Modelling of signalling cascades – the impact of RAS signal transduction on transcription

Within the Collaborative Reserch Center for Theoretical Biology: Robustness, Modularity and Evolutionary Design of Living Systems (SFB 618) the mechanisms of gene regulation through activated MEK/ERK signaling cascades were investigated in the reserach area "Molecular Systems" (subproject A1, jointly with Martin Vingron).

The execution of the oncogenic program is significantly influenced by large scale transcriptional alteration downstream of the RAS oncogene. Therefore we assessed some of the most frequently altered/deregulated transcription factors in detail and used a combination of experimental and theoretical approach to gain further insight into the molecular consequences of RAS activation.

Fra1 is the only AP1 member showing significantly increased levels upon comparison of HRASv12-transformed human embryonic kidney cells (HA1ER) to their immortal counterpart, HA1EB cells. From both cells, we generated genome-wide expression profiles after Fra1-siRNA-mediated knock-down by microarray expression analysis and observed large differences in the Fra1-regulated genes between the immortal and RAS-transformed cells. Functional enrichment analysis identified transcriptional regulators as a major group of Fra1-regulated genes only in the RAS-transformed cells. We confirmed Fra1-binding to regulatory regions of several of these genes by ChIP and verified HMGA1, HMGA2, AEBP1, NPAS2 and TCFL5 to be directly regulated by Fra1. Our results suggest novel regulatory feed-back mechanisms stabilizing mitogenic signalling and AP1/Fra1-dependent transcription in transformed cells thus strongly favouring a role for Fra1 as a master transcriptional regulator in tumors. (Opens external link in current windowSFB 618),

 

Supported by: DFG (SFB 618)

05/2009 – 06/2013

Group leader

Prof. Dr. rer. nat. Christine Sers
Head of group Mol. Tumor Pathology, Head of group Tumor Systems Biology
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