompanies a young female scientist through her career in academia until
she reaches her specific goal. In case of obstacles and difficulities, the mentor is trying to find solutions
for her mentée. Christine Bandtlow, Roswitha Gruber-Sgonc, Gabriele Werner-Felmayer of the
Biocenter are appointed mentors.
Basic research
Publications
Patents
Spin-offs
http://www.imed.ac.at/gleichstellung/mentoring/mentorinnen.html
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Publications 2002 - 06 Impact factors
Biocenter
2168
citations
8227
The Biocenter
Support & Collaboration
ONCOTYROL
05
Institute for Biomedical Aging Research
Austrian Academy of Sciences
The Biocenter
SFB021
Special Research Program
http://www.sfb021.at/
MEMBERS
Baccarini Manuela
Baier Gottfried
Bonn Günther
Fässler Reinhard
Geley Stephan
Greil Richard
Hengst Ludger
Huber Lukas A. (Coordinator)
Kofler Reinhard
Tinhofer Inge
Villunger Andreas
Biochemistry, Molecular Biology (Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, Vienna)
Experimental Cell Genetics (Department for Medical Genetics, Molec. and Clinical Pharmacol., Innsbruck Medical University)
Analytical Chemistry (Institute of Analytical Chemistry and Radiochemistry, University of Innsbruck)
Adhesion, Mouse Migration, Mouse genetics (Max Planck Institute of Biochemistry, Martinsried)
Cell Biology, Cancer Research (Biocenter, Division of Molecular Pathophysiology, Innsbruck Medical University)
Tumor Immunology and Clinical Oncology (3. Medical Department, LIMCR, University Hospital Salzburg)
Cell Biology, Cancer Research (Biocenter, Division of Medical Biochemistry, Innsbruck Medical University)
Cell Biology (Biocenter, Division of Cell Biology, Innsbruck Medical University)
Molecular Oncology (Biocenter, Division of Molecular Pathophysiology, Innsbruck Medical University)
Leukemia Research, Immunology (3. Medical Department, LIMCR, University Hospital Salzburg)
Cellular Immunology, Tumor Biology, Apoptosis (Biocenter, Division of Developmental Immunology, Innsbruck Medical University)
ASSOCIATED MEMBERS
Gastl Guenther
Schneider Rainer
ASSOCIATED MEMBERS
Tumor Profiling (Division of Haematology and Oncology, Department of Internal Medicine, Innsbruck Medical University)
Biochemistry (Department of Biochemistry, University of Innsbruck)
The major goals of the SFB021 are to understand molecular pathways that link signals leading either to cell death/survival or to cell proliferation/cell
cycle arrest in tumors. The SFB021 also aims to better understand, why the immune system apparently fails to eliminate tumor cells focusing on the
established pathways regulating T cell activation thresholds. In continuation of the work during the first funding period (2003-2007) SFB021 scientists
propose the coordinated use of biochemical and genetic as well as proteomic/transcriptomic approaches to delineate changes in cellular pathways
that occur in several types of tumors, namely epithelial tumors (breast cancer, liver, skin), chronic myeloic leukemia (CML) or tumors of lymphatic
origin (acute lymphatic leukemia (ALL) and multiple myeloma). In addition, for the second funding period (2008-2010) they have now extended their
experimental approaches towards antigen receptor signal processing machinery in T cells during immunesurveillance in tumors, adhesion signaling
in tumor cells, as well as posttranslational modifications of the Cdk inhibitor p27Kip1.
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The Biocenter
www.proteomics.or.at/
Professor Lukas A. Huber is coordinator of the
Austrian Proteomics Platform.
Proteomics is one of the greatest challenges in basic science of our age, where the
human genome has already been sequenced.
Together with Professors Günther Bonn (Innsbruck), Peter Oefner (Regensburg) and
Giulio Superti-Furga (Vienna, Austria), Lukas Huber is organizing the annual
International Symposia of the APP in the charming winter resort Seefeld/Tyrol.
Two members of the Biocenter are also members of the
Austrian RNomics Platform
Andrea Barta, Vienna
Ivo Hofacker, Vienna
Alexander Hüttenhofer, Innsbruck
Javier Martinez, Vienna
Ronald Micura, Innsbruck
Norbert Polacek, Innsbruck
Renee Schroeder, Vienna
and are involved in a concerted research action on the study of noncoding (nc)RNAs in
several organisms. ncRNAs are newly discovered RNA species which exert a profound
regulatory role on gene expression and - in altered state - are thought to be responsible
for various human diseases.
http://www.cemit.at/folgeseite.cfm?id=187
http://www.gen-au.at/projekt.jsp?projektId=60&lang=de
www.gen-au.at
www.cemit.at/
07
The Biocenter
Neopterin Network
Dietmar Fuchs and Ernst Werner of the division of Biological Chemistry are founding
and steering members of the International Neopterin-Network. They organize since
many years the annual Winter Workshop on Clinical, Chemical and Biochemical
Aspects of Pteridines in St. Christoph/Arlberg/Austria.
www.neopterin.net
Apoptosis Research Network
Andreas Villunger of the Biocenter Innsbruck is integrated into a Transeuropean
Network of Apoptosis research laboratories (ApopTrain)
GrowthStop Network
Lukas A. Huber of the Biocenter Innsbruck is coordinator of the EU-FP6 (Framework
Program 6) research project entitled GROWTHSTOP, which started in October 2006.
The topics and goals are: IDENTIFICATION, DEVELOPMENT AND VALIDATION OF
NOVEL THERAPEUTICS TARGETING PROGRAMMED CELL DEATH IN TUMORS.
A total of 12 international partners from different EU countries together with Israel are
participating in this four year project. CEMIT is supporting the project coordinator and
project partners in administrative aspects.
www.cemit.at
08
The Biocenter
Retreat & Fiestas
Retreat in Grafenast/Tyrol 2006
09
The Biocenter
PhD Conference
10
Poster Party at annual meeting
of our PhD students
The Biocenter
Awards
START-Awards *) of the Austrian Science Foundation (FWF) have been given to 3 scientists of The BIOCENTER
Norbert Polacek
Division of Genomics and RNomics
2006 - 2012
Alexandra Lusser
Division of Molecular Biology
2005 - 20011
Andreas Villunger
Division of Developmental Immunology
2003 - 2009
Novartis Award for Medical Science 2007 to Andreas Villunger
Novartis Award for Medical Science 2007 to Norbert Polacek
Wilhelm Auerswald Award 2007 for the best M.D. thesis in Austria to Michael Haffner, laboratory of Wolfgang Doppler
*) The START-Prize represents the award of the FWF that is of highest reputation as well as amount of support (i.e. 1.200.000 Euro) given to the awardee. These
require to be under 35 years of age. The prize is announced every year and has been founded in 1996. Applicants are selected by an international jury of renowned
scientists. Successful applicants are supported for up to 6 years.
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The Biocenter
Publications 2006 - 07
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Brandacher, G.; Margreiter, R.; Fuchs, D.: Implications of IFN-gamma-mediated tryptophan catabolism on solid organ transplantation. CURRENT DRUG METABOLISM. 2007;
8(3); 273-282.
Brandacher, G.; Margreiter, R.; Fuchs, D.: Interferons, immunity and cancer immunoediting leading to impaired immune function in cancer patients. NATURE REVIEWS
IMMUNOLOGY. 2007; 7(1);
Brandacher, G.; Perathoner, A.; Ladurner, R.; Schneeberger, S.; Obrist, P.; Winkler, C.; Werner, ER.; Werner-Felmayer, G.; Weiss, HG.; Gobel, G.; Margreiter, R.;
Konigsrainer, A.; Fuchs, D.; Amberger, A.: Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: Effect on tumor-infiltrating T cells.
CLINICAL CANCER RESEARCH. 2006; 12(4); 1144.
Brandacher, G.; Winkler, C.; Aigner, F.; Schwelberger, H.; Schroecksnadel, K.; Margreiter, R.; Fuchs, D.; Weiss, HG.: Bariatric surgery cannot prevent tryptophan depletion
due to chronic immune activation in morbidly obese patients. OBESITY SURGERY. 2006; 16(5); 541-548.
Brandacher, G.; Winkler, C.; Schroecksnadel, K.; Margreiter, R.; Fuchs, D.: Antitumoral activity of interferon-gamma involved in impaired immune function in cancer patients.
CURRENT DRUG METABOLISM. 2006; 7(6); 599-612.
Bratslavska, O.; Platace, D.; Miklasevics, E.; Fuchs, D.; Martinsons, A.: Influence of neopterin and 7,8-dihydroneopterin on the replication of Coxsackie type B5 and influenza A
viruses. MEDICAL MICROBIOLOGY AND IMMUNOLOGY. 2007; 196(1); 23-29.
Buser, AC.; Gass-Handel, EK.; Wyszomierski, SL.; Doppler, W.; Leonhardt, SA.; Schaack, J.; Rosen, JM.; Watkin, H.; Anderson, SM.; Edwards, DP.: Progesterone receptor
repression of prolactin/signal transducer and activator of transcription 5-mediated transcription of the beta-casein gene in mammary epithelial cells. MOLECULAR
ENDOCRINOLOGY. 2007; 21(1); 106-125.
Causevic, A.; Gentil, MV.; Delaunay, A.; Abu El-Soud, W.; Garcia, Z.; Pannetier, C.; Brignolas, F.; Hagege, D.; Maury, S.: Relationship between DNA methylation and histone
acetylation levels, cell redox and cell differentiation states in sugarbeet lines. PLANTA. 2006; 224(4); 812-827.
Cavarretta, IT.; Neuwirt, H.; Untergasser, G.; Moser, PL.; Zaki, MH.; Steiner, H.; Rumpold, H.; Fuchs, D.; Hobisch, A.; Nemeth, JA.; Culig, Z.: The antiapoptotic effect of IL-6
autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1. ONCOGENE. 2007; 26(20); 2822-2832.
Chan, CP. Y.; Choi, JW. Y.; Cao, KY.; Wang, M.; Gao, Y.; Zhou, DH.; Di, B.; Xu, HF.; Leung, MF.; Bergmann, A.; Lehmann, M.; Nie, YM.; Cautherley, GW. H.; Fuchs, D.;
Renneberg, R.; Zheng, BJ.: Detection of serum neopterin for early assessment of dengue virus infection. JOURNAL OF INFECTION. 2006; 53(3); 152-158.
Chu, I.; Sun, J.; Arnaout, A.; Kahn, H.; Hanna, W.; Narod, S.; Sun, P.; Tan, CK.; Hengst, L.; Slingerland, J.: p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2.
CELL. 2007; 128(2); 281-294.
Concannon, CG.; Koehler, BF.; Reimertz, C.; Murphy, BM.; Bonner, C.; Thurow, N.; Ward, MW.; Villunger, A.; Strasser, A.; Kogel, D.; Prehn, JH. M.: Apoptosis induced by
proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway. ONCOGENE. 2007; 26(12); 1681-1692.
Csordas, A.; Wick, G.; Bernhard, D.: Hydrogen peroxide-mediated necrosis induction in HUVECs is associated with an atypical pattern of caspase-3 cleavage.
EXPERIMENTAL CELL RESEARCH. 2006; 312(10); 1753-1764.
Cuffy, MC.; Silverio, AM.; Qin, LF.; Wang, YN.; Eid, R.; Brandacher, G.; Lakkis, FG.; Fuchs, D.; Pober, JS.; Tellides, G.: Induction of indoleamine 2,3-dioxygenase in vascular
smooth muscle cells by interferon-gamma contributes to medial immunoprivilege. JOURNAL OF IMMUNOLOGY. 2007; 179(8); 5246-5254.
Dieplinger, B.; Schiefermeier, N.; Juchum-Pasquazzo, M.; Gstir, R.; Huber, LA.; Klimaschewski, L.; Vietor, I.: The transcriptional corepressor TPA-inducible sequence 7
regulates adult axon growth through cellular retinoic acid binding protein II expression. EUROPEAN JOURNAL OF NEUROSCIENCE. 2007; 26(12); 33583367.
Easmon, J.; Purstinger, G.; Thies, KS.; Heinisch, G.; Hofmann, J.: Synthesis, structure-activity relationships, and antitumor studies of 2-benzoxazolyl hydrazones derived from
alpha-(N)-acyl heteroaromatics. JOURNAL OF MEDICINAL CHEMISTRY. 2006; 49(21); 6343-6350.
Eden, A.; Price, RW.; Spudich, S.; Fuchs, D.; Hagberg, L.; Gisslen, M.: Immune activation of the central nervous system is still present after > 4 years of effective highly active
antiretroviral therapy. JOURNAL OF INFECTIOUS DISEASES. 2007; 196(12); 1779-1783.
Eisendle, M.; Schrettl, M.; Kragl, C.; Muller, D.; Illmer, P.; Haas, H.: The intracellular siderophore ferricrocin is involved in iron storage, oxidative-stress resistance, germination,
and sexual development in Aspergillus nidulans. EUKARYOTIC CELL. 2006; 5(10); 1596-1603.
Ekoff, M.; Kaufmann, T.; Engstrom, M.; Motoyama, N.; Villunger, A.; Jonsson, JI.; Strasser, A.; Nilsson, G.: The BH3-only protein Puma plays an essential role in cytokine
deprivation-induced apoptosis of mast cells. BLOOD. 2007; 110(9); 3209-3217.
Erlacher, M.; Labi, V.; Manzl, C.; Bock, G.; Tzankov, A.; Hacker, G.; Michalak, E.; Strasser, A.; Villunger, A.: Puma cooperates with Bim, the rate-limiting BH3-only protein in
cell death during lymphocyte development, in apoptosis induction. JOURNAL OF EXPERIMENTAL MEDICINE. 2006; 203(13); 2939-2951.
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Erlacher, MD.; Lang, K.; Wotzel, B.; Rieder, R.; Micura, R.; Polacek, N.: Efficient ribosomal peptidyl transfer critically relies on the presence of the ribose 2 '-OH at A2451 of 23S
rRNA. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. 2006; 128(13); 4453.
Fiegl, H.; Elmasry, K.: Cancer diagnosis, risk assessment and prediction of therapeutic response by means of DNA methylation markers. DISEASE MARKERS. 2007; 23(1-2);
89-96.
Frick, B.; Gruber, B.; Schroecksnadel, K.; Leblhuber, F.; Fuchs, D.: Homocysteine but not neopterin declines in demented patients on B vitamins. JOURNAL OF NEURAL
TRANSMISSION. 2006; 113(11); 1815-1819. 45. Fuchs, D.: Clinical relevance of indoleamine 2,3-dioxygenase. CURRENT DRUG METABOLISM. 2007; 8(3); 195-195.
Furchert, SE.; Lanvers-Kaminsky, C.; Jurgens, H.; Jung, M.; Loidl, A.; Fruhwald, MC.: Inhibitors of histone deacetylases as potential therapeutic tools for high-risk embryonal
tumors of the nervous system of childhood. INTERNATIONAL JOURNAL OF CANCER. 2007; 120(8); 1787-1794.
Geiger, R.; Hammerer-Lercher, A.; Url, C.; Schweigmann, U.; Puschendorf, B.; Sommer, R.; Stein, JI.; Mair, J.: NT-proBNP concentrations indicate cardiac disease in pediatric
patients. INTERNATIONAL JOURNAL OF CARDIOLOGY. 2007; 123(1); 63-65.
Grimmier, M.; Wang, YF.; Mund, T.; Cilensek, Z.; Keidel, EM.; Waddell, MB.; Jakel, H.; Kullmann, M.; Kriwacki, RW.; Hengst, L.: Cdk-inhibitory activity and stability of p27(Kip1) are
directly regulated by oncogenic tyrosine kinases. CELL. 2007; 128(2); 269-280.
Hacker, G.; Bauer, A.; Villunger, A.: Apoptosis in activated T cells - What are the triggers, and what the signal transducers? CELL CYCLE. 2006; 5(21); 2421-2424.
Haffner, MC.; Berlato, C.; Doppler, W.: Exploiting our knowledge of NF-kappa B signaling for the treatment of mammary cancer. JOURNAL OF MAMMARY GLAND BIOLOGY
AND NEOPLASIA. 2006; 11(1); 63-73.
Haffner, MC.; Petridou, B.; Peyrat, JP.; Revillion, F.; Muller-Holzner, E.; Daxenbichler, G.; Marth, C.; Doppler, W.: Favorable prognostic value of SOCS2 and IGF-I in breast cancer.
BMC CANCER. 2007; 7(5);
Hagen, S.; Marx, F.; Ram, AF.; Meyer, V.: The antifungal protein AFP from Aspergillus giganteus inhibits chitin synthesis in sensitive fungi. APPLIED AND ENVIRONMENTAL
MICROBIOLOGY. 2007; 73(7); 2128-2134.
Halfter, H.; Friedrich, M.; Resch, A.; Kullmann, M.; Stogbauer, F.; Ringelstein, EB.; Hengst, L.: Oncostatin M induces growth arrest by inhibition of Skp2, Cks1, and cyclin A
expression and induced p21 expression. CANCER RESEARCH. 2006; 66(13); 6530-6539.
Haller, I.; Hausott, B.; Tomaselli, B.; Keller, C.; Klimaschewski, L.; Gerner, P.; Lirk, P.: Neurotoxicity of lidocaine involves specyic activation of the p38 mitogen-activated protein
kinase, but not extracellular signal-regulated or c-jun N-terminal kinases, and is mediated by arachidonic acid metabolites. ANESTHESIOLOGY. 2006; 105(5);
1024-1033.
Hammerer-Lercher, A.; Fersterer, J.; Holzmann, S.; Bonatti, J.; Ruttmann, E.; Hoefer, D.; Mair, J.; Puschendorf, B.: Direct comparison of relaxation and cGMP production in human
coronary by-pass grafts in response to stimulation with natriuretic peptides and a nitric oxide donor. CLINICAL SCIENCE. 2006; 111(3); 225-231.
Hammerer-Lercher, A.; Geiger, R.; Mair, J.; Url, C.; Tulzer, G.; Lechner, E.; Puschendorf, B.; Sommer, R.: Utility of N-terminal pro-B-type natriuretic peptide to differentiate cardiac
diseases from noncardiac diseases in young pediatric patients. CLINICAL CHEMISTRY. 2006; 52(7); 1415-1419.
Hammerer-Lercher, A.; Haeusler, C.; Prelog, M.; Bonatti, J.; Hoefer, D.; Ruttmann, E.; Laufer, G.; Werner, ER.; Dirnhofer, S.; Puschendorf, B.; Mairu, J.: Thermal preconditioning
protects the human internal mammary artery from hypoxia/re-oxygenation-induced damage. CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND
PHYSIOLOGY. 2006; 33(7); 584-590.
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Schroecksnadel, K.; Fiegl, M.; Prassl, K.; Winkler, C.; Denz, HA.; Fuchs, D.: Diminished quality of life in patients with cancer correlates with tryptophan degradation.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY. 2007; 133(7); 477-485.
Schroecksnadel, K.; Frick, B.; Fiegl, M.; Winkler, C.; Denz, HA.; Fuchs, D.: Hyperhomocysteinaemia and immune activation in patients with cancer. CLINICAL CHEMISTRY
AND LABORATORY MEDICINE. 2007; 45(1); 47-53.
Schroecksnadel, K.; Frick, B.; Winkler, C.; Fuith, LC.; Fuchs, D.: Relationship between homocysteine and neopterin concentrations in patients with gynecological cancer.
CANCER LETTERS. 2006; 240(2); 198-202.
Schroecksnadel, K.; Fuchs, D.: Interferon-gamma for counteracting T-cell activation. TRENDS IN IMMUNOLOGY. 2006; 27(9); 398-398.
Schroecksnadel, K.; Gruber, B.; Frick, B.; Jenny, M.; Ledochowski, M.; Leblhuber, F.; Fuchs, D.: Long-term supplementation with B vitamins does not change plasma
neopterin concentrations in demented patients. PTERIDINES. 2006; 17(4); 135-144.
Schroecksnadel, K.; Weiss, G.; Stanger, O.; Teerlink, T.; Fuchs, D.: Increased asymmetric dimethylarginine concentrations in stimulated peripheral blood mononuclear cells.
SCANDINAVIAN JOURNAL OF IMMUNOLOGY. 2007; 65(6); 525-529.
Schroecksnadel, K.; Winkler, C.; Duftner, C.; Wirleitner, B.; Schirmer, M.; Fuchs, D.: Tryptophan degradation increases with stage in patients with rheumatoid arthritis.
CLINICAL RHEUMATOLOGY. 2006; 25(3); 334.
Schroecksnadel, K.; Winkler, C.; Fuchs, D.: Method for urinary neopterin measurements by HPLC. JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS. 2006;
66(1-3); 99.
Schroecksnadel, K.; Zangerle, R.; Bellmann-Weiler, R.; Garimorth, K.; Weiss, G.; Fuchs, D.: Indoleamine-2,3-dioxygenase and other interferon-gamma-mediated pathways in
patients with human immunodeficiency virus infection. CURRENT DRUG METABOLISM. 2007; 8(3); 225-236.
Schroecksnadel, Katharina; Frick, Barbara; Winkler, Christiana; Fuchs, Dietmar: Crucial role of interferon-gamma and stimulated macrophages in cardiovascular disease.
CURRENT VASCULAR PHARMACOLOGY. 2006; 4(3); 205-213.
Schubert, C.; Noisternig, B.; Fuchs, D.; Konig, P.; Chamson, E.; Mittnik, S.; Schussler, G.; Geser, W.: Multi-faceted effects of positive incidents on stress system functioning
in a patient with systemic lupus erythematosus. STRESS AND HEALTH. 2006; 22(4); 215-227.
Schweigreiter, R.; Bandtlow, CE.: Nogo in the injured spinal cord. JOURNAL OF NEUROTRAUMA. 2006; 23(3-4); 384-396.
Schweigreiter, R.; Roots, BI.; Bandtlow, CE.; Gould, RM.: Understanding myelination through studying its evolution. INTERNATIONAL REVIEW OF NEUROBIOLOGY. 2006;
73(3-4); 219-+.
Schweigreiter, R.; Stasyk, T.; Contarini, I.; Frauscher, S.; Oertle, T.; Klimaschewski, L.; Huber, LA.; Bandtlow, CE.: Phosphorylation-regulated cleavage of the reticulon
protein Nogo-B by caspase-7 at a noncanonical recognition site. PROTEOMICS. 2007; 7(24); 4457-4467.
Schweigreiter, R.: The dual nature of neurotrophins. BIOESSAYS. 2006; 28(6); 583-594.
Shcherbakov, D.; Dontsova, M.; Tribus, M.; Garber, M.; Piendl, W.: Stability of the 'L12 stalk' in ribosomes from mesophilic and (hyper)thermophilic Archaea and Bacteria.
NUCLEIC ACIDS RESEARCH. 2006; 34(20); 5800-5814.
Shcherbakov, D.; Piendl, W.: A novel view of gel-shifts: Analysis of RNA-protein complexes using a two-color fluorescence dye procedure. ELECTROPHORESIS. 2007;
28(5); 749-755.
Shwab, EK.; Bok, JW.; Tribus, M.; Galehr, J.; Graessle, S.; Keller, NP.: Histone deacetylase activity regulates chemical diversity in Aspergillus. EUKARYOTIC CELL. 2007;
6(9); 1656-1664.
Skvortsov, S.; Skvortsova, I.; Stasyk, T.; Schiefermeier, N.; Neher, A.; Gunkel, AR.; Bonn, GK.; Huber, LA.; Lukas, P.; Pleiman, CM.; Zwierzina, H.: Antitumor activity of
CTFB, a novel anticancer agent, is associated with the down-regulation of nuclear factor-kappa B expression and proteasome activation in head and neck squamous
carcinoma cell lines. MOLECULAR CANCER THERAPEUTICS. 2007; 6(6); 1898-1908.
Sobieszek, A.; Matusovsky, OS.; Permyakova, TV.; Sarg, B.; Lindner, H.; Shelud'ko, NS.: Phosphorylation of myorod (catchin) by kinases tightly associated to molluscan and
vertebrate smooth muscle myosins. ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS. 2006; 454(2); 197-205.
Spannhoff, A.; Heinke, R.; Bauer, I.; Trojer, P.; Metzger, E.; Gust, R.; Schule, R.; Brosch, G.; Sippl, W.; Jung, M.: Target-based approach to inhibitors of histone arginine
methyltransferases. JOURNAL OF MEDICINAL CHEMISTRY. 2007; 50(10); 2319-2325.
Spannhoff, A.; Machmur, R.; Heinke, R.; Trojer, P.; Bauer, I.; Brosch, G.; Schule, R.; Hanefeld, W.; Sippl, W.; Jung, M.: A novel arginine methyltransferase inhibitor with
cellular activity. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. 2007; 17(15); 4150-4153.
Sperner-Unterweger, B.; Winkler, C.; Fuchs, D.: Immune activation in autism. PEDIATRIC NEUROLOGY. 2006; 34(4); 333-333.
Speth, C.; Rambach, G.; Hagleitner, M.; Konstanzer, K.; Hollmuller, I.; Dierich, MP.; Mohsenipour, I.; Maier, H.: Immune response to retroviral infections of the brain.
FRONTIERS IN BIOSCIENCE. 2007; 12(12); 1508-1519.
Stadlmann, S.; Pollheimer, J.; Renner, K.; Zeimet, AG.; Offner, FA.; Amberger, A.: Response of human peritoneal mesothelial cells to inflammatory injury is regulated by
interleukin-1 beta and tumor necrosis factor-alpha. WOUND REPAIR AND REGENERATION. 2006; 14(2); 187-194.
19
20
Stadlmann, S.; Renner, K.; Pollheimer, J.; Moser, PL.; Zeimet, AG.; Offner, EA.; Gnaiger, E.: Preserved coupling of oxidative phosphorylation but decreased mitochondrial
respiratory capacity in IL-1 beta-treated human peritoneal mesothelial cells. CELL BIOCHEMISTRY AND BIOPHYSICS. 2006; 44(2); 179-186.
Stasyk, T.; Schiefermeier, N.; Skvortsov, S.; Zwierzina, H.; Peranen, J.; Bonn, GK.; Huber, LA.: Identification of endosomal epidermal growth factor receptor signaling targets
by functional organelle proteomics. MOLECULAR & CELLULAR PROTEOMICS. 2007; 6(5); 908-922.
Taub, N.; Teis, D.; Ebner, HL.; Hess, MW.; Huber, LA.: Late endosomal traffic of the epidermal growth factor receptor ensures spatial and temporal fidelity of mitogenactivated protein kinase signalling. MOLECULAR BIOLOGY OF THE CELL. 2007; 18(12); 4698-4710.
Teis, D.; Taub, N.; Kurzbauer, R.; Hilber, D.; de Araujo, ME.; Erlacher, M.; Offterdinger, M.; Villunger, A.; Geley, S.; Bohn, G.; Klein, C.; Hess, MW.; Huber, LA.: p14-MP1MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis. JOURNAL OF CELL BIOLOGY. 2006; 175(6); 861-868.
Tishchenko, S.; Nikonova, E.; Kljashtorny, V.; Kostareva, O.; Nevskaya, N.; Piendl, W.; Davydova, N.; Streltsov, V.; Garber, M.; Nikonov, S.: Domain I of ribosomal protein L1
is sufficient for specific RNA binding. NUCLEIC ACIDS RESEARCH. 2007; 35(21); 7389-7395.
Tishchenko, S.; Nikonova, E.; Nikulin, A.; Nevskaya, N.; Volchkov, S.; Piendl, W.; Garber, M.; Nikonov, S.: Structure of the ribosomal protein L1-mRNA complex at 2.1
angstrom resolution: common features of crystal packing of L1-RNA complexes. ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL
CRYSTALLOGRAPHY. 2006; 62(9); 1545-1554.
Ueberall, Florian; Fuchs, Dietmar; Vennos, Cécile: [Anti-inflammatory potential of Padma 28--review of experimental data on the antiatherogenic activity and discussion of the
multi-component principle]. FORSCHENDE KOMPLEMENTARMEDIZIN. 2006; 13 Suppl 1; 7-12.
Van Eden, W.; Wick, G.; Albani, S.; Cohen, I.: Stress, heat shock proteins, and autoimmunity: How immune responses to heat shock proteins are to be used for the control of
chronic inflammatory diseases. ANNALS OF THE NEW YORK ACADEMY OF SCIENCES. 2007; 1113(1); 217-237.
Van Eyk, JE.; Huber, LA.; Cowsert, LM.; McLeod, HL.: Genomics, proteomics and pharmacogenetics - experimental approaches. CURRENT OPINION IN MOLECULAR
THERAPEUTICS. 2006; 8(3); 183-184.
Vietor, I.; Huber, LA.: Role of TIS7 family of transcriptional regulators in differentiation and regeneration. DIFFERENTIATION. 2007; 75(9); 891-897.
Walder, G.; Dietmar, F.; Sarcletti, M.; Berek, K.; Falkensammer, B.; Huber, K.; Petrovec, M.; Dierich, MP.; Wurzner, R.: Human granulocytic anaplasmosis in Austria:
Epidemiological, clinical, and laboratory findings in five consecutive patients from Tyrol, Austria. INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY. 2006; 296(1);
297-301.
Wandke, C.; Geley, S.: Generation and characterization of an hKid-specific monoclonal antibody. HYBRIDOMA. 2006; 25(1); 41.
Weinlich, G.; Murr, C.; Richardsen, L.; Winkler, C.; Fuchs, D.: Decreased serum tryptophan concentration predicts poor prognosis in malignant melanoma patients.
DERMATOLOGY. 2007; 214(1); 8-14.
Werle, M.; Schmitz, T.; Huang, HL.; Wentzel, A.; Kolmar, H.; Bernkop-Schnurch, A.: The potential of cystine-knot microproteins as novel pharmacophoric scaffolds in oral
peptide drug delivery. JOURNAL OF DRUG TARGETING. 2006; 14(3); 137-146.
Werner, ER.; Hermetter, A.; Prast, H.; Golderer, G.; Werner-Felmayer, G.: Widespread occurrence of glyceryl ether monooxygenase activity in rat tissues detected by a novel
assay. JOURNAL OF LIPID RESEARCH. 2007; 48(6); 1422-1427.
Werner, ER.; Werner-Felmayer, G.: Substrate and cofactor requirements of indoleamine 2,3-dioxygenase in interferon-gamma-treated cells: Utilization of oxygen rather than
superoxide. CURRENT DRUG METABOLISM. 2007; 8(3); 201-203.
Wesierska-Gadek, J.; Gueorguieva, M.; Kramer, MP.; Ranftler, C.; Sarg, B.; Lindner, H.: A new, unexpected action of olomoucine, a CDK inhibitor, on normal human cells:
Up-regulation of CLIMP-63, a cytoskeleton-linking membrane protein. JOURNAL OF CELLULAR BIOCHEMISTRY. 2007; 102(6); 1405-1419.
Wick, G.; Andersson, L.; Hala, K.; Gershwin, ME.; Selmi, C.; Erf, GF.; Lamont, SJ.; Sgonc, R.: Avian models with spontaneous autoimmune diseases. ADVANCES IN
IMMUNOLOGY. 2006; 92(9); 71-117.
Wick, G.; Raine, CS.: Konrad Schauenstein (1944-2007) - Obituary. JOURNAL OF NEUROIMMUNOLOGY. 2007; 190(1-2); 1-2.
Wick, G.: The heat is on - Heat-shock proteins and atherosclerosis. CIRCULATION. 2006; 114(9); 870-872.
Wilkins, MR.; Appel, RD.; Van Eyk, JE.; Chung, MC. M.; Gorg, A.; Hecker, M.; Huber, LA.; Langen, H.; Link, AJ.; Paik, YK.; Patterson, SD.; Pennington, SR.; Rabilloud, T.;
Simpson, RJ.; Weiss, W.; Dunn, MJ.: Guidelines for the next 10 years of proteomics. PROTEOMICS. 2006; 6(1); 4-8.
Winkler, C.; Frick, B.; Schroecksnadel, K.; Schennach, H.; Fuchs, D.: Food preservatives sodium sulfite and sorbic acid suppress mitogen-stimulated peripheral blood
mononuclear cells. FOOD AND CHEMICAL TOXICOLOGY. 2006; 44(12); 2003-2007.
Winkler, C.; Schroecksnadel, K.; Moheno, P.; Meerbergen, E.; Schennach, H.; Fuchs, D.: Calcium-pterin suppresses mitogen-induced tryptophan degradation and neopterin
production in peripheral blood mononuclear cells. IMMUNOBIOLOGY. 2006; 211(10); 779-784.
Winkler, C.; Schroecksnadel, K.; Schennach, H.; Fuchs, D.: Vitamin C and E suppress mitogen-stimulated peripheral blood mononuclear cells in vitro. INTERNATIONAL
ARCHIVES OF ALLERGY AND IMMUNOLOGY. 2007; 142(2); 127-132.
Winkler, C.; Ueberall, F.; Fuchs, D.: In vitro testing for anti inflammatory properties of compounds. CLINICAL CHEMISTRY. 2006; 52(6); 1201-1202.
Winkler, C.; Wirleitner, B.; Schroecksnadel, K.; Schennach, H.; Fuchs, D.: Beer down-regulates activated peripheral blood mononuclear cells in vitro. INTERNATIONAL
IMMUNOPHARMACOLOGY. 2006; 6(3); 390-395.
Winter, F.; Edaye, S.; Huttenhofer, A.; Brunel, C.: Anopheles gambiae miRNAs as actors of defence reaction against Plasmodium invasion. NUCLEIC ACIDS RESEARCH.
2007; 35(20); 6953-6962.
Wolf, F.; Geley, S.: A simple and stable autofocusing protocol for long multidimensional live cell microscopy. JOURNAL OF MICROSCOPY-OXFORD. 2006; 221(3); 72-77.
Wolf, F.; Sigl, R.; Geley, S.: '... The end of the beginning': Cdk1 thresholds and exit from mitosis. CELL CYCLE. 2007; 6(12); 1408-1411.
Wolf, F.; Wandke, C.; Isenberg, N.; Geley, S.: Dose-dependent effects of stable cyclin B1 on progression through mitosis in human cells. EMBO JOURNAL. 2006; 25(12);
2802-2813.
Yegnasubramanian, S.; Lin, XH.; Haffner, MC.; DeMarzo, AM.; Nelson, WG.: Combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes
(COMPARE-MS) for the rapid, sensitive and quantitative detection of DNA methylation. NUCLEIC ACIDS RESEARCH. 2006; 34(3); e19.
Yilmaz, A.; Fuchs, D.; Hagberg, L.; Nillroth, U.; Stahle, L.; Svensson, JO.; Gisslen, M.: Cerebrospinal fluid HIV-1 RNA, intrathecal immunoactivation, and drug concentrations
after treatment with a combination of saquinavir, nelfinavir, and two nucleoside analogues: the M61022 study. BMC INFECTIOUS DISEASES. 2006; 6(1);
You, H.; Pellegrini, M.; Tsuchihara, K.; Yamamoto, K.; Hacker, G.; Erlacher, M.; Villunger, A.; Mak, TW.: FOXO3a-dependent regulation of Puma in response to
cytokine/growth
factor withdrawal. JOURNAL OF EXPERIMENTAL MEDICINE. 2006; 203(7); 1657-1663.
Zeold, A.; Doleschall, M.; Haffner, MC.; Capelo, LP.; Menyhert, J.; Liposits, Z.; da Silva, WS.; Bianco, AC.; Kacskovics, I.; Fekete, C.; Gereben, B.: Characterization of the
nuclear factor-kappa B responsiveness of the human dio2 gene. ENDOCRINOLOGY. 2006; 147(9); 4419-4429.
Zurn, AD.; Bandtlow, CE.: Regeneration failure in the CNS: Cellular and molecular mechanisms. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY. 2006; 557; 5476.
Zvetkova, E.; Gluhcheva, Y.; Fuchs, D.: Use of neopterin as a bone marrow hematopoietic and stromal cell growth factor in tissue-engineered devices. ADVANCES IN
EXPERIMENTAL MEDICINE AND BIOLOGY. 2006; 585(3); 115-121.
21
204 Publications listed in PubMed
The Biocenter
Grants
22
Project owner
Division
Titel
Hüttenhofer, Alexander
Überall, Florian
Genomics and RNomics
Medical Biochemistry
PWS: Prader-Willi Syndrome: a model linking gene expression, obesity, and mental health
PKC isoforms and their relevance in human cancer response to radiotherapy
Investigations into new inhibitors of signal transduction, new antitumor drugs and their
mechanism of action
TOLERAGE (coordinator) (Tolerance in Aging)
TOLERAGE (portion of Innsbruck Medical University) (Tolerance in Aging)
Cell death: from basic principles to therapeutic application
Biognosis
Growthstop (identification, development and validation of novel therapeutics targeting
Growthstop - subproject of Lukas A. Huber
Prokinase research
EVGN (European Vascular Genomics Network)
MOLSTROKE: Molecular basis of vascular events leading to thrombotic stroke
TRANSFOG (Translational and Functional Oncogenomics)
MAPK Signaling
Cell proliferation and cell death in tumors (SFB 021-01)
Spatio-temporal regulation of MAP kinase signals (SFB F21-02)
Regulation of mitosis exit by protein modification (SFB F21-08)
Role of the BCL2 rheostat in glucocorticoid-induced apoptosis of leukaemic cells (SFB F21-09)
Apoptosis signals regulated by the BCL2 rheostat (SFB F21-10)
Modification of p27 kip1 (SFB F21-15)
EuroDYNA (Dynamic Nuclear Architecture and Chromatin Function): The role of linker histone
variants and their phosphorylation in chromatin structure and function
Identification of snmRNAs in Aspergillus fumigatus
Structure and function of ribosomal protein-FNA complexes
Histone deacetylase-HDA1 complexes in maize
LIMR, a novel type of endocytosis receptors
Transport pathways of nuclear receptor tyrosine kinases
Role of the TIS/SKMc15 gene in tissue regeneration
Glucocorticoid-induced apoptosis in lymphatic leukaemia of children
Siderophores and virulence of Aspergillus fumigatus
Nucleotid analogue interference in the ribosome
Endothelial cell autoantigens in systemic sclerosis
Bam - a novel glucocorticoid-regulated BH3 transcript
Epigenetic regulation in the immune system
Regulation of p27Kip1 by tyrosine phosphorylation
Molecular mechanisms of purine-mediated neuroprotection
Transcription regulation in Aspergillus: general and fungal-specific roles of histone deacetylases
Glyceryl ether monooxygenase
The role of PKCepsilon-modulated genes
Immunity against HSP60 in beginning atherosclerosis
The two sides of the neuronal growth factor Nogo-A
Characterization of the toxicity of the antifungal protein PAF
Molecular and functional analysis of Pctk1
MCBO - Sub06: Mitotic kinase targets: control of cell division and survival
MCBO - Sub07: Transcriptome analysis of p14/MP1/MAP kinase scaffold knockoout mice
MCBO - Sub09: Search for novel cell death regulators
MCBO - Sub11: STAT1 target genes in tumor cells and primary carcinomas
MCBO - Sub13: Functional cloning of gene networks responsible for glucocorticoid-induced
SPIN-Sub01: Reticulon proteins regulate neuronal morphology
SPIN-Sub03: Function of non-coding RNAs in brain
Functional relevance of CHD1, a chromatin packaging factor
Nucleotid-analogue interferences in ribosomes
Functional roles of distinct histone deacetylases in filam entous fungus Aspergillus nidulans
Iron assimilation and pathogenicity of Aspergillus
Hofmann, Johann
Wick, Georg
Wick, Georg
Villunger, Andreas
Huber, Lukas
Huber, Lukas
Huber, Lukas
Hofmann, Johann
Wick, Georg
Wick, Georg
Geley, Stephan
Huber, Lukas
Huber, Lukas
Huber, Lukas
Geley, Stephan
Kofler, Reinhard
Villunger, Andreas
Hengst, Ludger
Exper. Pathophysiol. and Imm.
Developmental Immunology
Cell Biology
Cell Biology
Cell Biology
Molecular Pathophysiology
Cell Biology
Cell Biology
Cell Biology
Lindner, Herbert
Clinical Biochemistry
Piendl, Wolfgang
Loidl, Peter
Redl, Bernhard
Offterdinger, Martin
Vietor, Ilja
Kofler, Reinhard
Haas, Hubertus
Polacek, Norbert
Gruber-Sgonc, Roswitha
Kofler, Reinhard
Yannoutsos, Nikolaos
Hengst, Ludger
Baier, Gabriele
Grässle, Stefan
Werner, Ernst
Hofmann, Johann
Wick, Georg
Schweigreiter, Rüdiger
Marx-Ladurner, Florentine
Geley, Stephan
Geley, Stephan
Huber, Lukas
Villunger, Andreas
Doppler, Wolfgang
Kofler, Reinhard
Bandtlow, Christine
Lusser, Alexandra
Polacek, Norbert
Graessle, Stefan
Hubertus Haas
Molecular Biology
Molecular Biology
Cell Biology
Cell Biology
Molecular Biology
Cell Biology
Neurobiochemistry
Molecular Biology
Biological Chemistry
Neurobiochemistry
Molecular Biology
Cell Biology
Neurobiochemistry
Molecular Biology
Molecular Biology
Molecular Biology
Agency
EU
EU
EU
EU
EU
EU
EU
EU
EU
EU
EU
EU
EU
EU
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
FWF
Emeriti Professors
Tel.: 0043 (512) 9003.70328
email: [email protected]
Wilhelm Sachsenmaier
Professor Sachsenmaier became in 1970 Full Professor of „Biochemistry“ and Chairman
of the newly founded “Institute of Biochemistry and Experimental Cancer Research” at
the Medical Faculty of the Leopold-Franzens-University of Innsbruck. Unlike Vienna and
Graz, Innsbruck university lacked then a modern biochemically oriented chair and
institute. The initiative of the Medical Faculty was advanced in order to implement the
obligatory curriculum of “Biochemistry” for medical students at Innsbruck and to comply
with international standards of high-level bioresearch. In 1974, he became Honorary
Professor of Biochemistry at the Natural Sciences Faculty of the Leopold-FranzensUniversity of Innsbruck. Between 1977-79, he was President of the Austrian Biochemical
Society. In 1995, he retired as Professor emeritus for Biochemistry.
In his active time, Professor Sachsenmaier conducted research on
-Molecular aspects of cell proliferation and used hereto a model system, i.e. the
multinuclear plasmodia of Physarum polycephalum, which he introduced from his former
affiliations with the McArdle Institute of Cancer Research, Madison/Wisconsin and the
German Cancer Research Center, Heidelberg. In particular, he studied
•the role of nucleotide salvage pathway enzymes as biochemical mitotic markers,
•the antimitotic effects of ionizing radiation and UV-light and
•the possible advantage of the combined action of radiation and chemotherapy for cancer
treatment. Based on the results of these studies (in collaboration with P. Loidl and J.
Tyson), the “titration model” of cell cycle regulation was proposed which gained
international attention.
In addition, several international congresses and symposia were organized by the
institute in Innsbruck, such as the joint Meetings of the Biochemical Societies of
Germany, Switzerland and Austria, the biannual Meeting of the German Natural Scientists
and Physicians as well as various symposia and wWorkshops on cell cycle research.
Current activities
Teaching: Seminar “Special problems of
Biochemistry”, “Onkology-Seminar” (coordination
of guest lecture programs; recent top speaker:
Nobel Laureate Sir Tim Hunt/UK “Getting in and out
of Mitosis” 04.02.2008).
Organization of international meetings: Cooperation
with local colleagues (L. Hengst, L. A. Huber, S.
Geley, P. Loidl, J. Troppmair) in organizing international Workshops on “Cell Cycle Control”.
Recent and future events: Mayrhofen/AUT (2001)
together with K. Nasmyth/Vienna. Spetses/GR,
(2007) toge-ther with C. Sekeris/ Athens.
Montpellier/F (2010) together with E. Schwob,
Montpellier.
Austrian Cancer Society – Tyrol: Reactivation of the
Society as President in 1970 and permanent
member of its research advisory board thereafter.
Present number of active members: ~400. In 2008
financial support from fund-raising money (300.000
EUR) is granted by the society for 53 selected
research projects of predominantly young scientists
(< 35 y) including 30.000 EUR for the recipient of a
“Molecular Cell Biology-Oncology Award Fellowship” (Dipl.-Ing. Marin Barisic, MCBO-graduate student programme).
23
Emeriti Professors
Autoimmunity Lab
www2.i-med.ac.at/expatho/wick.html
Tel.: 0043 (512) 9003.70960
Georg Wick
This group works on two major research projects, i.e. the immunology of
atherosclerosis and the immunology of fibrosis. Both areas of research are
supported by competitive grants, notably from the Austrian Science Fund (FWF)
and the Framework 7 (FR7) Program of the European Union. Additional Support
is obtained from private foundations.
The Immunology of Atherosclerosis
This project has been in the center of Georg Wick’s group for the last two decades and
resulted in the formulation of a new “autoimmune” hypothesis for the development of
Atherosclerosis supported by solid data from in vitro and animal experiments as well as
from cross-sectional and prospective longitudinal studies in human cohorts. In essence,
this hypothesis states that classical atherosclerosis risk factors, the well proven
atherogenic role of which is not disputed, first act as endothelial stressors inducing the
expression of a stress protein (heat shock protein 60 – Hsp60) that then acts as a “danger
signal” and thus serves as a target for preexisting innate and adaptive anti Hsp60
immunity. The present research of the group is on one hand focussed on the elucidation
of the HSP60-inducing role of classical atherosclerosis risk factors in endothelial cells and
on the other hand on the identification of the earliest immunologic effector mechanisms
leading to the first inflammatory stage of atherosclerosis.
The Immunology of Fibrosis
24
Fibrosis is an important consequence of various pathological conditions
ranging from tissue damage, over inflammation, reactions against foreign
body implants to “spontaneous” fibrotic diseases. In spite of these
heterogenic causes, the final stage of fibrogenesis is very stereotypic and
always associated with inflammatory immunologic processes. The focus of
research of the group in this area is put on the clarification of the imbalance
of pro- and antifibrotic cytokines produced by the mononuclear inflammatory
cells in tissues with incipient fibrotic changes.
Group members
Giovanni Almanzar-Reina, Alexandar Backovic, Adam Csordas, Cecilia
Grundtmann, Julianna Leuenberger, Christina Mayerl, Nadine Plank,
Evelyn Rabensteiner
International collaborators
Immunology of atherosclerosis
Ruurd Van der Zee, Institute of Infectious Diseases and Immunology,
Faculty of Veterinary Medicine, University of Utrecht; Ban Hock Toh,
Monash Institute of Medical Research, Melbourne, Australia; Rudi Tanzi,
Department of Neurology, Massachusetts General Hospital, Harvard
Medical School, Boston, USA); ECIBUG (9 partners – Austria, Finland,
France, Germany); TOLERAGE (10 partners – Austria, Switzerland,
Sweden, Germany, France, Italy, Netherlands)
Immunology of Fibrosis
Olov Ekwall and Palle Kämpe, Department of Medical Sciences,
University Hospital, Uppsala; Russell Wilson, Autoimmune Technologies,
LLC, New Orleans, Louisiana, USA); Yehuda Shoenfeld, tgel Hashomer,
Israel
Awards
Georg Wick: “Vienna Award for Humanistic Aging Research 2006” of the
Austrian Soc. f. Geriatry & Gerontology; Dolores Wolfram-Raunicher:
„Lecture Award 2007“ of the Austrian Soc. f. Plastic, Reconstructive &
Aesthetic Surgery“
Future goals
Immunology of Atherosclerosis
1. Elucidation of the role of Chlamydiae as potent inducers of HSP60
expression by infected endothelial cells. 2. Microarray analysis of altered
gene expression by endothelial cells after treatment with cigarette smoke
extract. 3. Phenotypic and functional characterization of T-cells obtained
from early, clinically inapparent atherosclerotic lesions.
Immunology of fibrosis
-Functional analysis of proteins and cells adhering to silicone surfaces
Obituary
Bernd Puschendorf †
Former Director of the Division of Clinical Biochemistry
deceased in 2008
For 32 years he headed the Department (now called Division) of Clinical Biochemistry and
also took several terms as head of the Department of Medical Biochemistry at the
University of Innsbruck. At the end of September 2007, Prof. Bernd Puschendorf retired
and a farewell symposium on cardiac markers, one of his major research areas, was held
in the auditorium maximum of the Innsbruck Medical University (IMU).
On behalf of the rector’s office, Vicerector Manfred Dierich thanked Professor
Puschendorf for his great commitment. He praised Puschendorf’s selfless work for IMU
self-management and his constructive and pertinent contributions to numerous internal
commissions. The vicerector also singled out Puschendorf’s enthusiastic work on the
reform of the medical curriculum and emphasized his strong sense of the common good.
Prof. Hans Grunicke, founding rector of the IMU and for many years head of the
Department of Medical Biochemistry, recalled a largely joint academic career with
Puschendorf in Freiburg as well as in Innsbruck. Grunicke pointed out the exceptional
organizational talent of his colleague and his essential contribution to the team spirit at
the institute, which at one time consisted of nearly a hundred people. He thanked
Puschendorf for many years of selfless work. “Nobody owes him more than I do. My life
in Innsbruck would have been a lot more difficult without him”, admitted Hans Grunicke.
Andrea Griesmacher of the Austrian Society of Laboratory Medicine and Clinical
Chemistry spoke of the important role Puschendorf played in implementing new research
findings within routine laboratory medicine and emphasized his commitment to various
academic societies.
Substantial scientific oeuvre
In his laudatio Professor Hermann Wisser from Stuttgart paid tribute to the scientific
work of Bernd Puschendorf. His key research had ranged from the fields of clinical
chemistry and pathobiochemistry of the cardiovascular system to muscular structural
proteins to analyzing the role and function of histones. For a long time, the search for
new biochemical markers in cardiology dominated his work. As early as 1983, he first
published on a particular cardiac marker which, from 1986 onwards, became the research
focus of the entire department. This research was carried out in close cooperation with
the university clinics in Innsbruck as well as with researchers in Freiburg, Vienna, Berlin
and Montpellier. At the same time, Puschendorf maintained collaborations with the
departments for Trauma Surgery & Sports Medicine and Neurology in Innsbruck and with
Slovak researchers for studying sceletal muscle proteins.
These research efforts yielded new insights on excentric and concentric
loads in training and in zero gravity. Puschendorf’s scientific oeuvre
comprises some 150 pieces of original work, 15 reviews and 27 articles.
He received a string of awards for his work, including the Byk Gulden
research award, the Leonor Michaelis medal and several times the
Hoechst award. Puschendorf was very active in devolved university selfmanagement and for more than thirty years acted as examiner for
chemistry and biochemistry.
From Berlin and Freiburg to Tyrol
Bernd Puschendorf was born in Berlin in 1942 and studied medicine at the
University of Freiburg from 1961 to 1966, where he worked as a medical
assistant from 1967 to 1968. From September 1968, he became research
assistant in the team of Hans Grunicke at the Institute of Biochemistry at
the Medical Faculty of the University of Freiburg. In 1969, he became a
lecturer and started work on the impact of pharmaceuticals on the
structure and function of nucleic acids and chromatin. In 1973,
Puschendorf applied to qualify as a professor by receiving the “venia
docendi” and submitted his work on the function and effect of distamycin
A. At the beginning of 1975, he moved to the Medical Faculty of the
University of Innsbruck and became head of the Department of Clinical
Biochemistry at the Institute of Medical Biochemistry which, at that time,
was led by Hans Grunicke. Here, Bernd Puschendorf concentrated on
building up his department and on reforming the curriculum in chemistry
and biochemistry as well as establishing the new optional subject of
Clinical Chemistry and Laboratory Diagnostics. In 1979, Puschendorf
became professor of Medical Chemistry and served several terms
(1982-1984, 1994-1996, 1999-2003) as head of the institute. After the
creation of Innsbruck Medical University and the establishment of the
Innsbruck Biocenter, Bernd Puschendorf headed the Division of Clinical
Biochemistry until his retirement.
25
The Biocenter
Our good staff
26
Administration
(1st row)
Irina Berger
Petra Daum
Gernot Grissenauer
Gertrude Huber
Ilona Lengenfelder
Rosanna Nagele
Claudia Ram
Manuela VillungerGfreiner
Angelika Walter
Glassware cleaning
(2nd row)
Brigitte Andrä
Cicek Aydemir
Renate Gamper
Monika Hertscher
Karoline Hörtnagel
Vinca Ljesic
Bettina Unterberger
Ayten Yigit
Laboratory assistances
(3rd row )
Christian Eller
Maria Gleinser
Karin Lentsch
Lukas Sattler
Stefan Steixner
Animal house
technicians
(4th row)
Nadja Haas
Melanie Heymann
Bernhard Rieder
www.i-med.ac.at/ imcbc/medclinchemfolder/medclinchem.html
Ludger Hengst
Tel.: 0043 (512) 9003.70131
Director
Groups within the Division of Medical Biochemistry
Cell Cycle & Proliferation
Signal Transduction & Proliferation
Ribosomal Proteins
Bioinformatics
Cell Cycle and Proliferation
Ludger Hengst
Karl Maly
Wolfgang Doppler
Johann Hofmann
Wolfgang Piendl
Florian Überall
Ludger Hengst
Our group investigates molecular mechanisms that permit or restrict cell proliferation in
mammalian cells. Deregulation of cell proliferation can lead to various human diseases
including cancer. We therefore also study how these mechanisms are deregulated during
oncogenesis.
Group members
Andrea Casari, Christoph Dohmesen, Karin Ecker,
Daniela Höller, Heidelinde Jäkel, Michael Keith Kullmann, Lisa Kindler-Maly, Karl Maly, Georg Nikolaidis,
Silvio Podmirseg, Jonathan Vosper, Christina Weinl
The eukaryotic cell division cycle is divided into four phases. DNA
replication during S-phase is separated by so-called gap phases, G1 and
G2, from the segregation of the duplicated DNA and other cellular
components in mitosis. At the end of M phase, two daugher cells are
generated by cytokinesis.
Cells decide and commit to divide during a specific window in the mammalian cell cycle or
during quiescence. At this time, they are especially responsive to various mitogenic and
antimitogenic signals. We study how these diverse signals are integrated and how they
impinge on the cell cycle control machinery. At the core of this machinery is a conserved
family of protein kinases called cyclin-dependent kinases (Cdks). Cdk inhibitor proteins
bind to these kinases and regulate their catalytic activity.
Current research projects in the lab focus on two main areas: 1. Function and regulation
of Cdk-inhibitory proteins. 2. Role of translational control for the decision between cell
proliferation and withdrawal from the cell cycle.
Ongoing research
Regulation of cell cycle progression through G1 phase by tyrosine kinases, translational control in
and of the cell cycle; temporal and spatial regulation of Cdk-inhibitory proteins during cell cycle
progression.
International collaborators, institutions
Joyce M Slingerland, University of Miami, U.S.A.; Richard W. Kriwacki, St. Jude Hospital of Sick Childreen, Memphis, U.S.A.; Markus Gerhard, Klinikum Rechts der
Isar, München, Germany; Hartmut Halfter, Universität Münster, Germany
Until they progress over the
restriction point in
G1 phase, cells
frequently respond
to growth or differentiation signals
that can lead to
proliferation
or
growth arrest.
27
www.i-med.ac.at/imcbc/staff_doc/doppler_wolfgang.html
Ludger Hengst
Tel.: 0043 (512) 9003.70135
Director
Signal Transduction
Group members
Nirmala Parajuli, Michael C.Haffner, Benedikt Koller,
Lára Hannesdottir, Anto Nogalo, Sonja Philipp
Wolfgang Doppler
Signal transduction in mammary gland development and cancer
Our group is investigating the intracellular signaling pathways induced by the action of
hormones (steroid hormones, prolactin, insulin like growth factors) and how they influence
proliferation, differentiation and survival of mammary epithelial cells. We compare the
operation of these pathways during normal mammary gland development with the
signaling in mammary carcinoma.
Special emphasis is put on members of the family of signal transducers and activators of
transcription (STAT factors). Our aim is to understand the role of STAT factors on the
balance between cell proliferation and cell death in the normal mammary gland as well as
in mammary carcinomas.
Current research is focusing on the role of STAT1 in tumor biology and in the response to
chemotherapeutics by using STAT1 proficient or deficient MMTV-neu tumor mice.
New insights into the role of STAT factors in cancer: The STAT5 target genes SOCS2 and IGF-I
were found to be favorable prognostic markers in breast cancer.
STAT1 activation was shown to serve as a potential predictive marker of response to adjuvant
chemotherapy in squamous cell cancer of the oral cavity.
Evaluation of the significance of nuclear IGF binding protein IGFBP5: In contrast to previous
reports in the literature, nuclear uptake of IGFBP-5 was demonstrated to be restricted to artificial
conditions such as expression of non-secreted forms of IGFBP-5 or selective permeablization of the
plasma membrane by digitonin.
Definition of a novel molecular mechanism by which the progesterone receptor represses the
expression of milk protein genes.
28
Akihiko Yoshimura, Kyushu University, JAPAN; Jean Phillipe Peyrat, Centre Oscar
Lambret, Lille, FRANCE; Dean P. Edwards, Baylor College of Medicine, Houston,
Texas
Pregnancy
Lactation
Involution
STAT proteins are activated during mammary gland development
and in a variety of tumors. Whereas STAT5 and STAT3 have been
implicated in tumor formation and progression, STAT1 activation is
mainly considered as an antioncogene and linked to cell cycle arrest
and apoptosis. In accordance with this function, we have observed a
link between STAT1 activation and good prognosis in primary human
breast cancer.
STAT1 DNA binding & Tyr Phosphorylation
100
Relapse-free survival (%)
Major achievements in 2007
80
60
40
20
0
0 1 2 3
4
5 6 7 8 9 10 11 12
Time (years)
www.i-med.ac.at/imcbc/staff_doc/hoffman_johann.html
Ludger Hengst
Tel.: 0043 (512) 9003.70130
Director
Group members
Peter Gruber, Florian Rechfeld, Simone Stenico, Dorata Garcza-
Johann Hofmann
Research Areas
Investigations into the function of unknown genes or ESTs regulated by
PKCepsilon.
Development of antagonists of PKCepsilon by interference between PKCepsilon
and RACK2
Investigations into the mechanism of action of novel bicyclic hydrazones with
antitumor activity.
rczyk
RACK2 (green) with inhibitory octapeptide EAVSLKPT (blue).
RACK2 represents a protein that by binding to PKCepsilon
defines its final sorting in the cell, e.g. for anchoring PKCepsilon
onto cardiac myofilaments/myofibrils. (RACK = receptor for
activated C kinases). The octapeptide shown here is part of the
RACK2-binding domain on PKCepsilon. By using such peptides
or similaryl structured other small molecules, the translocation
and thus the function of PKCepsilon can be inhibited, and thus its
biological functions.
Major achievements
Progress in elucidation of the mechanism of action of heterocyclic hydrazones
Progress in the development of peptidomimetics as PKCe antagonists
PATENT
Heterocyclic Hydrazones for use as anti-cancer agents, No. 1286987, No. 1361224, Johann
Hofmann
Future goals
Explanation of the mechanism of action of heterocyclic hydrazones
Development of a PKCepsilon antagonist
Janet Lord, University of Birmingham; Lorenzo Pinna, University of Padova; Peter Goekjian,
University of Lyon; Jouni Jokela, University of Helsinki; Andrew Marston, University of Geneva
29
Colocalization
of RACK2 and
PKCepsilon in
the Golgi
http://www.i-med.ac.at/imcbc/staff_doc/piendl_wolfgang.html
Ludger Hengst
Tel.: 0043 (512) 9003.70331
Director
Ribosomal Proteins
Wolfgang Piendl
Interaction of ribosomal proteins with rRNA and mRNA
Interaction of ribosomal proteins with rRNA and mRNA
Ribosomal proteins S8, L1 and L10 (as part of the L10/L124 complex) from different
(hyper)thermophilic Archaea and Bacteria exhibit a 10 to 100 fold higher affinity to their
specific binding sites on rRNA and mRNA compared to that of their mesophilic
counterparts. This stronger protein-RNA interaction might substantially contribute to the
thermal tolerance of ribosomes in thermophilic organisms. Our investigations are focusing
on the identification and characterization of those structural features of RNA-binding
proteins that modulate the affinity for their specific RNA binding site. Similarly, we are
studying the structural elements of the L1-binding site on 23S rRNA and mRNA, that
define them as a high or low affinity binding sites, respectively.
Control of ribosomal protein synthesis in mesophilic and thermophilic
Archaea
As Bacteria and Eukarya, Archaea have to coordinate the synthesis of about 60
ribosomal proteins with each other and with three rRNAs. Research is focusing
on the MvaL1 operon (encoding ribosomal proteins L1, L10 and L12) from
mesophilic and thermophilic Methanococcus species. As in Bacteria, regulation
of this operon takes place at the level of translation. The regulator protein MvaL1
binds preferentially to its binding site on the 23S rRNA, and, when in excess,
binds with a 20-fold lower affinity to its regulatory binding site on its mRNA (a
structural mimic of the 23S rRNA binding site) and thus inhibits translation of all
three cistrons of the operon. MvaL1 inhibits its own translation before or at the
formation of the first peptide bond, but Mval1 does not inhibit the formation of the
functional ternary initiation complex. Our data suggest a novel mechanism of
translational inhibition that is different from the displacement or entrapment
mechanism described for the regulation of ribosomal proteins in Bacteria. Our
next aim is to pinpoint exactly the translation step at which MvaL1 inhibits its
own synthesis.
Function of ribosomal protein L1
L1 is a two-domain protein with N and C termini located in domain I. In close collaboration
with a Russian group we succeeded in constructing a truncation mutant of L1
representing domain I by deletion of the central part of L1 (= domain II). We could
demonstrate that domain I alone is sufficient for specific RNA binding, whereas domain II
stabilizes the L1-23S rRNA complex.
In the ribosome L1 is located in the stalk region proximal to the E-site where the
deacylated tRNA is ejected. We plan to study the exact function of L1, especially of its
domain II in the process of protein synthesis.
Major achievements
Construction of a truncated mutant of ribosomal protein L1 and its crystallization
Future goals
30
- To study the role of ribosomal protein L1 and its individual domains within the
ribosome.
- To define the translational step at which archaeal L1 inhibits its own synthesis.
Prof. Dr. M. Garber, Institute of Protein Research, Russian Academy of Sciences,
Pushchino, Moscow Region, Russia
Ribosomal protein L1 from the archaeon Sulfolobus
acidocaldarius in complex with 23S rRNA
www.i-med.ac.at/imcbc/staff_doc/ueberall_florian.html
Ludger Hengst
Director
Tel.: 0043 (512) 9003.70120
Bioinformatics
Group members
Kathrin Becker, Angela Klein-Wondrak, Maria Ebner, Marcel Jenny,
Claudia Ott, Oliver Wrulich
Florian Überall
Functional Gene Expression Bioinformatics, Signal Transduction
We are working on high throughput screening data-driven systems biology
solutions to simulate biochemical/signal transduction pathways. Our systems
theorety-based approach consists of abstraction, model generation from
experimental data and model validation in the real world. Currently we are
developing a framework for grid-enabled spatiotemporal simulation.
In living organisms, serine and threonine phosphorylation is associated with
signaling pathways controlling a wide variety of processes including cellular
growth, proliferation, differentiation, cell polarity, cytoskeletal architecture, stress
response and apoptosis. Aberrant phosphorylation is detrimental for cell function
and is associated with human disease. Protein kinase C isotypes (PKC) are
central within these functions. Since its discovery more than 18 years ago, the
atypical PKC (aPKC) family has attracted great interest. Our group in parallel
investigates aPKC function in cell proliferation, growth control, migration,
apoptosis and oncogene-induced cell survival.
In addition we are interested in nutrigenomics of chronic inflammatory disorders
and develop strategies to modify novel molecular targets for chemoprevention. In
a more biotechnical concern we are intested in the molecular analysis of natural
compounds for cancer prevention and novel strategies of therapy.
Major achievements
SoftNode classification algorithm, workflow-oriented gene expression bioinformatics, superarray data
analysis workflow
Future goals
Spatiotemporal simulation of metabolic and signal transduction pathways (systems biology)
Identification of novel PKC isotype interacting partners (nutrigenomics)
Altieri D., Yale, USA: Serine-threonine phosphorylation of survivin; Biden T, Melbourne, Australia:
Atypical PKCiota in insulin signaling; Pestell R., New York, USA: Cyclin D1 signal transmission; Role
of PKC isotypes; Ullrich A., Martinsried, Germany: Signaling of Trk- and EGF receptor mutants.
31
http://www.i-med.ac.at/imcbc/clinbiochemfolder/clinbiochem.html
Clinical Biochemistry
Ludger Hengst
Tel.: 0043 (512) 9003.70310
Provisional Director
Protein Analysis Group
Herbert Lindner
Development of high-resolution methods for the separation and identification of
post-translationally modified proteins and for investigating their biological
significance.
Our group concentrates on the development of rapid and efficient methods for the
separation and characterization of proteins and their posttranslational modifications with
closest attention to the family of histone and HMG proteins. Histone analysis was always
a driving force behind the biological research in this field, because it consistently provided
a better insight into the complexity of this protein family. It is this complexity of histones
that, because of their varied modifications and their interplay, gives us new information for
such important biochemical processes as, for example, the activation and repression of
genes. Because of the intricacy of histones it is not too surprising that an entire repertoire
of analytical methods is used for their separation. For this purpose, a set of separation
methods based on capillary electrophoresis (CE), reversed-phase chromatography,
hydrophilic interaction liquid chromatography (HILIC) and mass spectrometry (MS) was
introduced in our lab.
At present, our main research interest focuses on modifications of linker histones. One of
the most important modification is the phosphorylation on certain serine and threonine
residues located in the C- and N-terminal domains. Phosphorylation is cell cycle
dependent, and individual H1 subtypes differ in their degree of phosphorylation, which is
usually lowest in G1 phase, rises continuously during S and G2 reaching a maximum
during mitosis. Using HILIC and MS, various phosphorylated H1 forms were separated
and their phosphorylation sites and patterns identified.
Main technologies
32
- ESI- and MALDI-TOF mass spectrometry
- HPLC, e.g. RPC, HILIC, IEC, GPC
- Capillary electrophoresis
- Chromatin immunoprecipitation
- Phosphoproteomics
- Coimmunoprecipitation
- Generation of site-specific phospho-antibodies
Group members
Sabine Chwatal, Astrid Devich, Fatma Dikmen, Bernhard
Halfinger, Leopold Kremser, Michaela Pfister, Michael Rittinger,
Bettina Sarg, Heribert Talasz
From these data, particular site-specific phospho-antibodies were
generated as tools for analysing the involvement of particular site-specific
phosphorylated H1 subtypes in processes like cell cycle progression,
gene expression, DNA replication or repair.
S17p
of
H1.5
(p1g)
HILIC
H1.5p0 p1g
p1m
p2
S172p
of
H1.5
(p1m)
p3
0
20
Time (min)
40
60
Fig.1: Left: HILIC separation of non-, mono- di-, and triphosphorylated
forms of H1.5 from interphase cells. HILIC enables even the separation of
distinctly site-specifically phosphorylated proteins, e.g. the two monophosphorylated forms p1g from p1m.
Right: Immunofluorescence images of interphase cells. red= alpha
tubulin; green=specific phospho-sites of histone H1.5. Clinical Biochemistry
Ludger Hengst
Protein Analysis Group
Herbert Lindner
IFTZ
Major achievements
-Development of affinity based enrichment methods for MS-based structural investigation of
bioactive peptides
- Generation of polyclonal peptide antibodies against phosphorylated Ser17, Ser172, Thr10 of H1.5
- Identification of phosphorylation pattern and sites of testis specific H1t
Main Aims and Projects
- Development of multidimensional LC/CE-MS-based methods
- Generation of further site-specific phospho-antibodies
- PTM identifications of various nuclear proteins
- Identification of novel phospho-histone binding proteins
- Identification of histone modification patterns at the nucleosomal level
International Cooperations
I. Rundquist (Linkoping University, Sweden); N. Guzman (Johnson&Johnson, New York); J. Thomas
(Dep. of Biochemistry, Cambridge); R. Schneider (MPI Freiburg); F. Azorin (Institute for Research in
Biomedicine, Barcelona); Roche Diagnostics, Penzberg, Germany
T10p of H1.5
+1
y9
1006.5
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
0
MS/MS
y +1
10
1103.4
Relative Abundance
Our group is also operating the Protein Micro-Analysis Facility funded by and established
within the IFTZ (Interdisziplinäres Forschungs- und Therapiezentrum) at Innsbruck
Medical University. The protein facility is dedicated to provide investigators with
equipment, expertise and custom services for the detection, characterization and
quantification of proteins and peptides on a recharge basis. The facility maintains a suite
of state of the art instrumentation including a MALDI TOF/TOF 4800 plus analyzer
(Applied Biosystems), a hybrid FT mass spectrometer LTQ Orbitrap XL (ThermoScientific), a Procise 492 protein sequencer (Applied Biosystems), Nano-LC gradient
systems UltiMate 3000 (Dionex), a Probot microfraction collector (LC-Packings) for online MALDI target preparations. Various capillary electrophoresis and HPLC Systems and,
in addition, a solar M6 dual Zeeman spectrometer (ThermoScientific) for trace element
analysis are operated in the facility.
b +1
+2
b 17
8
829.4
935.4
y +2
15
828.6
+2
y 14
793.1
y +2
7
419.8
b +1
3
359.9
+1
y3
315.3
200
+1
b4
430.8
y +1
4
482.4
y +2
16
877.8
y+1
13
1456.4
+1
y 11
1284.4
+1 b +1
y5
7
610.3 728.1
+1
b 12
1249.9
+1
y12
1355.5
y+1
15
1656.5
+1
y16
1753.5
b +1
17
1870.1
400
600
800
1000
1200
1400
1600
1800
m/z
Fig.2: Left: Identification of phosphorylated T10 (fragment 1-20) of
H1.5 by nanoLC-MS/MS.
Right: Immunofluorescence image of cells in mitosis or G1 phase:
red=a-tubulin; green=T10p
33
www.i-med.ac.at/imcbc/molecularcellbiologyfolder/molcellbiol.html
Biological Chemistry
Peter Gröbner
Tel.: 0043 (512) 9003.70330
Director
Fuchs
This Division is organized in four independent working groups, lead by senior
investigators/professors, who attempt to persue an overlapping, interdepen-dent,
common and sustainable scientific goal, as outlined below.
Biochemistry and Biological Significance of Cytokine-Induced Metabolic Pathways:
Identification of neopterin as a marker for T-cell activation dates back to the 1980s. This
was the starting point to further investigate the mechanisms that lead to increased
neopterin formation and to establish its nowadays well-accepted clinical relevance.
Neopterin concentrations are among the best predictors of the future disease course in
patients with cardiovascular disorders, after multiple trauma and with several types of
cancer. In patients with HIV infection neopterin concentrations are even more closely
related with survival than virus load. Monitoring neopterin concentrations also allows
early detection of immunological complications in allograft recipients. Because of its high
sensitivity to detect acute virus infections early, neopterin screening is nationwide in use
to improve virus safety in blood donation in Austria. Neopterin concentrations are useful
for monitoring therapy and support differentiation between viral and bacterial lower
respiratory tract infections (fur further detail see, e.g, www.neopterin.net). In addition, a
cell-culture test for pyrogenic contamination based on neopterin detection could be
developed and the monitoring of neopterin concentrations in stimulated peripheral blood
mononuclear cells sensitively allows the detection of pro- and anti-inflammatory effects
of drugs, plant components and chemicals.
34
Small molecules with central functions: Neopterin is a product of human
monocyte-derived macrophages and dendritic cells formed preferentially in
response to interferon-gamma but also to some other pro-inflammatory
stimuli. It stems from 7,8-dihydroneopterin-triphosphate, a metabolite in the
formation of 5,6,7,8-tetrahydrobiopterin (H4-biopterin) from GTP. H4biopterin is a cofactor for hydroxylating aromatic amino acids and is hence
of crucial importance for neurotransmitter formation, for nitric oxide (NO)
formation from L-arginine, a key molecule for neurotransmission, blood
pressure regulation and immune function, and for ether lipid
monooxygenase (Figure 1, 2 pages later).
Tel.:
Tel.:
Tel.:
Tel.:
Golderer
0043 (512) 9003.70350
0043 (512) 9003.70332
0043 (512) 9003.70340
0043 (512) 9003.70351
Werner
Werner-Felmayer
email: gabriele.werner-felmayer@
i-med.ac.at
Earlier work of our group characterized various cell types and
immune stimuli for increased H4-biopterin formation and we
showed for the first time that intracellular H4-biopterin levels
control cytokine-induced and constitutive NO formation.
A major achievement was also our contribution to clarifying the
molecular mechanism by which H4-biopterin catalyses NO
formation from L-arginine, which is essentially different from that
found in aromatic amino acid hydroxylases since only one
electron is donated and a pterin-radical is formed. In the
following, the relationship of endogenous H4-biopterin levels and
its interplay with NO synthases, peroxynitrite and superoxide
was investiga-ted showing that suboptimal cofactor levels lead to
formation of radicals involved in tissue damage.
Peter Gröbner
Director
Radical formation is reduced by ascorbic acid or by trolox, a tocopherol derivative, due to
stabilizing H4-biopterin and thus preventing superoxide formation by impaired NO
synthase function. On the other hand, neopterin is able to amplify deleterious effects of
radicals in various cellular systems and seems to be part of the pro-inflammatory and
cytocidal armature of the activated human macrophage.
Pharmacological effects of H4-biopterin: In analogy to folates and antifolates, we designed the H4-biopterin-analogue 4-amino-H4-biopterin and showed that it is an effective
inhibitor of all three NO synthase isoenzymes with a preference for the cytokine-induced
enzyme. In vivo, 4-amino-H4-biopterin prolonged allograft survival in a mouse heart
transplantation model with an efficacy comparable to cyclosporine A and rescued rats
from septic shock. However, the immunosuppressive effect of 4-amino-H4-biopterin cannot be entirely explained by its capacity to inhibit NO synthase because in different experimental settings, the cofactor of NO synthase, i.e. H4-biopterin, and the inhibitor of NO
synthase, i.e. 4-amino-H4-biopterin, have similar effects. In mouse macrophages, we
showed that H4-biopterin and its amino-analogue added to culture media suppressed NO
synthase gene expression via hydrogen peroxide formation and induced apoptosis. In a
mouse model, cardiac allograft survival was prolonged by both H4-pteridines
independently from their effect on NO synthase expression or activity, whereas on
dendritic cells only the amino analogon selectively suppressed MHC class II protein
content and antigen response.
Molecular biology of H4-biopterin biosynthetic enzymes: H4-biopterin is formed by
three biosynthetic enzymes from guanosine triphosphate (GTP), i.e GTP cyclohydrolase I,
6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase. We have shown that
cytokines regulate the first step of this biosynthesis, by inducing GTP cyclohydrolase I
and repressing its feedback regulatory protein. Neopterin derivatives accumulate in
human cells and in particular in human macrophages due to a low activity of the second
enzyme of the pathway, 6-pyruvyol tetrahydropterin synthase. The mechanistic basis of
this is selective skipping of exon 3 of this enzyme in the splicing process which is
particularly effective in human macrophages in which H4-biopterin is undetectable. GTP
cyclohydrolase I is induced by cytokines in alternatively spliced RNAs, and coexpression
of the spliced truncated forms of this enzyme cause decrease in activity and protein,
presumably by accelerated decay.
Related pathways and clinical relevance: In conditions leading to increased neopterin
formation, i.e. activation of NK and T-cells and hence of macrophages as well, a number
of further cytokines and metabolic pathways are induced (Figure 2, next page).
Group members
Birgit Fischer, Astrid Haara, Marcel Jenny, Markus Keller,
Martin Kerber, Christian Kositz, Elena Ledjeff, Petra Loitzl,
Nina Madl, Elisabeth Maier, Verena Melichar, Claudia Nagl,
Gabriele Neurauter, Sandra Pittl, Elisabeth Santer, Birgit
Schraberger, Katrin Watschinger
35
Peter Gröbner
Director
We were among the first to clone and characterize a novel small T-cell attracting CXC
chemokine, i.e. CXCL11, and to show its cross-reactivity with other CXC chemokines
reacting with the CXCR3 receptor and its involvement in allograft rejection. A metabolic
pathway induced in response to T-cell activation is degradation of the essential amino
acid tryptophan by indoleamine 2,3-dioxygenase (IDO). Patients with a negative
prognosis have increased IDO activities in addition to increased neopterin levels in a
number of conditions. Like other pathways induced by interferon-gamma, this strategy of
the immune system serves to restrict growth of pathogens or malignant cells but, when
getting beyond control, can also lead to immune deficiency, impairment of erythropoiesis
and increased probability to develop depression because of affecting the serotonin/
tryptophan metabolism. Finally there exists a potential association of subnormal
tryptophan degradation and the course of allergy and asthma, as has been investigated in
patients suffering from pollinosis under specific immunotherapy.
Physarum nitric oxide synthase: Physarum polycephalum is a single-cell multinuclear
model organism used in cell biology because of its naturally synchronous cell cycle and
its ability to undergo differentiation. Remarkably, this organism expresses the only thus
far known fully functional NO synthase outside the animal kingdom, an enzyme required
by this organism to gain sporulation competence thus establishing a novel role for the H4biopterin/NO/cGMP axis in cell differentiation. Moreover, we were involved in initiating
the Physarum genome project which was started in August 2004 by the National Human
Genome Research Institute (NHGRI) following an initiative of an international Physarum
genome consortium headed by J. Gott, Cleveland. Together with W. Marwan, Magdeburg, and G. Gloeckner, Jena, a transcriptome project of the plasmodial stage analysed
about half of the protein coding genes of Physarum, yielding an important resource for
the ongoing genome project. In the near future, these projects will allow to study
signalling networks and protein expression related to cell differentiation in a systematic
large-scale approach.
36
Figure 1: Biosynthesis and known cofactor roles of
tetrahydrobiopterin
Figure 2: TH1-type immune response and some of its metabolic effects
Current focus: Tryptophan degradation is still in focus of our
experimental and clinical studies. In an intense collaboration with
the NCI/Bethesda, the role of IDO and its relationship to
regulatory T-cells and dendritic cells in the development of
immunodeficiency is investigated in HIV infection and in
experimental SIV infection of rhesus macaques. The influence of
tryptophan degradation on the course of neuropsychiatric
symptoms is investigated in patients with HIV infection (e.g. in
collaboration with UCSF) and with cancer. To further characterize
the role of immune activation and inflammation in cardiovascular
diseases, the relationship between metabolism of homocysteine
and asymmetric dimethylarginine (ADMA) is investigated in vitro
and in vivo.
Peter Gröbner
Director
For investigating a potential influence of immune activation and oxidative stress on the
metabolism of phenylalanine, a new HPLC method is to be developed and clinical
collaboration studies are under way. The relationship between tryptophan metabolism
and allergy development will be further investigated in patients and in vitro. Special
attention is given to antioxidant compounds like vitamins supplements and preservatives.
Further experimental studies are devoted to the influence of plant compounds such as
cannabinoids on activated peripheral blood mononuclear cells in vitro. In the animal
models investigated in collaboration with the General and Transplantation Surgery group,
we intend to optimize treatment conditions of H4-biopterin in attenuating ischemia
reperfusion injury with the aim to develop a novel therapeutic strategy also applicable in
humans. In our biochemical work, we currently aim to overexpress recombinant
Physarum NO synthases in sufficient quality and quantity to allow crystallization by our
cooperation partners at the Scripps Research Institute, La Jolla, USA. So far, no fulllength NO synthase was crystallized but only its oxygenase or reductase domains.
Physarum NO synthases may be sufficiently different from animal NO synthases and
therefore it might be possible to crystallize the full-length enzyme for the first time.
Another focus is on the molecular characterization of glyceryl ether monooxygenase, an
enzyme that may contribute to metabolic actions of H4-biopterin, the sequence of which
is unknown.
International cooperations: National Cancer Inst, NIH, Bethesda,
MD, USA; The Scripps Research Institute, Dept. of Mol. Biol., La Jolla,
CA, USA; Skaggs Institute for Chemical Biology Deparment.of Surgery,
Yale University School of Medicine, New Haven, CT, USA; NIMH Healthy
Living Project, UCSF, San Francisco, California, USA; Department. of
Psychiatry, Oregon Health & Science University, Portland, Oregon, USA;
UKSanRx Pharmaceuticals, San Diego, California, USA; Department of
Chemistry, University of Science and Technology, Hong Kong, HK;
Dept.of Molecular Medicine and Pathology, University of Auckland, NZ;
Institute for Molecular and Cellular Biology, University of Jena, D; Leibniz
Institute for Age Research – Fritz Lipmann Institute, Jena; Max-Planck
Institut für Dynamik komplexer technischer Systeme; RNA Center, Case
Western Reserve Institute, Cleveland; Institute Francois Magendie,
University of Bordeaux II, Bordeaux, F; Department of Infectious
Diseases, Östra Hospital, University of Goeteborg, S; Department of
Immunology, Imperial College London, London, UK; Chirurgische Klinik
und Poliklinik, Universität München, D; Synlab Medizinisches
Versorgungszentrum für Labordiagnostik, Heidelberg, D; Department.of
Toxicology, Faculty of Pharmacy, Hacettepe University, Ankara, TR;
Dandrit Biotech, Copenhagen, DK
Additional activities: The meeting series “International
We have developed a 5 orders of magnitude more sensitive assay for this enzyme, and
aim at purifying, sequencing and characterizing of the physiological significance of this
protein. Related with this project, we study the metabolic fate of of long chain fatty aldehydes using a novel, fluorescence-labelled compound.
Winterworkshop on Clinical, Chemical and Biochemical Aspects of
Pteridines” is organized annually. The International Society of
Pteridinology (current president: Dietmar Fuchs) is publishing the peerreviewed international Journal Pteridines (current executive editor:
Dietmar Fuchs). In 2007, Gabriele Werner-Felmayer initiated Ethucation at
the MUI, a nation-wide network for introducing bioethics and research
ethics in the medical syllabus and for developing an interdisciplinary
dialogue on science, technology & society (more information on the
activities of the network on www.i-med.ac.at/ethucation). This network is
the Austrian unit of NIMED, an international network of the UNESCO
Chair in Bioethics (IL).
37
www.i-med.ac.at/ imcbc/neurobiochemistry/
Neurobiochemistry
Christine Bandtlow
Tel.: 0043 (512) 9003.7070281
Director
Groups within the Division of Neurbiochemistry
Neurobiochemistry
Neurotoxicity
Christine Bandtlow
Gabriele Baier-Bitterlich
Neurobiochemistry
Christine Bandtlow
The lab is primarily interested in delineating the physiological functions of reticulon
proteins (RTN) and their signaling molecules in the nervous system. Related to their
association with the ER, RTN proteins have been suggested to play a role in the
regulation of intracellular trafficking of proteins involved in exo- and endocytosis, but their
precise cellular functions remain unknown. Although many RTN isoforms show distinct
expression patterns in the CNS and PNS - both in the developing and mature nervous
system – RTN4-A/Nogo, is the only RTN member with a defined function in the adult
brain. Nogo-A was originally identified as a myelin-derived inhibitor of neurite outgrowth
and has been implicated as a major factor preventing neuronal regeneration and
compensatory sprouting in the adult CNS. Over the past few years, considerable progress
has been made in our understanding of the structure-function relationship of Nogo-A, its
axonal receptors, and the intracellular signaling cascades mediating axon outgrowth
inhibition. However its physiological significance as an intracellular protein of neurons is
unknown. Recent studies in our lab highlight novel functions of RTN-4A/Nogo-A and other
RTN isoforms as important intracellular regulators of axonal and dendritic morphogenesis
in vitro and in vivo. Present aims are to unravel the molecular mechanisms that mediate
these effects and to analyse proteins that specifically interact with neuronally expressed
RTN proteins. In addition, we use several knock-out mouse model systems to explore and
define the role of the Nogo receptor components p75NTR and NgR in normal and
diseased brains.
Major achievements
38
Identification of a noncanonical caspase recognition site in Nogo-B
Future goals
Characterization of the physiological function of RTN proteins in neurons
Stefan Frentzel, Novartis Pharma, Basel, Switzerland; Mathias Klugmann,
Physiological Chemistry, Mainz, Germany; Martin Korte, Marta Zagrebelsky, TU
Braunschweig, Germany; Roland Martin, ZMNH, Hamburg, Germany
Group members
Igea Contarini, Levent Kaya, Florian Kern, Barbara Meissner,
Rudolf Schicho, Rüdiger Schweigreiter, Katja Jacob, Sandra
Trojer
Neurobiochemistry
Christine Bandtlow
Tel.: 0043 (512) 9003.70289
Director
Group member: Bettina Thauerer (former Tomaselli)
Neurotoxicity
Gabriele Baier-Bitterlich
To reduce apoptosis in the brain is central to functional recovery after stroke.
Present search is focused on the development of drugs that block the apoptotic
process in the hope to improve clinical outcome. The purine nucleoside
adenosine is produced and released in the central nervous system in response
to ischemia and hypoxia. It acts as a powerful endogenous neuroprotectant
during ischemia-induced energy failure, by decreasing neuronal metabolism
and increasing cerebral blood flow. Purine nucleosides thereby are inducing
several distinct intercellular signaling pathways. This is particularly the case in
the brain, which expresses high concentrations of adenosine receptors. These
effects are mediated through interaction of adenosine with specific receptors.
Stimulation and subsequent signaling functions of the adenosine receptors
were hypothesized to result in an effective treatment of stroke. Previous results
in this laboratory demonstrated the positive impact of the purine nucleosides
adenosine, inosine and guanosine on viability and neurite outgrowth of
neuronal PC12 cells and on primary rat cerebellar granule neurons. Our data
on the activation and potential causal roles of p42/p44 mitogen-activated
kinases (alias ERK1/2) and hypoxia-inducible transcription factor-1 (HIF1alpha) in these pathways supported the investigation of the molecular effector
pathways of MAPK/HIF1-alpha in purine nucleoside-mediated signaling leading
to regeneration and/or survival of neurons.
Major achievements
Establishment of positive effect of purine nucleosides on viability and neurite outgrowth
and of the special role of p42/44 MAPK and HIF-1alpha
Future goals
Analysis of p42/44 MAPK substrates in purine-mediated protection
Hypoxic cell death of
cerebellar granule
neurons
Bruno Frenguelli, Univ. of Warwick, UK
Hoechst/PI
39
Cell Biology
Lukas A. Huber
www.i-med.ac.at/cellbio/
Tel.: 0043 (512) 9003.70171
Director
Groups within the Division of Cell Biology
Signal Transduction and Proteomics
Gene Regulation and Molecular Immunology
Membrane Traffic & Signaling
Lukas A. Huber
Ilja Vietor
Martin Offterdinger
Nikos Yannoutsos
David Teis
Signal Transduction/Proteomics
Lukas A. Huber
For many years, it was thought that signaling from receptor tyrosine kinases
(RTKs) to MAP kinase (ERK) occurres only at the plasma membrane and is
mediated by a simple, linear Ras-dependent pathway. However, the limitation of
this model became apparent with the discovery that Ras and ERK can be
activated at various intracellular compartments and that RTKs can modulate
Ras/ERK signaling from these sites. Moreover, ERK-scaffolding proteins and
signaling modulators have been identified that play critical roles in determining
strength, duration and location of RTK-mediated ERK signaling. In this context
we focus on the pathophysiological role of the late endosomal p14/MP1- scaffold
complex. Interestingly, loss or mislocalization of the p14/MP1 complex was found
to have no significant effect on the early activation of ERK at the plasma
membrane, but did in fact alter the sustained ERK activation seen on
endosomes.
40
Group members
Mariana Eca Guimaraes de Araujo, Stefan Ascher, Traudl
Erdel, Beatrix Fürst, Diana Hilber, Sandra Morandell, Ivan
Prokudin, Julia Scheffler, Natalia Schiefermeier, Simon
Schnaiter, Taras Stasyk, Nicole Taub, Cornelia Thoeni,
Winfred Wunderlich
More recently, conditional disruption of p14 in mice
has been found to impair late endosomal trafficking
as well as endosomal ERK activation, resulting in cell
proliferation defects that disrupt early embryogenesis
and tissue homeostasis. Our aim is to provide further
evidence that endosomal ERK signalling has
important consequences in the regulation of cell
proliferation, cell death and cell migration in tumor
cells.
Cell Biology
Lukas A. Huber
Director
Major achievments
Using conditional gene disruption of p14 in mice, we recently demonstrated that the p14/
MP1-MEK1 signaling complex regulates late endosomal traffic and cellular proliferation.
This function is essential for early embryogenesis and during tissue homeostasis as
revealed by epidermis-specific deletion of p14. These findings show that endosomal p14/
MP1-MEK1 signaling has a specific and essential function in vivo and therefore implicate
that regulation of late endosomal traffic by extracellular signals is required to maintain
tissue homeostasis. Interestingly, the endosomal adaptor protein p14 is also critical for the
function of neutrophils, B-cells, cytotoxic T-cells and melanocytes. By combining genetic
linkage studies and transcriptional profiling analysis, a homozygous point mutation was
identified in patients in the 3’ UTR of p14 mRNA resulting in decreased protein
expression. In p14-deficient cells from patients, the bioge-nesis of late endosomes was
severely affected, suggesting a novel role for p14 in controlling membrane transport. The
newly described syndrome belongs to a constellation of autosomal recessive disorders
that also includes the Chediak-Higashi, Griscelli and Hermansky-Pudlak syndromes. The
genes associated with these other disorders encode well-known regulators of intracellular
protein trafficking, organelle movement as well as proteins of poorly understood molecular
function.
Cooperations
Division of Histology & Embryology, Medical University of Innsbruck (Michael Hess);
Institute of Molecular Pathology, IMP, Vienna; Beatson Institute for Cancer Research,
Glasgow, UK; Boehringer Ingelheim Austria, Vienna; UgiChem, Innsbruck; Center for
Academic Spin-Offs Tyrol, CAST
www.i-med.ac.at/cellbio/labore/sigtranslab/index.html
Signal Transduction/Proteomics Lukas A. Huber
Figure: Schematic representation of the intracellular routes taken by the
activated EGF receptor, the KSR1-MAP kinase complex at the plasma
membrane and the p14/MP1/MAP kinase complex on late endosomes.
Our working hypothesis is that signal specificity within a limited pool of
available MAP kinases is generated by their specific association with
scaffold complexes in different combinations and at different subcellular
locations: e.g. KSR1 on the plasma membrane and p14/MP1 in the
perinuclear region on late endosomes. In addition, the activated
receptors traffic through the cells and contribute to the spatio-temporal
regulation of signal transduction.
41
Cell Biology
www.i-med.ac.at/cellbio/labore/celldifflab/index.html
Lukas A. Huber
Tel.: 0043 (512) 9003.70175
Director
Group members
Katherin Patsch, Domagoj Cikes, Karin Schluifer
Ilja Vietor
The interplay between cell proliferation and differentiation controls not only development
but also regeneration. Therefore its regulatory mechanisms are of interest, also as
possible therapeutic targets. Based on our studies, we predict that the transcriptional corepressor TPA inducible sequence 7 (TIS7) is one of the players affecting cellular
regeneration events. TIS7, induced by the mitogen TPA or growth factors, is differentially
expressed in various polarized cell types. We have shown that TIS7 interacts with the
SIN3 complex and represses transcription in an HDAC-dependent manner. In the TIS7regulated downstream target genes we have identified a common regulatory motif C/
EBPalpha-Sp1 transcription factor "module". Furthermore, TIS7 has the ability to inhibit
the Wnt signaling in an HDAC-dependent manner. TIS7 expression increases during the
process of tissue regeneration following a challenge like muscle crush damage or
intestinal resection. Our previous studies have shown that in TIS7 knockout mice the
expression of myogenic regulatory proteins is deregulated and the differentiation and
fusion potential of muscle satellite cells is impaired.
A second member of a novel gene family, SKMc15, is a protein
which shares with TIS7 high homology at the amino acid level.
Therefore our laboratory generated SKMc15 single as well as
TIS7 SKMc15 double knockout mice and now concentrates on
the identification of the functional role of both genes and their
protein products.
Major achievements
In a recent publication from our laboratory analyzing primary adult sensory neurons from
dissociated dorsal root ganglia of TIS7+/+ and TIS7-/- mice we have shown that TIS7
plays a role in axon outgrowth. Lack of TIS7 does not affect normal mouse neuron
development but TIS7 plays a role in the process of axon regeneration since axon
outgrowth of neurons in culture was modified by the absence of TIS7.
42
Lack of TIS7 enhanced the effects of nerve growth factor on axon
branching, affecting the retinoic acid (RA) signaling pathway through
CRABP II expression, a TIS7-regulated gene which we have identified also
in a previously performed DNA CHIP analysis from TIS7 over-expressing
cells.
Muscle satellite cells grown under differentiation conditions. TIS7
+/+ (A) vs. TIS7 -/- cells (B). Immunofluorescence microscopy
images depict: desmin (green), beta catenin (red) and DAPI
(blue) © Natalia Schiefermeier.
See also:
http://www.i-med.ac.at/mypoint/news/2005121401.xml
Cell Biology
Lukas A. Huber
Director
Ilja Vietor
Future goals
1) Identification of genes differentially expressed in wild type and TIS7 SKMc15 double
knock out mice using Affymetrix DNA microarray analysis. The regulation of candidate
genes’ expression should allow us to decipher the mechanisms of action of both proteins
with the further goal to be able to design strategies for intervention with possible signaling
pathways.
2) Identification of TIS7-interacting proteins and analysis of their biological role. In this
project we will concentrate on further characterization of interactions between TIS7
protein complex components, mainly on their in vivo interactions within the living cell. The
main focus will be on the regulatory mechanism by which TIS7 modulates gene
expression of muscle-specific genes during the myogenesis.
3) For possible clinical application of the knowledge gained in cell culture experiments
and knockout mice we will analyze the expression of both proteins, TIS7 and SKMc15 in
human patients’ samples. The expression of both proteins will be detected in muscles
freshly after contusion and also following the wound healing to compare their expression
in intact and injured tissues. The final goal of this project is improvement of differentiation
and thereby regeneration of tissues following an injury.
Cooperations
Department of Medicine, Washington University School of Medicine, St Louis, Missouri,
USA; Division of Molecular Immunology at Cincinnati Children's Hospital Medical Center,
Cincinnati, Ohio, USA; Department of Immunology, Lerner Research Institute,Cleveland,
Ohio, USA; Institute of Physiology, University of Bonn, Germany
TIS7 -/- mouse embryonic fibroblasts grown without (A) and with
(B) laminin coating. Scanning electron microscopy image ©
Kristian Pfaller
43
Cell Biology
www.i-med.ac.at/cellbio/staff2/martin_offterdinger.htmll
Lukas A. Huber
Tel.: 0043 (512) 9003.70175
Director
Martin Offterdinger
Transmembrane receptor tyrosine kinases (RTKs) generally exert their "classical"
biological functions after extracellular binding of peptide growth factors evoking several
intracellular signaling cascades initiated by the receptors' tyrosine kinase activities.
Subsequently, signal amplification occurs via cytoplasmic signaling (phosphorylation)
cascades, resulting in modulation of transcription through phosphorylation of specific
transcription factors in the cell nucleus, which eventually induces transcription.
A number of recent publications, however, have demonstrated the existence of additional
non-classical functions of RTKs involving direct nuclear translocation of intact full length
receptors. Prominent examples of RTKs with nuclear localization include the FGF
receptors (Maher, 1996; Stachowiak, 1996, 1997) and all members of the EGF receptor
family (Lin, 2001; Ni, 2001; Offterdinger, 2002; Xie & Hung, 1994).
Whereas several nuclear activities for RTKs have been described previously, very little is
known about how nuclear import of RTKs is actually achieved. I am therefore
investigating the pathways leading to nuclear import of full length RTKs.
How do nuclear receptor tyrosine kinases leave the membranous fraction and enter the
soluble/cytoplasmic fraction?
For FGFR, it has previously been suggested that nuclear accumulation is not originating
from the plasma membrane (Peng, 2002), but rather from newly synthesized, though fully
glycosylated material. It has therefore been proposed that FGFR is released from the ER
membrane to the cytosol, facilitated by an atypical beta-sheet structure of the
transmembrane domain in FGFR-1 (Myers, 2003).
44
These data support a model in which nuclear EGFR originates at the
plasma membrane and is partially transported to the nucleus after EGF
stimulation (Lin, 2001). The involved transport routes are currently
poorly understood and could occur via a multi-step pathway involving
endocytosis, retrograde transport to the ER, membrane extraction of
the receptor and finally nuclear import via the importin pathway.
The images show nuclear translocation (blue = nucleus) of EGF
receptor (green fluorescence) after EGF stimulation
Co
EGF
Future goals
We plan to apply light microscopic imaging techniques in order to
understand the pathways leading to nuclear localizations of RTKs.
Cooperations
Prof. Philippe I. Bastiaens, Max-Planck-Institute for Molecular Physiology,
Dortmund, Germany
Cell Biology
www.i-med.ac.at/cellbio/labore/labore
Lukas A. Huber
Director
Tel.: 0043 (512) 9003.70187
Group member: Przemyslaw Filipek
Nikos Yannoutsos
While the information encoded in the DNA of the genes is ultimately the blueprint of an
organism, the regulation of the expression of this information is of critical importance for
the realization of the blueprint. This regulation depends on DNA sequences such as
promoters, enhancers and locus control regions (LCRs) which surround the genes in the
non-transcribed and non-translated areas of the genome. However, gene expression is
also regulated by "epigenetic" information, i.e. by inherited states of gene regulation that
lie outside of the DNA of a gene and that dictate its specific macromolecular structure.
Such epigenetic mechanisms include DNA methylation, histone modifications and RNA
interference (RNAi). Recent research indicates that the mechanisms are interrelated and
affect the packaging of the genes into chromatin. The dynamic change of the threedimensional architecture of chromatin is a modulator of the accessibility of the genes to
the transcriptional apparatus and to specific regulatory mechanisms in different tissues
and developmental stages and is, itself, modulated by them.
The immune system is as complex as the nervous system. It is characterized by
communication among its component cells as well as between them and the environment.
This communication is based on the biochemical specificity of the molecules carried by
individual cells, the B or T cell receptors (BCR and TCR). V(D)J recombination creates
BCRs and TCRs by looping out and eliminating large chromosomal segments that
separate the regions which encode the Variable (V), the Diversity (D) and the Joining (J)
parts of these receptors. The process occurs in four subpopulations of lymphocyte
precursors, namely in pro- and pre-B cells in the bone marrow and in double negative
(DN) and double positive (DP) T cells in the thymus.
The two genes are closely linked and conserved in evolution. Transcription of the genes is
coordinately up regulated in pro-B and DN T cells, down regulated as the cells proliferate
and up regulated again as the cells become pre-B and DP T. Finally, the genes are down
regulated again as the cells mature into the B and T cells of the immune system.
Several elements in cis, in the areas of the DNA surrounding the
genes, act in concert to effect this regulation by silencing and
antisilencing mechanisms that are still not well understood. Our
current research indicates that these mechanisms include
secondary, epigenetic, regulation of the Rag locus over at least
100 kilobases.
This picture shows areas of the mouse Rag
locus stained red and green within a DAPI
stained interphase nucleus of a DP
thymocyte.
We are interested in clarifying the cis and trans regulation of this
locus including genetic and epigenetic mechanisms. Major
discovery in this area is the interplay between a silencer between
the two genes and an antisilencer (ASE), which counteracts its
action on the two promoters. Both elements seem to be the link of
the chromatin regulation of the locus to epigenetic mechanisms.
45
Cell Biology
Lukas A. Huber
Director
Nikos Yannoutsos
Major achievements
Research in our laboratory depends on the generation of transgenic and knock-out
mouse models. Since the establishement of this laboratory in November 2005, a major
effort has been to create a laboratory for the generation of such mice by pronuclear and
blastocyst microinjection. By 2007, a major achievement has been the establishment of
this unit to functional status which has already generated successfully different transgenic
mouse lines - in Specific-Pathogen-Free (SPF) status - and has gained support by the
IFTZ (Integrated Research & Therapy Center):
www.i-med.ac.at/iftz/zentrale_gruppen/mouseunit/
Future goals
a) Further clarification of the silencing versus active status of the Rag locus.
b) Elucidation of several leukemias in relation to dysregulation of the Rag locus, utilizing
4C technology (3C on chip) and pyrosequencing.
c) Generating a mouse model for follicular lymphoma, a disease in which the aberrant
action of the Rag-dependent rearrangement occurs in the early stages of B cell
development.
d) Further development of the transgenic unit. A goal in the near future will be to establish
cryopreservation of embryos and sperm, while overall research into stem celltechnology
and newer versions of mouse embryonic stem cell lines is a goal for the longer term.
The enzymes that arre required for this process are the
products of the Recombination Activation Genes RAG1q
and RAG2
Cooperations
Dr. Hendriks and his laboratory at Erasmus University in Rotterdam, The Netherlands, Dr.
Bonifer, University of Leeds, U.K.
46
The enzymes that are required for this process are the
products of the Recombination Activating Genes RAG1
and RAG2.
Cell Biology
www.i-med.ac.at/cellbio/
www.icmb.cornell/
Lukas A. Huber
Tel.: 0043 (512) 9003.70187
Director
Membrane Traffic and Signaling
email:[email protected]
David Teis
The downregulation of cell surface receptors in lysosomes is essential to
regulate receptor signaling. The ESCRT (Endosomal Sorting Complex Required
for Transport) complexes are required for the formation of multivesicular bodies
(MVB) and mediate lysosomal degradation of ubiquitinated transmembrane
proteins. Consequently, the ESCRT machinery is involved in diverse cellular and
developmental processes and its dysfunction contributes to many diseases
ranging from cancer to neurodegeneration.
My goal is to understand how the ESCRT machinery sorts signaling receptors
and forms MVBs and how this essential process regulates signaling.
Endo-membrane system of eukaryotic cells. My research focusses on
endocytic and recycling pathways of signaling cell surface receptors
Major achievements
Fluorescence detection of sequential conformational rearrangements that nucleate
ESCRT-III assembly.
The ordered assembly of ESCRT-III complex on endosomes is required to sequester
cargo during MVB formation.
Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4
phosphoinositide phosphatase.
Future goals
Dynamics of ESCRT machinery, system biology of endosomal traffic, postranslational
regulation of trafficking complexes.
Collaborations
Prof. Scott D. Emr (Cornell University, Ithaca, NY)
This picture shows downregulation of cell surface proteins. Yeast cells
expressing a GFP-tagged cell surface receptor (Mup1). In nonstimulated cells (- methionine), the receptors are at the cell surface,
whereas upon stimulation they are transported and sorted to the
vacuole by the ESCRT. MUP1-GFP (methionine transporter) green,
FM4-64 red
47
genomics.i-med.ac.at/
Genomics & RNomics
Alexander Hüttenhofer
Tel.: 0043 (512) 9003.70250
Director
Groups within the Division of Genomics & RNomics
Experimental RNomics
Molecular Biology of Ribonucleoprotein Complexes
Experimental RNomics
Norbert Polacek
Non-coding RNAs in model organisms: identification and function
In cells from all organisms studied to date two different types of RNAs are
found: messenger RNAs (mRNAs), which are translated into proteins, and socalled nonprotein-coding RNAs (ncRNAs), which are not translated into proteins
but function at the level of the RNA itself. Many known ncRNAs, such as
microRNAs, are involved in the regulation of gene expression and thus act as
molecular switches. While the proteome of most model organisms is rather well
defined, e.g. the total number of protein-coding genes, we are only at the very
beginning of describing the ncRNA transcriptome. Thus, the predictions on the
number of ncRNA genes in the human genome range from about 1.000 up to
400.000 (estimated from tiling-array experiments); in comparison, about 20.000
protein-coding genes are being estimated. NcRNAs are often found in complex
with proteins that are bound to the RNA and thus form ribonucleoprotein
complexes (RNPs).
Group members
Roland Hutzinger, Christoph Joechl, Simone Barbara Kreutmayer, Melanie Lukasser, Jan Mrazek, Andreas Ploner, Mathieu
Rederstorff, Konstantinia Skreka, Yuuichi Soeno
Such RNPs, present in cellular compartments as diverse
as the nucleolus or dendritic processes of nerve cells,
exhibit a surprisingly diverse range of functions. However,
the biological role of some of them remains elusive.
Moreover, most systematic genomic searches are biased
against their detection and comprehensive identification by
computational analysis of the genomic sequence of any
organism remains an unsolved problem.
Hundreds of genes and their RNA products may thus
remain undetected. Their functions, interactions in cellular
circuits and roles in disease would remain unknown and
our understanding of the functioning of a cell would be
incomplete. Therefore, our goal is to directly identify
ncRNAs and their genes in the human genome and those
of various model organisms as well as to elucidate their
functions in cellular processes and/or human diseases.
48
Service
Sequencing facility: Applied Biosystems (ABI 3100)
http://genomics.i-med.ac.at/service/
http://genomics.i-med.ac.at/wg/func_genomics1.html
Genomics & RNomics
Director
Experimental RNomics Alexander Hüttenhofer
Research
Our group works on the identification of small non-coding RNAs (ncRNAs) in various
model organisms for which we have coined the term “experimental RNomics". By this
approach we want to complement the human and other genome projects in identifying all
non-protein-coding RNAs in addition to protein-coding mRNAs. We therefore have
generated cDNA libraries from various model organisms encoding ncRNA species. From
these studies, we have identified so far more than 700 novel small, ncRNAs in model
organisms like the mouse Mus musculus, the plant Arabidopsis thaliana, the Nematode
C. elegans or bacterial and archaeal species like Escherichia coli and Archaeoglobus
fulgidus.
Up to now, most ncRNAs have been shown to be ubiquitously expressed. This is not
unusual since these RNAs - like tRNAs or small nuclear RNAs - are involved in
housekeeping functions like protein synthesis or splicing. In mouse for the first time, we
have identified brain-specific ncRNAs, which implies a novel function of these RNA
species other than housekeeping functions. Accordingly, our goal is to identify the
biological functions of tissue-specifc ncRNAs in mammalian cells. The genes of three of
the brain-specific non-messenger RNAs are located on chromsome 15q11-13 in human
(two of them in multy-copy repeats). This region is involved in the etiology of the PraderWilli-Syndrome (PWS), a neurogenetic disease. We could show that the brain-specific
RNAs are not expressed in PWS patients pointing to a role of these RNAs in disease. We
are currently investigating the role of brain-specific non-messenger RNAs in the etiology
of PWS in a mouse model.
Major achievements
Identification of ncRNAs in HIV and EBV infected cells which regulate viral infections.
Future goals
Identification of the biological functions of novel ncRNAs.
Generation of regulatory ncRNA networks.
Joerg Vogel, MPI, Berlin, Germany; Ralph Bock, MPI Potsdam, Germany; Jürgen Brosius, University
of Münster, Germany
Sequencing facility
The Division of Genomics and RNomics owns a 16-capillary
sequenator from Applied Biosystems (ABI 3100). We offer to
the scientific community in Innsbruck (institutes, clinics,
companies, etc.) the possibility to run your sequencing
reactions on the ABI 3100. For this purpose, sequencing
reactions employing the BigDye sequencing kit from ABI,
should be carried out at the respective lab or institute (for
sequencing instructions and purifications of sequencing
reactions see: http://genomics.i-med.ac.at/service/ seq_prot.
html). Subsequently, reactions are run on our capillary sequenator machine in the building Peter-Mayr-Str. 4b, 3. floor.
Sequencing data can be retrieved online via the internet
without any delay of time. Contact [email protected]!
49
http://genomics.i-med.ac.at/wg/func_genomics2.html
Genomics & RNomics
Tel.: 0043 (512) 9003.70251
Director
Ribonucleoprotein Complexes
Norbert Polacek
Probing ribosome functions by nucleotide analogue interference
Ribosomes are multifunctional ribonucleoprotein (RNP) complexes that translate the
genome's message into proteins needed for life in every living cell. As they are so
fundamental to life and represent one of the main targets for antibiotics, comprehending
how they work is at the heart of a molecular understanding of biology. Decades of biochemical and recent crystallographic studies revealed the ribosome as an RNA-enzyme
(ribo--zyme) with roots in the 'RNA world'. From an evolutionary point of view it is
fascinating that the modern ribosome, the mother of all protein enzymes, still relies on
RNA catalysis to synthesize proteins. The aim of the project is to gain molecular insight
into fundamental ribosomal reactions by employing a newly developed in vitro
reconstitution assay of ribosomal particles. This allows the site-specific incorporation of a
single modified nucleotide analog into 23S rRNA and to study the functional effects on the
performance of the peptidyl transferase center. With this procedure, it is possible to
identify crucial functional groups in the active site with improved precision and an
enlarged chemical variety of nucleosides compared to regular mutagenesis. The main
focus of our group lies in the elucidation of molecular aspects of peptide bond formation
and peptide release; the two main reactions promoted by the peptidyl transferase center
during the elongation and termination phases of protein synthesis, respectively. In
addtion, we are studing the molecular requirements of elongation factor G (EF-G)-driven
tRNA translocation and ask how the large ribosomal subunit is assembled into a
functionally competent RNP particle.
50
Group members
Melanie Amort, Kamilla Bakowska-Zywicka, Anna Chirkova, Nina
Clementi, Matthias Erlacher, Maren Fischer, Constanze Nandy,
Krista Trappl, Marek Zywicki
Peptide bond formation is a fundamental reaction in biology, catalyzed by
the ribosomal peptidyl transferase ribozyme located in the large
ribosomal subunit. The means by which the ribosome promotes this
reaction has been a subject of intense discussions over the last decades.
By applying an “atomic mutagenesis” approach of active site rRNA
residues, we revealed the crucial functional group on 23S rRNA. By
combining these novel findings with previously published data, we were
able to propose a comprehensive model for peptide bond synthesis
Genomics & RNomics
Director
Ribonucleoprotein Complexes Norbert Polacek
The elusive molecular biology of the vault RNA and the vault RNP
In a recent genomic non-coding RNA (ncRNA) screen we have identified the vault RNP
associated RNAs to be significantly upregulated in human B cells upon Epstein Barr virus
(EBV) infection. Very little is known about the function of this ncRNA class, mainly
because the vault complex has been overlooked by cell biologists for many years. Here
we address the question whether vault RNA upregulation is indeed causally linked to the
virus infection and which function the vault RNAs might exert during virus propagation.
Furthermore we will assess the structure-function relationship of vault RNAs which will
eventually reveal the so far enigmatic molecular biology of this interesting ncRNA species.
Major achievements
START Prize of the Austrian Research Fonds 2006 to Norbert Polacek:
Novartis-Award 2007 to Norbert Polacek
Future goals
Understanding non-coding RNA structure and function relationships in molecular detail
Alexander Mankin, University of Illinois at Chicago, USA; Knud Nierhaus, Max-Planck
Institute, Berlin, Germany; Daniel Wilson, Gene Center, Munich, Germany
NOVARTIS-Awardées
2007
Norbert Polacek,
Kathrin Breuker,
Andreas Villunger
51
mol-biol.i-med.ac.at/
Molecular Biology
Peter Loidl
Chromatin & Epigenetics
Director
Tel.: 0043 (512) 9003.70200
Groups within the Division of Molecular Biology
Chromatin and Epigenetics
-Structure and Function of Chromatin: Maize and Mouse
-Structure and Function of Chromatin: Filamentous Fungi
-Chromatin Assembly and Remodeling
Applied Mycology
Lipocalins
Peter Loidl
Gerald Brosch &
Stefan Grässle
Alexandra Lusser
Hubertus Haas
Florentine Marx
Bernhard Redl
Research of the division is devoted to various topics of molecular biology,
including molecular microbiology, epigenetics, applied microbiology and lipocalin
structure and function. Research is mainly focused on the regulation of gene
expression in lower eukaryotes, plants and cultured mammalian cells. Several
independent research teams try to hold an internationally recognized position
within their research field. The division of Molecular Biology is responsible for
teaching and training students of the Innsbruck Medical University and the
Faculty of Biology of the University of Innsbruck in molecular biology. The
division moreover has teaching responsibilities for medical students in
microbiology and infectious disease control.
52
Research of the Chromatin & Epigenetics Group: Nuclear DNA is
compacted into chromatin which represents a complex structure basically
built from repeating units, the nucleosomes. These consist of 145 bp of DNA
wrapped around an octamer of basic proteins, the core histones. The
octamer is formed by 2 molecules each of histones H2A, H2B, H3, and H4.
At least 2 domains can be distinguished in histones, a globular domain
involved in histone-histone interactions (containing the histone fold motif)
and the flexible N terminal tails (H3, H4) or N terminal and C terminal tails
(H2A, H2B).
Loidl, Brosch,
Grässle, Lusser
A series of consecutive nucleosomes forms a beads-on-a-string structure.
A further level of compaction is the 30 nm fiber with 6 nucleosomes per
turn in a solenoid arrangement. In the past years our traditional picture of
chromatin as a static and largely repressive functional state has changed
to a more complex view of chromatin as a highly dynamic state that is
essential for cellular regulation. The dynamic properties of chromatin are
mediated by multiprotein complexes with different functions that set marks
overlying the stable information of the DNA. The most prominent factors
that influence chromatin are enzymes that modify histones and chromatin
remodeling machines which utilize ATP. Histones have been conserved
during evolution. However, they are dynamically changed by
posttranslational modifications of various kinds like acetylation,
methylation, phosphorylation and others which all can cause structural
and functional rearrangements in chromatin and therefore represent
essential elements of the complex epigenetic histone code. To decipher
this code which is recognized and interpreted by transcriptional regulators
and chromatin remodeling machines is one of the central challenges of
chromatin research. Moreover, numerous regulatory, non-histone proteins
are modified by histone acetyltransferases (HATs) and histone
deacetylases (HDACs).
Tasks
1. - identification and functional analysis of HDACs, histone methyltransferases
and demethylases in filamentous fungi
- role of HDACs in host-microbe interactions
- mechanism of action of HDAC and protein methyltransferase inhibitors
2. - histone acetylation/ methylation in murine cells with a focus on nucleolar
chromatin
3. - HATs, HDACs and protein methyltransferases in plants
4. - functional significance of histone and non-histone protein modifications for cell
cycle regulation (p130)
5. - chromatin assembly and remodeling
mol-biol.i-med.ac.at/wg/chromatin_lab_mm.html
Molecular Biology
Peter Loidl
Director
Structure and Function of Chromatin: Maize and Mouse
Peter Loidl
Group members
Research Topics
-Histone deacetylases and protein methyltransferases during maize embryo
germination
-Acetylation of nonhistone, nuclear proteins (Acetoproteomics)
-Acetylation of nucleolar proteins (UBF, PAF53)
-Acetylation of cell cycle regulatory pocket proteins
Walid Abu El-Soud, Maria Goralik-Schramel, Adele Loidl, Joachim
Meraner, Muhammad Saeed, Florian Schwarze
My laboratory is engaged in the investigation of core histone acetylation. We have
intensively studied histone acetylation in the acellular slime mold Physarum polycephalum
and in plants. In particular, we have purified, characterized and identified histone
acetyltransferases and histone deacetylases in Zea mays and Arabidopsis thaliana. In the
course of these studies we identified a novel, plant specific type of histone deacetylase
(HD2) and a yet unknown level of regulation of an HD-A type deacetylase; maize HD1A is
regulated by limited proteolytic cleavage. Currently we investigate this type of regulation
in more detail and we extended our investigations in maize for the purification and
characterization of histone/protein methyltransferases.
During the last years it became more and more clear that a huge number of non-histone
proteins are substrates for enzymes that were initially identified as histone-modifying
enzymes; this holds true, in particular, for histone acetyltransferases and deacetylases
and histone methyltransferases. Just recently, we focused our research on the analysis of
the functional consequences of acetylation of UBF and PAF53 (nucleolar transcription
regulators/adaptors) and p130 (a cell cycle regulatory pocket protein).
Major achievements
We have identified the nucleolar protein PAF53 and the pocket protein 130 as proteins that are
acetylated by HATs and we could at least partially unravel the functional significance of the
modification. Moreover, we could identify 14:3:3 proteins in maize, that are methylated during embryo
germination.
Future goals
We would like to understand the complex interrelation between regulatory non-histone proteins that
are acetylated/deacetylated by HATs/HDACs and chromatin.
Ingrid Grummt (Heidelberg), Manfred Jung (Freiburg), Bernd Lüscher (Aachen), Jonathan Walton
(East Lansing)
53
mol-biol.i-med.ac.at/wg/chromatin_lab_ff.html
Molecular Biology
Peter Loidl
Director
Group members
Ingo Bauer, Johannes Galehr, Hermann Krabichler, Divyavaradhi Varadarajan
Structure and Function of Chromatin: Filamentous fungi
Histone methylation in filamentous fungi
Gerald Brosch
Protein methylation involves the transfer of a methyl group from S-adenosylmethionine to acceptor
groups on substrate proteins. Arginine residues of proteins are modified by members of the protein
arginine methyltransferase (PRMT) family. Arginine methylation has been observed on a variety of
proteins associated with gene regulation, including DNA-binding transcriptional activators,
transcriptional coactivators, and many RNA-binding proteins involved in RNA processing, transport,
and stability. The long-term objective of our research is to investigate the functional role of protein
methylation in filamentous fungi. We have identified three distinct PRMTs which all exhibit histone
methyltransferase activity in vitro and in vivo. One of these proteins, termed RmtB, has an
exceptional position because it displays both enzymatic and structural properties that are different
from other known PRMTs. To study the functional role of PRMTs in A. nidulans we are currently
deleting the corresponding PRMT genes by targeted gene replacement and are analysing putative
growth defects of rmtA/rmtB, and rmtC deletion mutants under various growth conditions. These
studies will be completed by the generation of double and triple mutant strains and the concomitant
investigation of physiological and developmental effects. Finally, the analysis of global gene
expression patterns, the study of effects of rmtA, rmtB, and rmtC deletion on the regulation of genes
involved in secondary metabolism pathways, and the identification of novel substrate proteins of
PRMTs will help to clarify the role of arginine methylation in Aspergillus.
Besides the functional analysis of histone modifying enzymes, our group is also involved in the
biological evaluation of small molecule inhibitors in cooperation with different pharmaceutical
laboratories. Such inhibitors are potent inducers of differentiation and bear considerable potential as
drugs for chemoprevention and treatment of cancer.
54
Tel.: 0043 (512) 9003.70211
Functional roles of distinct histone deacetylases in the filamentos fungi
Stefan Grässle
Histone acetylation plays a crucial role in the processes of gene
regulation in eukaryotes. In particular, histones can be acetylated by
histone acetyltransferases (HATs) and can be deacetylated by a second
group of enzymes, the histone deacetylases (HDACs). In contrast to
HATs, for which to date no potent inhibitors are known, there is a panel of
structurally unrelated agents available that affect HDACs in a very
selective way. Today these inhibitors are important tools for the study of
histone acetylation processes. Our working group studies histone
acetylation/deacetylation processes and attempts to purify HATs and
HDACs of multiple organisms. Recently, we have identified and partially
characterized HDACs of different classes in the filamentous fungus
Aspergillus nidulans. The further characterization and the clarification of
the function of these enzymes within our model organism is the goal of
this project. Since filamentous fungi are more complex than yeast in many
important aspects, yet genetic manipulation is relatively simple and easy
to perform, they have widely been regarded as model systems to study
the basis of eukaryotic gene regulation. Moreover, many of these
organisms contribute to the decay of organic material and thereby play an
important role in the spoilage of food. But there are also filamentous fungi
which represent dangerous pathogenic agents for people such as the
closely related species to A. nidulans, A. fumigatus, which can cause lifethreatening infections in patients that have a compromized immune
system. For these reasons the study of these group of organisms is also
of economic and medical interest.
Tel.: 0043 (512) 9003.70218
Molecular Biology
Peter Loidl
Director
Gerald Brosch
& Stefan Grässle
Major achievements
Histone methylation: We could demonstrate that deletion of Aspergillus PRMTs positively or
negatively affect penicillin biosynthesis, indicating that PRMT activity is involved in the regulation of
secondary metabolism. Compound screening and chemical manipulations of lead compounds
identified potent and specific inhibitors of PRMTs; inhibition assays and biological evaluation experiments revealed in vivo activity and selectivity of isolated drugs.
Histone acetylation: We show that deletion of hdaA, encoding an Aspergillus nidulans HDAC,
causes transcriptional activation of two telomere-proximal gene clusters and subsequently leads to
increased levels of the corresponding molecules (toxin and antibiotic). Introduction of two additional
HDAC mutant alleles in a delta HdaA background had minimal effects on expression of the two
HdaA-regulated clusters. Treatment of other fungal genera with HDAC inhibitors resulted in overproduction of several metabolites, suggesting a conserved mechanism of HDAC repression of defined
secondary metabolite gene clusters. Depletion of RpdA, another fungal HDAC, leads to a drastic
reduction of growth and sporulation of Aspergillus nidulans. Functional studies revealed that a short
C terminal motif unique for RpdA-type proteins of filamentous fungi is required for the catalytic
activity of the enzyme and, consequently, can not be deleted without affecting the viability of A.
nidulans. Moreover, evidence is provided that this motif is also essential for other, if not all,
filamentous fungi.
Future goals
• To clarify the functional role of protein methylation in Aspergillus nidulans
• To investigate the impact of histone modifications on the regulation of secondary metabolism in A.
nidulans
• To clarify the molecular mechanism of the C-terminal motif of RpdA and its role as new target for
fungal-specific HDAC-inhibitors
• Since several euascomycetes are not only well known for infection of food and crop plants, but also
represent causative agents of infections in human beings, the development of novel antimyco-tic
substances is highly desirable
Nancy Keller, Department of Plant Pathology, University of Wisconsin-Madison, USA; Manfred Jung,
Department of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Germany; Antonello
Mai, Dipartimento Studi Farmaceutici Università degli Studi di Roma "La Sapienza“, Italy; Jonathan
Walton, Department of Energy Plant Research Laboratory, Michigan State University, East Lansing;
Gianluca Sbardella, Dipartimento di Scienze Farmaceutiche, Università di Salerno, Fisciano, Italy
Figure above: Production of the fungal secondary
metabolites sterigmatocystin (ST, a toxin), penicillin (PN,
an antibiotic), and terraquinone (TR, an antitumor agent)
in histone deacetylase (HdaA) and putative methyltransferase (LaeA) deletion mutants. (A) and (C) are thin layer
chromatographies of ST and TR, (B) is a bacterial growth
inhibition assay showing PN production. From Eukaryot.
Cell. 2007, 6: 1656-64.
55
mol-biol.i-med.ac.at/wg/chromatin_assembly.html
Molecular Biology
Peter Loidl
Tel.: 0043 (512) 9003.70210
Director
Chromatin Assembly & Remodelling Alexandra Lusser
The way in which eukaryotic DNA is organized in chromatin has profound effects on all
processes that direct DNA metabolism (such as transcription, replication, repair and
recombination). We are interested to learn how the establishment and maintenance of
eukaryotic chromatin affects those processes. We are approaching this question by
studying the molecular mechanism and biological context of the chromatin assembly
process.
Chromatin assembly is a fundamentally important process that is tightly linked to DNA
replication and enables the cell to faithfully duplicate the chromosomes. In addition,
chromatin assembly occurs independently of replication to turn-over histones, for instance
during transcription or DNA damage repair. We have recently identified Drosophila CHD1
as an ATP-dependent chromatin assembly factor that belongs to the SNF2 superfamily of
ATPases. Many members of this large group of molecular motor proteins are involved in
the modification of chromatin structure. Only members of two SNF2-subfamilies, namely
CHD1, and the previously identified ISWI are known to catalyze the ATP-dependent
assembly of chromatin. ISWI and its human homolog hSNFH function as part of the
Drosophila ACF and CHRAC chromatin assembly complexes and the human RSF
complex, whereas Drosophila CHD1 appears to predominantly operate as a monomer.
CHD1 and ACF enzymes catalyze the ATP-dependent assembly of periodic arrays of
nucleosomes. Interestingly, these enzymes generate different types of chromatin in terms
of internucleosomal spacing distance and linker histone H1 content.
We are particularly interested in the biological functions of CHD1 which has been
implicated in the regulation of transcriptional elongation and termination processes. To
study the implications of chromatin assembly in processes of DNA metabolism, we use a
biochemical approach employing in vitro chromatin reconstitution and transcription
systems. In addition, chromatin assembly defects are investigated in tissue culture as well
as in mutant Drosophila lines.
04
Group members
Beatriz Campo-Fernández, Maria Goralik-Schramel, Stefano
Morettini, Paolo Piatti, Valerie Podhraski, Gabriele Scheran,
Martin Tribus, Hildegard Wörle, Anette Zeilner
Future goals
We are currently investigating functions of CHD1 in vivo that are distinct
from its role in early fly development. We wish to elucidate the molecular
mechanisms by which CHD1 operates to remodel chromatin in
transcription-dependent and transcription-independent processes.
Dmitry Fyodorov, Albert Einstein College of Medicine, Bronx, USA; Jim
Kadonaga, University of California, San Diego, USA; Benjamin Loppin,
Universitè Claude Bernard, Lyon, France; Gregory Bowman, Johns
Hopkins University, Baltimore, USA
Major achievements
In our studies of the biological roles of the ATP-dependent chromatin remodeling
factor we found that CHD1 has a crucial role in vivo in the remodeling of sperm
chromatin during fertilization. CHD1 is essential for the incorporation of the variant
histone H3.3 into paternal DNA during early Drosophila development. Thus, CHD1 is
the first ATP-dependent remodeling factor that is linked to an H3.3 specific
nucleosome assembly pathway.
A Working Model for Chromatin Assembly
mol-biol.i-med.ac.at/wg/molec_microbiol.html
Molecular Biology
Peter Loidl
Tel.: 0043 (512) 9003.70205
Director
Hubertus Haas
Fungi affect the life of mankind positively and negatively. On the one hand, fungi are major players in
saprobic decomposition, mutually interact with plants (mycorrhiza), serve directly as food
(mushrooms) or in food production (e.g., bread, cheese, alcohol), and produce widely used primary
(e.g. citric acid) and secondary metabolites (e.g. penicillin,). On the other hand, some fungi are
pathogens of plants (e.g. Fusarium spp.) and animals (e.g. Aspergillus fumigatus), or spoil food by
contamination or toxin production (e.g. aflatoxin). Therefore, fungi impact ecology, biotechnology,
medicine, agriculture and food industry. The best studied fungal organism is Saccharomyces
cerevisiae. In several respects, however, the physiology of this yeast is not comparable with that of
filamentous fungi (e.g. iron metabolism, light regulation, secondary metabolism). We are mainly
interested in the molecular elucidation of the peculiarities of filamemtous fungi´s physiology.
Our current research focus is the iron/siderophore metabolism of Aspergilli. A. fumigatus is a typical
saprobic filamentous ascomycete but also the most common airborne fungal pathogen of humans. It
causes allergic and invasive disease depending on the immune system. Unsatisfying diagnostic and
therapeutic possibilities are reflected in a high mortality rate. The low-pathogenic relative Aspergillus
nidulans represents an established genetic model system.
Both Aspergillus species produce an extracellular siderophore (triacetylfusarinine C) for iron
acquisition and an intracellular siderophores (ferricrocin) for iron storage. Siderophore biosynthesis is
regulated by two transcription factors, SreA and HapX. Siderophores are central components of the
fungal metabolism as they affect germination, sexual and asexual reproduction, oxidative stress
resistance and virulence. Lack of siderophore biosynthesis renders A. fumigatus apathogenic.
Consequently, the siderophore system represents a novel target for antifungal therapy.
Additional research topics are light regulation, nitrogen metabolism, noncoding RNA´s, chromatin
modification, improvement of molecular tools for the manipulation of fungi.
Our cental research goal is to characterize the fungal metabolism and to exploit this knowledge for
both improvement of antifungal therapy and improvement of the fungi´s biotechnological potential.
Group members
Beate Abt, Michael Blatzer, Martin Eisendle, Mario Gründlinger,
Claudia Kragl, Bea Lechner, Tarek Moussa, Jasmina Sabiha,
Claudia Sigl, Markus Schrettl, Anna Wallner, Daniel Wechselberger
Elaine Bignell, Dep. Molec. Microbiol. & Infec., Imperial Coll. London; Axel
A. Brakhage, Leibniz-Inst. for Natural Product Res. & Infection Biol., F.
Schiller Univ. Jena; R. Fischer, Dep. Applied Microbiol., Univ. Karlsruhe;
William C. Nierman, J. Craig Venter Institute, The George Washington
Univ. Sch. Med., Rockville, MD, USA; Gillian Turgeon, Dep. Plant Pathol.,
Cornell Univ., Ithaca, NY, USA; Günther Winkelmann, Dep. Microbiol. &
Biotechnol., Univ. Tuebingen
Major achievements
05
- Identification of a novel mechanism for iron regulation in A. nidulans
- Dissection of the role of extracellular and intracellular siderophores in physiology and virulence of
A. fumigatus
- Molecular analysis of the intracellular fate of siderophores after uptake in A. fumigatus
Future goals
Aspergillus fumigatus:
Detailed characterization of the iron homeostasis-maintaining mechanisms of filamentous fungi (in
particular of Aspergilli) and applied medical and biotechnological exploitation of the gained
knowledge
A, on plates; B, scanning electron-microscopy of hyphae
and conidia
(courtesy of K. Pfaller); C, siderophore
metabolism.
mol-biol.i-med.ac.at/wg/applied_mycol.html
Molecular Biology
Peter Loidl
Director
Tel.: 0043 (512) 9003.70207
Applied Mycology
Group members
Ulrike Binder, Andrea Eigentler, Nikoletta Hegedüs, Renate
Weiler-Görz
Florentine Marx
Filamentous fungi secrete a wide array of different proteins into the external medium
where they accomplish most diverse functions, e.g. assimilation of complex nutrients,
communication between other fungal cells, interaction between pathogenic fungi and their
host and others. Apart from some secreted enzymes which have been developed for a
variety of commercial uses (mainly for the fermentation industry), only few extracellular
proteins are well characterized with respect to their function as pathogenic factors or as
cell signalling factors.
Our main scientific interest is to identify, isolate and further characterize on the molecular
and functional level novel extracellular proteins with antimicrobial activity from Penicillium
chrysogenum, Aspergillus nidulans and Aspergillus fumigatus. Antimicrobial proteins are
promising candidates for the development of novel therapies applicable in medicine as
well as in agriculture and in the food industry to prevent and treat microbial infections.
Therefore, the detailed characterization of the mode of action of these proteins is of
crucial importance and a prerequisite for its successful application in the future for the
development of new therapeutic approaches.
Major research interests
-Characterization of the mode of action of antimicrobial proteins secreted by filamentous fungi on the
molecular and cellular level
-Identification and characterization of molecular targets in sensitive fungi
-Localization studies and characterization of endocytotic pathways in fungi
-Structural biology
-Determination of the relevance and function of antimicrobial proteins for the producing organisms
Major achievements
04
First steps towards biotechnological utilization of antimicrobial proteins
Future goals
Identification of molecular targets for the development of new therapeutic drugs
Gyula Batta, University of Debrecen, HU; Mogens Trier Hansen, Novozyme, Bagsvaert,
DK; Vera Meyer, Technical University Berlin; István Pócsi, University of Debrecen, HU;
Nick Read, University of Edinburgh, UK
specific binding to receptor
molecule situated
in the cell wall and / or plasma
membrane
heterotrimeric Gprotein
signaling
increased ion
permeability (K+-efflux)
membrane
hyperpolarization
active
internalization
(endocytosis-like
mechanism)
reactive oxygen
species (ROS)
mitoptosis
programmed cell death mechanism
mol-biol.i-med.ac.at/wg/lipocalin_lab.html
Molecular Biology
Peter Loidl
Director
Tel.: 0043 (512) 9003.70203
Lipocalins
Group members
Maria-Laura Fluckinger, Hermann Krabichler, Petra Merschak,
Alexandra Pipal, Linda Teufel
Bernhard Redl
Structure and Function of Lipocalins and their Cellular Receptors
Our group investigates structural and functional features of human lipocalins. The protein
superfamily of „lipocalins“ consists of small, mainly secretory proteins defined on the
basis of conserved amino acid sequence motifs and their common structure. Functionally,
they were found to be important extracellular carriers of lipophilic com-pounds in
vertebrates, invertebrates, plants, and bacteria. There is increasing evidence that this
group of proteins is involved in a variety of physiological processes including retinoid, fatty
acid, and pheromone signaling, immunomodulation, inflammation, detoxification,
modulation of growth and metabolism, tissue development, apoptosis, and even
behavioral processes. Whereas the structural basis of lipocalin-ligand binding is now well
understood, there is a major lack of knowledge regarding the mechanisms by which
lipocalins exert their biological effects. This is mainly due to the fact that only limited data
are available on lipocalin receptors and lipocalin-receptor interactions, although it is well
accepted that many, if not all, of these proteins are able to bind to specific cell receptors.
A
C
Current research projects of our lab focus on the following subjects:
-Identification of cellular lipocalin receptors, characterization of the molecular mechanism
of the receptor-ligand interaction and the biological processes beyond receptor binding.
-Evaluation of novel functions of lipocalins in innate immunity and allergy.
Major achievements
Identification of a cellular receptor for beta-lactoglobulin
Arne Skerra, TU Munich, Freising-Weihenstephan; Ben J. Glasgow, UCLA School of Medicine, Los
Angeles, CA, USA
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A. Structure of Lipocalins; B. Lipocalin receptors;
C. Cellular targeting of Lipocalins
05
www2.i-med.ac.at/expatho/sgonc.html
erimental
unology
Exp. Pathophysiology & Imm.
Lukas A. Huber
Tel.: 0043 (512) 9003.70970
Group members
Ruth Holzer, Marion Mailänder, Gabriele Stöckl
Experimental Rheumatology
Roswitha Sgonc
Our group is interested primarily in the pathogenesis of systemic sclerosis (SSc),
which we study in human patients as well as in the spontaneous UCD-200/206
model. UCD-200/206 chickens are the only animal model, that manifests the
whole clinical, histopathological and serological spectrum of human SSc. This
makes it the ideal tool to investigate the initial patho-mechanisms, and to test
new evidence based therapies.
Thus, only the comparative study of UCD-200/206 and human SSc made it
possible to identify microvascular endothelial cells as the primary target of the
autoimmune attack, which subsequently undergo apoptosis. In the follow-up
study, we could show that endothelial cell apoptosis in SSc is induced by AECA
(anti-endothelial cell antibody)-dependent cellular cytotoxicity (ADCC) via the
Fas/Fas ligand pathway.
Currently, we focus on two main projects:
1. the identification of (auto)antigens expressed by microvascular endothelial
cells, using a proteomic approach, and
2. the therapy of ischemic lesions in SSc.
EC-apoptosis
Human SSc
Major achievements
Identification of two autoantigens expressed by microvascular endothelial cells and recognized by
chicken and human SSc sera.
Future goals
60
1. Further elucidation of early pathomechanisms in SSc.; 2. development of new, highly
specific diagnostic tests for an earlier diagnosis of SSc; 3. development of efficient
therapies based on our research results.
Jeremy Saklatvala, Kennedy Institute of Rheumatology, Imperial College London; Robin
Wait, Kennedy Institute of Rheumatology, Imperial College London; Oliver Distler,
Center of Exp. Rheumatology, University Hospital Zurich; Andreas Zisch, Department
of Obstetrics, University Hospital Zurich; Olov Ekwall, Department of Medical
Sciences, Uppsala University
UCD-200
EC-apoptosis
www2.i-med.ac.at/expatho/boeck.html
erimental
unology
Lukas A. Huber
Tel.: 0043 (512) 9003.70385
Biophysics & Biooptics
Günther Böck
The aim of our biophysics-biooptics group is to provide a service for the various
cell biology groups within as well as outside the Biocenter.
This includes mainly flow cytometry and flow sorting. Some examples of these
developments are given below:
a) the use of a fluorescence-activated cell sorter (FACS) for single cell level
receptor demonstration and biochemical characterization
b) demonstration of apoptosis with various staining methods
c) detection of apoptosis together with Ca2+ fluxes
FL4H
1000
800
600
400
200
10E0
0
10E1
10E2
SSC-W
10E3
61
www2.i-med.ac.at/expatho/schwarz.html
erimental
unology
Lukas A. Huber
Tel.: 0043 (512) 9003.70975
Molecular Endocrinology
Siegfried Schwarz
Research
This laboratory's work has focussed on the study of various hormone/neurotransmitter
binding proteins and receptors as well as their ligands. Key papers describe:
- Sex Hormone Binding Globulin (SHBG) and steroids in cerebrospinal fluid (CSF) and
interaction with Danazol (non-genomic actions of steroids?)
- Demonstration of homocysteate as an NMDA-selective excitatory agonist
- Description of an epitope map of the glycoprotein hormone hCG
- Construction of epitope-selective immunoassays for glycoprotein hormones
- Demonstration of different orientations of receptor-bound agonistic vs. antagonistic hCG
- Prediction of the 3D structure of the extracellular domain of the hCG receptor
- Characterizartion of an apoptotic activity within urinary hCG preparations towards
Kaposi‘s sarcoma cells
-Demonstration of the importance of vasopressin in critical ill patients.
Therefore, teaching of Pathophysiology is stratified
over five semesters instead
of the previously two. Except for infectious disea-ses
and cancer, the entire
teaching of Pathophysiology in main lectures is covered by Prof. Schwarz.
In addition, he is appointed
coordinator of the module
„Endocrinology“, coordinator of the 4th semester,
organisator of the SIP3
(summative integrative examination at the end of the
7th semester).
http://www2.i-med.ac.at/expatho/
molecules_of_life_anncmt.html
Book Award 2003 by the British
Medical Association
Teaching Pathophysiology
The University law 2002 mandated the implementation of the NEW CURRICULUM
HUMAN MEDICINE at the Innsbruck Medical University. The latter required a full-time
teaching devotion for the subject PATHOPHYSIOLOGY. In accordance with these duties,
Professor Schwarz published two textbooks, one in 2002, the other in 2007, on molecular
aspects of pathophysiology.
62
In contrast to previous and „classical“ curricula, Pathophysiology is not any more
taught within 2 semesters as a separate and isolated subject, rather it is incorporated into an integrative teaching style of organ and disease modules . A module
is provided by lecturers from diverse preclinical and clinical disciplines. The modules
are the following: diagnostics and laboratory medicine, endocrinology, hematology,
cardiovascular diseases, nephrology, pulmonology, neurology & psychiatry,
infectious diseases + immunology, cancer, dermatology, gastroentero-logy,
osteology, teratology, environmental medicine.
Since 2008, Professor Schwarz is appointed guest professor for pathophysiology at
the Suranaree University of Technology (Korath/Nakhon Ratchasima, Thailand).
http://maudrich.com/
9783851758603.html
www.tkfi.at/dmp
Reinhard Kofler
Tel.: 0043 (512) 9003.70360
Director
Groups within the Division of Molecular Pathophysiology
Leukemia Apoptosis
Cell Cycle Control
Molecular Oncology
Reinhard Kofler
Stephan Geley
Arno Helmberg
Research
The aim of the Division of Molecular Pathophysiology (DMP) is to improve our
understanding of fundamental biological processes on the molecular level with
the ultimate goal to apply this knowledge to improved therapy and diagnosis of
human diseases. Specifically, we investigate apoptosis (Kofler), cell cycle control
(Geley) and proteins interacting with the glucocorticoid receptor (Helmberg). Our
Division participates in the local Research Program Project (SFB, "Spezialforschungsbereich“ 021) and other internationally reviewed programs.
Leukemia - Apoptosis
Kofler
Group members
Martina Brunner, Michela Carlet, Mayra Eduardoff, Georg Gruber,
Barbara Gschirr, Ines Jaklitsch, Anita Kofler, Susanne Lobenwein,
Muhammad Mansha, Christine Mantinger, Sylvia Maurer, Christian Ploner, Johannes Rainer, Muhammad Wasim
Glucocorticoid-iniduced apoptosis
Reinhard
Resistance to anticancer therapy means an inefficient or ineffective respon-se to
treatment. Glucocorticoids (GC), resembling one of the hormones of our body, cortisol,
have many effects; most strikingly, in high doses, they can trigger a suicide program called apoptosis - in certain leukemia cells. GC are therefore used in many therapeutic
regimens for hematological malignancies, like the successful Berlin-Frankfurt-Münster
(BFM) - protocol. Here, children suffering from acute lymphoblastic leukemia (ALL)
receive glucocorticoids for 1 week before being assigned to a polychemotherapy regimen
of a risk-dependent intensity. In most cases, GC treatment results in a remarkable
reduction of tumor cells. However, if the patients fail to respond to this therapy they
require an intensified chemotherapy. We aim to understand the effects of GC on leukemia
cells on a molecular level as well as to identify the various resistance mechanisms. This
knowledge should allow us to develop concepts for new therapies. Four major research
strategies are persued in our division:
63
www.tkfi.at/dmp/en/research/detail.php?id=2
Reinhard Kofler
Director
Leukemia - Apoptosis
Reinhard Kofler
1) Identification of candidate genes for the anti-leukemic effects of GC, i.e. determination of the
gene expression profile of such cells in the absence or presence of GC, in a clinical setting, i.e. in
patients with acute lymphoblastic leukemia (ALL) using whole genome microarray-based expression
profiling (performed in the "Expression Profiling Unit“, a core facility of this university). By inclusion of
peripheral blood lymphocytes from GC-exposed healthy donors, GC-sensitive and resistant ALL cell
lines and mouse thymocytes, an essentially complete list of GC-regulated candi-date genes in clinical
settings and experimental systems was generated, allowing immediate analysis of any gene for its
potential significance to GC-induced apoptosis.
2) Verification of regulation and functional analysis of the candidate genes on the RNA and
protein level is currently under way by real time RT-PCR and Western blotting technologies and
lentiviral, conditional systems for gene over-expression and RNA interference-based systems for
gene knock-down, respectively.
3) Analyses of model systems of GC resistance. To understand how leukemia cells escape cell
death induced by GC, we have generated a large number of GC-resistant leukemia cell lines which
we investigate with respect to the mechanism(s) of resistance development. Analyses include
determination of GC-receptor structure and expression, DNA finger printing, expression profiling, and
FACS-based analyses.
4) Novel therapeutic combinations in preclinical models. From the knowledge obtained in the
above studies we try to develop concepts for novel therapeutic combinations, e.g. GC combined with
2-deoxyglucose (an inhibitor of glucolysis), which yielded a remarkable effect on an ALL model
system.
Current results
Comparing gene expression in patient samples with those in model systems clearly
demonstrated the relevance of research done on patient material: In several instances,
we could not verify the assumed significance of genes identified in model systems in
previous studies. In contrast our study revealed some genes so far not implied in any
hypothesis on glucocorticoid-induced apoptosis. Among those are genes involved in
energy-metabolism and a potentially new member of the apoptosis-related molecule
family of BH3-only molecules, which mediates death signals.
Major achievements
Defining the role of the BCL2 rheostat in glucocorticoid-induced apoptosis
Detection of glucocorticoid-regulated microRNAs
64
Future goals
A better delineation of the transcriptional response to glucocorticoids in normal and
malignant cells of the lymphoid lineage as it relates to the anti-leukemic and other
effects of glucocorticoids and resistance to this substance.
Major collaborators
J.A. Irving, Northern Institute for Cancer Research, Newcastle Upon Tyne; H. Kovar,
R. Panzer, S. Strehl, St.Anna Kinderspital, Vienna; Z. Trajanoski, Technical University
Graz
The Expression Profiling Unit (EPU) of the Innsbruck Medical
University (head: Reinhard Kofler) provides a number of
services and bioinformatic support related to microarray-based
technologies including expression profiling on various Affymetrix
arrays and microRNA screening, genome-wide detection of DNAbinding proteins (ChIP-on-CHIP technology), etc. The EPU is
currently located both at the Division of Molecular Pathophysiology and the Tyrolean Cancer Research Institute. For
further details, please visit the EPU home
page ( http://www.gdcf-epu.info/ ).
Reinhard Kofler
Tel.: 0043 (512) 9003.70366
Director
Group member: Karin Ecker
Molecular Oncology
Arno Helmberg
Having our roots in Reinhard Kofler's lab, glucocorticoids are at the center of our interest.
We currently search for proteins interacting with the glucocorticoid receptor.
Glucocorticoids, a class of steroid hormones released from the adrenal gland with the
goal of enabling the organism to cope with stress situations, play a key role in the
modulation of glucose, fat and protein metabolism as well as in the regulation of immune
and inflammatory reactions. Synthetic equivalents are widely used drugs to treat
inflammatory diseases and certain malignant neoplasms, especially of lymphocytic origin.
Glucocorticoids are an important part of chemotherapy protocols because, in high doses,
they induce apoptosis in many lymphatic leukemia and lymphoma cells.
The glucocorticoid receptor (GR) acts as a ligand-dependent trancription factor that is
able to induce or repress a large array of genes. While this function has been analyzed in
great detail, less attention has been devoted to potential functions of the GR other than
transcription regulation. As such potential other functions would likely be mediated by the
GR making contact with as yet unknown proteins, our laboratory has been working to
identify proteins that interact with the glucocorticoid receptor.
The classical tool to detect low to intermediate affinity protein-protein interactions is the
yeast two-hybrid system. In its commonly used form, it makes use of protein– protein
interactions to reconstitute a transcription factor necessary for the expression of betagalactosidase or other reporter genes. Although powerful, this system has inherent
limitations. Proteins like the GR, containing transactivating domains, cannot be used as
bait, as they would directly activate expression of reporter genes independently of an
interaction partner. To overcome these limitations, we have modified a specialized,
cytoplasmic form of the two-hybrid system developed by A. Aronheim. By tethering the
GR to the plasma membrane of the yeast cell, we have been screening a HeLa library for
proteins interacting with the receptor. Isolated candidate proteins are then assayed in
human cell lines for interaction with the receptor. By doing so, we have isolated a KRABcontaining zinc finger protein that can be coprecipitated with the receptor and seems to
target the receptor to specific areas of chromatin.
Looking for glucocorticoid receptor-interacting proteins. Scanning electron micrograph of a lymphocyte, courtesy of Kristian Pfaller
Major achievements
Identification of a KRAB-containing zinc finger protein as an interaction
partner of the glucocorticoid receptor
Future goals
•To learn about the function of the zinc finger protein in question
•To better understand glucocorticoid action by identifying further
interaction partners
65
Reinhard Kofler
Tel.: 0043 (512) 9003.703665
Director
Cell Cycle Control
Stephan Geley
Group members
Petra Mikolcevic, Cornelia Wandke, Benedicte Sohm, Marin Barisic, Reinhard Sigl
Function and regulation of cyclin dependent kinases (CDK)
CDKs are proline-directed serine/threonine kinases of the CMGC subgroup of
eukaryotic protein kinases. CDKs are activated by cylin subunits and are
involved in the control of cellular division, transcription, cell growth as well as
additional functions in differentiated cells such as neurons. Since deregulated
cell cycle control is a hallmark of tumorigenesis, a detailed understanding of cell
cycle control in normal and malignant cells is mandatory for a better
understanding of tumor development.
Our work focuses on the function and regulation of the mitotic cyclins A and B in
order to understand how these molecules control entry into, progression through
and exit from mitosis, respectively. In addition, we are interested in the function
of ‘orphan CDKs‘, i.e. members of the CDK family whose mode of activation and
function is still unknown.
Figure 1: Chromokinesins are microtubule plus
end-directed
motor
proteins that bind to
chromosomes
(red=
KIF4A; green= hKID
(KIF22)
Main aims and projects
• Function and regulation of mitotic cyclins
• Functional analysis of mitotic phosphoproteins (Wandke, Sohm) (Figure 1, 2)
• Identification of novel cell cycle regulators (Barisic)
• Functional analysis of Fzr1 (Sigl, Wandke)
• Functional analysis of Pctk1 (Sigl, Mikolcevic)
66
Strategies and main technologies
• In vitro expression cloning
• Phosphoproteomics
• Recombineering and GATEWAY
technology
• Lentiviral gene transduction
• Lentiviral RNAi
• Gene targeting in mouse and human cell
lines
• AAV-mediated gene targeting
• Live cell imaging
Major achievements
• Fzr1 conditional knockout mouse
• Pctk1 conditional knockout mouse
• Novel roles of chromokinesins in mitosis
Future goals
• Identification of CDK substrates
• Function of Fzr1 in the mouse
• Function of Pctk1 in the mouse
Cooperations
T. Hunt (Cancer Research UK, London);
R. Fässler (MPI Martinsried, Munich)
Figure 2: Live cell
imaging reveals multiple
defects in KIF4A RNAi
cells: prolongation of
mitosis, broader metaphase plate, lack of central spindle. red: alpha
tubulin-mCherry; green:
H2B-GFP
www.sfb021.at/villunger/
Developmental
Andreas Villunger
Immunology
Tel.: 0043 (512) 9003.70380
Director
Groups within the Division of Developmental Immunology
Apoptosis
Glucocorticoids & Immunology
Andreas Villunger
Jan Wiegers
Apoptosis
Andreas Villunger
Research Focus 1 - BH3-only proteins in cell death and disease: Whether a cell
continues to live in response to diverse forms of stress or undergoes apoptosis along the
intrinsic cell death signaling pathway is largely determined by the complex interplay
between individual members of the Bcl-2 protein family that can either promote or prevent
apoptosis. The five known survival-promoting family members Bcl-2, Bcl-xL, Bcl-w, Mcl-1
and A1 share four Bcl-2 homology domains (BH1-BH4) amongst each other (except for
Mcl-1 containing only three of these domains). All these proteins are critical for cell
survival, since loss of any of them causes premature cell death of certain cell types.
Consistently, overexpression of Bcl-2 pro-survival molecules is associated with prolonged
(tumor) cell survival and drug-resistance in a number of models systems, but more
importantly, also in tumor patients. The pro-apoptotic Bcl-2 family members can be
divided into two classes: the Bax-like proteins (Bax, Bak, Bok) that contain three BHdomains (also called BH123 or multi-domain pro-apoptotic Bcl-2 proteins) and the BH3only proteins. The latter include Bim, Bid, Puma, Noxa, Bmf, Bad, Hrk and Bik that are
unrelated in their sequence to each other or other Bcl-2 family members (except for the
BH3-domain).
We study the role of BH3-only proteins using genetically modified mouse models,
focusing on the role of Bmf and Puma.
Two major signalling pathways trigger cell death in mammals (fig. 1). The Bcl-2 regulated
apoptosis signaling pathway, conserved in C. elegans, and the 'death receptor' pathway.
Both converge at the level of effector caspase activation that causes cellular demolition.
In certain tumor-derived cell lines and cells derived from endodermal tissues, such as
hepatocytes, members of the TNF-family have been reported to link the death receptor
pathway with the Bcl-2-regulated pathway via caspase cleavage-mediated activation of
the BH3-only protein Bid.
Group Members
Florian Baumgartner, Florian Bock, Ilenia Bertipaglia, Anna
Frenzel, Irene Gaggl, Francesca Grespi, Gerhard Krumschnabel,
Verena Labi, Claudia Manzl, Ruth Pfeilschifter, Kathrin Rossi,
Benedicte Sohm, Claudia Soratroi
67
Figure 1
Developmental
Andreas Villunger
Immunology
Director
Apoptosis
Andreas Villunger
Research Focus 2 - PIDD in the cellular response to DNA damage: The p53-induced
protein with a death domain (PIDD) has been identified as a gene activated in response
to p53 activation in a wide variety of cells and tissues. Together with the adapter molecule
RAIDD, PIDD is involved in the activation of caspase-2, triggering the formation of a proapoptotic complex, called the “PIDDosome”. Interestingly, PIDD has recently also been
implicated in DNA damage-induced NF-kB activation, promoting the transcription of cell
survival genes by forming a complex with the kinase RIP-1 and with Nemo (the regulatory
subunit of the IKK signalling complex). The mechanism that allows PIDD to sequentially
activate these two opposing signalling pathways involves auto-proteolytic cleavage of
PIDD, leading to the sequential generation of two fragments. One frargment, PIDD-C, is
able to recruit RIP-1 and Nemo leading to NF-kB activation, and the other, shorter one,
PIDD-CC, preferentially promotes caspase-2 activation via interaction with RAIDD (fig.
2A). Immunofluorescence staining of primary MEF transfected with FLAG-tagged PIDD
and the Golgi apparatus using anti-GM-130 as well as Hoechst for nuclear staining (fig.
2B)
Major achievements
Identification of Bmf function in lymphocyte homeostasis and transformation
Novartis Award for Medical Science 2007 to AV
Ongoing projects
•Investigating the drug-target potential of the BH3-only proteins Bim, PUMA and Bmf
•Bmf in c-myc-induced lymphomagenesis
•Analyzing the relevance of the BH3-only protein PUMA/bbc3 for tumor suppression
•PIDD in caspase-2 and NF-kB activation
•Redundancies and specificities of the BH3-only proteins Bim & Bmf
•Bim & Bmf in breast cancer development
Figure 2A
PIDD-Flag MEF
nucleus
GM-130
overlay
Georg Häcker, TU-Munich, GER; Andreas Strasser, WEHI, Melbourne, AUS; Jürg Tschopp,
Lausanne, CH; Apoptrain Network members
68
Figure 2B
Developmental
Andreas Villunger
Immunology
Tel.: 0043 (512) 9003.70390
Director
Group members
Ines Peschel, Patrick Clemens
Glucocorticoids and Immunity
Jan Wiegers
Selection processes in the thymus ensure that mature peripheral T-cells fulfill two essential
prerequisites: activation by foreign peptides bound to (host) MHC molecules, but tolerance to selfderived peptides presented in the same context. To that end, thymocytes that express T cell
receptors (TCRs) with high avidity for self antigen/MHC undergo apoptosis (negative selection), a
process ensuring that these potentially dangerous autoreactive T cells do not reach the periphery.
Thymocytes expressing TCR with absent or low avidity for self antigen/MHC enter a default
apoptosis pathway that has been termed ‘death by neglect’, whereras those thymocytes expressing
TCR with moderate avidity for self antigen/MHC are rescued and differentiate into mature T cells that
migrate to the periphery (positive selection). Until now, the molecular mechanisms underlying the
rescue of thymocytes with moderate avidity and the death of thymocytes with high avidity for self
antigen/MHC are not known. Recently, it has been suggested that glucocorticoid hormones (GC)
influence these processes. It has long been known that developing T cells can be induced to undergo
apoptosis by GC. Conversely, removal of endogenous GC by adrenalectomy leads to hypertrophy of
the thymus. Although both these effects are known for decades, their physiological relevance for T
cell development and selection remains unclear. Interestingly, it has recently been shown that the
thymus itself produces GC that can induce apoptosis at physiological levels. Despite intensive
research, the mechanism by which GC induce cell death remains largely unknown. A physiological
role of GC in T-cell development and selection is implied by the observation that TCR and
glucocorticoid receptor (GR) signalling demonstrate crosstalk. Thus, GC can affect TCR signalling
and may affect the selection window of developing thymocytes. In this way, aberrant GR signalling
might contribute to the pathogenesis of autoimmune diseases. In support of this, resistance of
thymocytes against GC-induced apoptosis has been reported in several animal models of
autoimmune diseases. To shed more light on the role of GC in thymocyte development and selection
we work on the following questions:
1. How do GC- and TCR-induced thymocyte apoptosis interact?
2. What is the molecular background of thymocyte resistance to GC-induced apoptosis in animal
models of autoimmune diseases?
3. Which role do thymus-derived GC play in T-cell development?
4. What factors determine sensitivity to GC-induced apoptosis in immature vs. mature thymocytes?
Major achievements
Glucocorticoids enhance thymocyte development at the double-negative (DN) level
Ongoing projects and future goals
Glucocorticoids and T cell development, GC and regulatory T cells, GC and thymic involution
CD4 + CD8 +
Isotype FITC
CD4 + CD8 +
GR-FITC
CD8 +
Isotype FITC
Falus A Department of Genetics, Cell- and Immunobiology
(earlier Department of Biology) at Semmelweis University,
Budapest; Reul JM Laboratories of Integrative
Neuroscience and Endocrinology (LINE), University of
Bristol, UK; Boyd RL Department of Immunology, Monash
University, Clayton, Victoria, Australia
GR
expression
does not correlate
with sensitivity to
GC-induced apoptosis of thymocytes: CD4+ CD8+
TCR-low thymocytes that are most
sensitive to GCinduced cell death
express the least
GR.
Thymocytes
were treated with
the GC corticosterone (1 M) and
apoptosis was determined after 20h.
In parallel experiments, thymo-cytes
were
surfa-cestained for CD4,
CD8, TCR and
intracellularly for either GR or Bcl-2.
Confocal laser microscopical analysis of GR in thymocytes.
Thymocytes
were
stained for CD4, CD8
and GR, washed and
mounted with Mowi-ol.
Isotype control and
GR stained thymocytes were mixed 1:1.
69
70
din
a4
the future
architects innsbruck
The New Biocenter 2011
A joint project between the University of Innsbruck and the Innsbruck Medical University
The New Biocenter 2011
On September 19, 2008, the foundation ceremony of the new research
building was held by federal minister Johannes Hahn, rector Karlheinz
Töchterle (University of Innsbruck), vice rector Manfred Dierich (Innsbruck Medical University) and Lukas A. Huber (director, Biocenter). The
facility, into which also the Biocenter will be incorporated, will comprise
35.000 sqm of laboratories, offices and lecture rooms, its building costs
amounting to 75 million Euros. By 2011, the new Biocenter is expected
to start full operation. As the minister said, this facility will be a landmark
for the life sciences in western Austria.
din
a4 71
architects innsbruck
72
This report has been designed and edited by Siegfried Schwarz, by order of the department conference of THE BIOCENTER and with the help of Peter Loidl and
Lukas A. Huber. The contents are based on informations provided by the directors and group leaders of the BIOCENTER. Gregor Retti is thanked for elaborating data
on publications and funds.
The logo of the BIOCENTER (to the left) was created by Siegfried Schwarz. Printed by Egger-Druck Imst/Tyrol, 2010.

Report 2008

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