Research Interests
1. Signaling-mediated regulation of gene expression via DNA methylation (Funding: Charité and Deutsche Krebshilfe)
Suppression of tumorsuppressor genes by DNA methylation is an early event during human tumorigenesis. In addition,
tumors are characterized by the activation of mitogenic and anti-apoptotic signaling pathways. Using high-throughput
transcriptomic approaches in RAS oncogene-transformed cells, we identified genes whose expression is governed by a
cross-talk between DNA methyltransferase activity and MEK/ERK signaling (Lund et al 2006). These observations suggest
that signaling cascades induce primary gene suppression and might further target DNA methyltransferases towards specific
promoters to strengthen gene suppression via DNA methylation. Several immune-modulatory genes are found among the genes
suppressed through a concerted action of DNA methylation and signaling cascades. Such genes have been shown to be inactivated
through DNA methylation during tumor development. These results connect earlier observations on the suppression of immune
regulatory genes with novel data on DNA methylation as a potential read-out of activated signaling cascades.
2. Mechanisms of gene regulation via activated mitogenic signaling cascades (Funding: SFB618, Deutsche Forschungsgemeinschaft)
In the course of SFB 618, ("Robustheit, Modularität und evolutionäres Design lebender Systeme”) project A1, we investigate the mechanisms of gene regulation
through activated MEK/ERK signaling cascades. We identified genes differentially regulated via the MEK signaling cascades in several cell systems and set out
to identify targets of individual transcription factors using transcription factor motif prediction. The role of individual transcription factors in gene
activation and repression is now investigated using a combination of siRNA mediated knock-down, transcriptome analysis and chromatin immunoprecipitation on
chip (ChIP-chip). For an improved prediction of transcription factor binding in a certain biological contex, we will use a combination of cell- and
molecular-biological methods with mathematical modeling.
3. Signaling networks: application of an integrated approach consisting of proteom- and transcriptome analysis to improve our understanding of signaling
plasticity during therapy (Funding: IBB)
The aim of this project is a combined phospho-proteome-transcriptome analysis investigating the role of clinically relevant signaling pathways such as PI3K,
JAK-STAT, MEK-ERK, Wnt, in therapy response. These interconnected pathways become constitutively active in most human neoplasias and can nowadays be inactivated
directly or indirectly through diverse inhibitors. However, in many cases either non-responsiveness is observed or adaptive processes via mutational or epigentic
mechanisms occur over time. Within this project, the effects of several inhibitors onto cell lines derived from human colon, breast or ovarian carcinomas will be
analysed at the level of the phospho-proteome and the transcriptome. These experiments are expected to provide novel insights into the mechanisms of signaling
inhibitor action and also to unravel previously undetected signaling network structures.
4. Genexpression and DNA methylation: an integrated approach consisting of transcriptome and methylation analysis for an improved understanding of chemotherapy resistance (Funding: Epigenomics; )
This is a pilot study performed in a collaboration between the Berlin-based Epigenomics AG and the Institute of Pathology, Chartié by C. Sers and M. Dietel
(Head of the Institute of Pathology). Within the last couple of years it was recognized that epigenetic alterations play an important role in chemotherapy resistance.
For the current project we made use of several cell culture models developed within the Institute of Pathology and reflecting the resistance of tumor cell lines against
Taxans or DNA intercalating substances (Platinum derivatives, Novantrone). In the current project we perform high-throughput transcriptome analyses to identify genes
differentially expressed between therapy-sensitive and therapy-resistant cells. At the same time, Epigenomics will perform a similar analysis on Differential Methylation
microarrays to investigate genes or loci differentially methylated between therapy-sensitive and therapy-resistant cells. This combined analysis aims to test the potential
application of high-throughput DNA methylation arrays, but in addition will also identify target genes, which might characterize distinct types of chemotherapy resistance.
Publications
2005 - 2007
Aurelia Noske, Carsten Denkert, Hagen Schober, Christine Sers, Bakhyt Zhumabayeva, Wilko Weichert, Manfred Dietel, Kai Wiechen (2005)
Loss of gelsolin expression in human ovarian carcinomas
Eur. J. Cancer 41:461-469
Dahl E, Sadr-Nabavi A, Klopocki E, Betz B, Grube S, Kreutzfeld R, Himmelfarb M, An HX, Gelling S, Klaman I, Hinzmann B, Kristiansen G, Grutzmann R, Kuner R, Petschke B, Rhiem K, Wiechen K, Sers C, Wiestler O, Schneider A, Hofler H, Nahrig J, Dietel M, Schafer R, Rosenthal A, Schmutzler R, Durst M, Meindl A, Niederacher D. (2005)
Systematic identification and molecular characterization of genes differentially expressed in breast and ovarian cancer
J. Pathol. 205:21-28
Kristina Lotz, Tobias Kellner, Michaela Heitmann, Irina Nazarenko, Anastassia Malek, Aurelia Noske, Artur Gontarewicz, Reinhold Schäfer and Christine Sers (2005)
Suppression of the TIG3 Tumorsuppressor Gene in Human Ovarian Carcinomas is mediated via Mitogen-activated Kinase-dependent and independent Mechanisms
Int J Cancer. 116: 894-902
Oliver Raudies, Ralf-Jürgen Kuban, Frank Hamacher, Ludger Klein-Hitpass, Oleg. I Tchernitsa, Christine Sers, Hans-Peter Herzel, Reinhold Schäfer (2005)
Functional analysis and secondary profiling of candidate genes deregulated in conjunction with oncogenic Ras signaling
Adv Enzyme Regul. 45:63-84
Raphaela Guenther, Lars Morawietz, Anja Dankof, Ingo Melcher, Klaus-Dieter Schaser, Hans-Udo Kasper, Ralf-Jürgen Kuban, Ute Ungethüm, Veit Krenn, Christine Sers (2005)
Giant cell tumors of bone: molecular profiling and description of Ephrin A1-Receptor, Claudin 7, CD52, FGFR3 and AMFR
Pathol Res Pract. 201:649-63
Per Lund, Karen Weißhaupt, Thomas Mikeska, Diana Jammas, Xiahua Chen, Ralf-Jürgen Kuban, Ute Ungethüm, Ulf Krapfenbauer, Hans-Peter Herzel, Reinhold Schäfer, Jörn Walter, Christine Sers (2006)
Oncogenic HRAS suppresses Clusterin and MMP2 expression through epigenetic modification
Oncogene, 25:4890-903
Irina Nazarenko, Glen Kristiansen, Yu Yongwei, Cornelia Gieseler, Karsten Schlüns, Reinhold Schäfer, Iver Petersen and Christine Sers (2006)
Cytoplasmic versus nuclear localization of the H-REV107-1 proteins is of prognostic value in non-small cell lung cancer
Am. Journal of Pathology, 169(4):1427-39
Oleg. I. Tchernitsa, Christine Sers, Anita Geflitter and Reinhold Schäfer (2006)
Oligonucleotide microarrays for studying the effects of Ras signal transduction on the genetic program
Signal Transduction 6, 209-218
Aurelia Noske, Wilko Weichert, Christine Sers, Silvia Niesporek, Ines Koch, Jalid Sehouli, Manfred Dietel, Steffen Hauptmann, Carsten Denkert (2007)
Specific inhibition of AKT2 by RNA interference results in reduction of ovarian cancer cell proliferation – increased expression of AKT in advanced ovarian cancer
Cancer Letters, 8; 246(1-2):190-200
Reinhold Schäfer, Oleg. I Tchernitsa, Balazs Györffy, Violeta Serra, Rula Abdul-Ghani, Per Lund and Christine Sers (2007)
Functional transcriptomics: An experimental basis for understanding the systems biology for cancer cells.
Advances in Enzyme Regulation 47, in press
Irina Nazarenko, Reinhold Schäfer, Christine Sers (2007)
The tumor suppressor H-REV107-1 induces apoptosis in ovarian carcinoma cells via negative regulation of PP2A
J Cell Science, in press
Yuan Chen, Fei Ye , Manuela Pacyna-Gengelbach, Thomas Knösel, Nicole Deutschmann, Per Lund, Christine Sers, Hiroaki Yasumoto , Tsuguru Usui and Iver Petersen (2007)
Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) has a potential tumor- suppressive activity in human lung cancer
J. Pathology, 18;211(4):431-438
2000 - 2005
Agnes Schwieger, Jörg Hanusch, Christine Sers, Reinhold Schäfer & Georg Bauer (2000)
Oncogenic transformation increases the sensitivity for apoptosis induction by inhibitors of macromolecular synthesis
International Journal of Oncolology 17, 89-95
Hanspeter Herzel, Dieter Beule, Szymon Kielbasa, Jan Korbel, Christine Sers, Arif Malik, Holger Eickhoff, Hans Lehrach, Johannes Schuchhardt (2001)
Extracting Information from cDNA Arrays
CHAOS 11 (1), 1-10
Kai Wiechen, Christine Sers, Manfred Dietel, Peter M. Schlag and Ulrike Schneider (2001)
Down-regulation of Caveolin-1, a candidate tumor suppressor gene, in sarcomas
American Journal of Pathology 158, 833-839
Agnes Schwieger, Lilian Bauer, Jörg Hanusch, Christine Sers, Reinhold Schäfer and Georg Bauer (2001)
RAS oncogene expression determines sensitivity for intercellular induction of apoptosis
Carcinogenesis 22, 1385-1392
Kai Wiechen, Luda Diatchenko, Alexander Agoulnik, Bakhyt Zhumabayeva, Sejal Desai, Sai Htun, K. Michael Scharff, Karim Hyder, Paul D. Siebert, Manfred Dietel, Reinhold Schäfer and Christine Sers (2001)
Caveolin-1 is down-regulated in human ovarian carcinomas and acts as a candidate tumor suppressor gene
American Journal of Pathology 159, 1635-1643
Stefanie Heigold, Christine Sers, Wibke Bechtel, Boris Ivanovas, Reinhold Schäfer and Georg Bauer (2002)
Nitric Oxide mediates apoptosis induction selectively in transformed fibroblasts
Carcinogenesis 23, 929-941
Christine Sers, Luda Diatchenko, Oleg I. Tchernitsa, Johannes Zuber, Kai Wiechen, Alexander Agoulnik, Bakhyt Zhumabayeva, Sejal Desai, Sai Htun, K.Michael Scharff, Karim Hyder, Paul D. Siebert and Reinhold Schäfer (2002)
Gene expression profiling in solid tumors and oncogene-transformed cell lines using subtractive suppression hybridization and cDNA arrays
Adv. Enzyme Reg. 42, 63-82
Christine Sers, Knut Husmann, Irina Nazarenko, Steffen Reich, Bakhyt Zhumabayeva, Punam Adhikari, Katharina Schroeder, Artur Gontarewicz, and Reinhold Schäfer (2002)
The classII tumorsuppressor gene H-REV107-1 is a target of interferon-regulatory factor 1 and is involved in IFN?-induced cell death in human ovarian carinoma cells
Oncogene 21, 2829-2839
Manik Chatterjee, Dirk Hönemann, Suzanne Lentzsch, Kurt Bommert, Christine Sers, Pia Hermann, Bernd Dörken and Ralf C. Bargou (2002)
In the presence of bone marrow stromal cells human multiple myeloma cells become independent of the Il-6/gp130/STAT3 pathway
Blood 100, 3311-3318
Orhan Sezer, Ulrike Heider, Christian Jakob, Ivana Zavrski, Jan Eucker, Christine Sers, Veit Krenn, Kurt Possinger (2002)
Immunocytochemistry reveals RANKL expression of myeloma cells.
(Letter to the Editor) Blood 99, 4646-4647
T Gehrke, C. Sers, L. Morawietz, G. Fernahl, J. Neidel, L. Frommelt and V. Krenn (2003)
RANKL is expressed in resident and inflammatory cells of the periprosthetic membrane of aseptically and septically loosened prostheses
Scand. J. Rheumatol. 32:287-294
Reinhold Schäfer, Oleg, I. Tchernitsa, Johannes Zuber, Christine Sers (2003)
Dissection of signal-regulated transcriptional modules by signaling pathway interference in oncogene-transformed cells
Adv. Enzyme Regul. 43:379-391
Glen Kristiansen, Yuan Yu, Karsten Schluens, Christine Sers, Manfred Dietel, Iver Petersen (2003)
Expression of the cell adhesion molecule CD146/MCAM in non-small cell lung cancer
Anal Cell Pathol. 25:77-81
Oleg I. Tchernitsa, Christine Sers, Johannes Zuber, Bernd Hinzmann, Martin Grips, Martin Hellriegel, André Rosenthal and Reinhold Schäfer (2004)
The transcriptional basis of KRAS-mediated cellular transformation in ovarian epithelial cells
Oncogene 23: 4536-4555
Reviews
Szymon Kielbasa, Nils Bluethgen, Christine Sers, Reinhold Schäfer, Hanspeter Herzel (2004)
Prediction of cis-regulatory elements of coregulated genes
Genome Inform Ser Workshop Genome Inform. 15:117-124
Manfred Dietel, Christine Sers (2006)
Personalized Medicine and Development of Targeted Therapies: The Upcoming Challenge for Diagnostic Molecular Pathology
Virchows Archiv, 448(6):744-55
Book chapters
Jürgen M. Lehmann, Christine Sers, Gert Riethmüller and Judith P. Johnson
cDNA cloning of two closely related melanoma glycoproteins: MUC18, a marker for tumor progression and MUC18rep, a new member of the immunoglobulin superfamily in Human Tumor Antigens and Specific Tumor Therapy
Alan R. Liss Inc (1989) pages 45-52
Reinhold Schäfer und Christine Sers
Molekulare Medizin. Grundlagen, Pathomechanismen, Klinik
3.9 Signalübertragung (167-168)
Walter de Gruyter 2000
Reinhold Schäfer, Oleg Tchernitsa and Christine Sers
Proteins and Cell Regulation:
Global effects of Ras signaling on the genetic program in mammalian cells.
Springer/Kluwer, in press 2006
Tchernitsa, O.I., Sers, C., Geflitter, A. and Schäfer, R.
Regulators and Effectors of small GTPases: Ras family Effects of Ras signaling on gene expression analyzed by customized microarrays.
Methods in Enzymology, vol. 407, Chapter 31, in press 2006
Reinhold Schäfer, Anja Schramme, Oleg I. Tchernitsa and Christine Sers
Oncogenic signaling pathways and deregulated target genes. In: Targeted Therapies in Cancer
Recent Results in Cancer Research, Springer, in press 2007
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PD
Dr. Christine Sers
