"C-Raf kontrollierte Signalwege zum Schutz der Tumorzelle vor Apoptose"

Die Serin-Threonin Kinase c-Raf spielt sowohl in der Kontrolle der Proliferation als auch in der Kontrolle der Apoptose in malignen Tumoren eine Schlüsselrolle. Ziel dieser Arbeit war es, Signalwege zu identifizieren, die für den Schutz vor Apoptose verantwortlich sind. Dazu wurden verschiedene Tum...

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Bibliographic Details
Main Author: Stübig, Thomas
Contributors: Müller, Rolf (Prof. Dr. ) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2007
Online Access:PDF Full Text
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The serine / threonine kinase, c-Raf, plays an essential role in the control of proliferation and survival in many human malignant tumors. The aim of this work was to detect mechanisms by which c-Raf controls the apoptotic pathways. By using specific antisense oligo-nucleotides (AS-ODN) and “small interfering RNA“ (siRNA) for gene knockdown experiments, the c-Raf mRNA levels were reduced. These effects were reproduced by using a c-Raf Inhibitor BAY 43-9006. As suspected, the fraction of apoptotic cells increased and interestingly, simultaneously, the mRNA levels of different epidermal growth factor receptor (EGF-Receptor) ligands decreased. To confirm that stimulation of the EGF-receptor is critical for cell survival, the different cell lines were treated with an EGF-receptor blocker. As expected the fraction of apoptotic cells increased again. These data suggest an autocrine loop of the EGF-receptor ligand controlled by c-Raf. To identify other signalling pathways which are involved in c-Raf mediated protection of apoptosis, cDNA array experiments were performed. Surprisingly, it could be shown that the tumor necrosis factor receptor 1 (TNF-R1) is also transcriptionally controlled by c-Raf, suggesting crosstalk between the classical Ras-Raf-MEK-Erk pathway and TNF-receptor signalling in tumour cells to escape apoptosis. This work supports the significance of c-Raf in the control of apoptosis and suggests two mechanisms as an explanation: an auotocrine EGF-receptor ligand loop and regulation of the TNFreceptor.