title: C-Raf controlled pathways in the protection of tumor cells from apoptosis.
abstract: The Raf serine-threonine kinase is upregulated in many human tumors and plays a pivotal role in tumor cell proliferation and survival. Abrogation of c-Raf expression by specific antisense oligonucleotides (Raf-AS-ODN) efficiently blocks tumor cell growth and induces apoptosis in human cancer cells. The signaling pathways and molecular mechanisms c-Raf utilizes to mediate the survival of tumor cells are, however, not well understood. Here we show that apoptosis triggered by Raf depletion cannot be overcome by ectopic Bcl-2 expression and occurs in the absence of cytochrome c release, arguing against a direct impact of c-Raf on mitochondrial pathways of apoptosis regulation. We also show that c-Raf depletion leads to a clearly decreased expression of different epidermal growth factor (EGF) receptor ligands, suggesting that the autocrine stimulation of an EGF receptor-mediated survival pathway might be involved in the blockade of tumor cell apoptotis by c-Raf.
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT) Philipps-University, Emil-Mannkopff-Strasse 2, 35033 Marburg, Germany.
authors.forename: Emily P
authors.initials: EP
authors.lastname: Slater
authors.forename: Thomas
authors.initials: T
authors.lastname: Stübig
authors.forename: Quek Choon
authors.initials: QC
authors.lastname: Lau
authors.forename: Tatjana V
authors.initials: TV
authors.lastname: Achenbach
authors.forename: Ulf R
authors.initials: UR
authors.lastname: Rapp
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D017209:Apoptosis; D003574:Cytochrome c Group / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D009369:Neoplasms / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000235:genetics
chemical_list: D003574:Cytochrome c Group; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D016211:Transforming Growth Factor alpha; C482128:MAP2K2 protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases