title: Raf-1 addiction in Ras-induced skin carcinogenesis.
abstract: Ras activation is common to many human cancers and promotes cell proliferation and survival by initiating multiple signaling cascades. Accordingly, Ras-transformed cells are generally considered too resourceful to become addicted to a single effector. In contrast to this tenet, we now demonstrate an absolute, cell autonomous requirement for Raf-1 in the development and maintenance of Ras-induced skin epidermis tumors. Mechanistically, Raf-1 functions as an endogenous inhibitor dimming the activity of the Rho-dependent kinase Rok-alpha in the context of a Ras-induced Raf-1:Rok-alpha complex. Raf-1-induced Rok-alpha inhibition allows the phosphorylation of STAT3 and Myc expression and promotes dedifferentiation in Ras-induced tumors. These data link the Raf-1:Rok-alpha complex to STAT3/Myc activation and delineate a pathway crucial for cell fate decision in Ras-induced tumorigenesis.
authors: Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.
authors: Karin
authors: K
authors: Ehrenreiter
authors: Florian
authors: F
authors: Kern
authors: Vanishree
authors: V
authors: Velamoor
authors: Katrin
authors: K
authors: Meissl
authors: Gergana
authors: G
authors: Galabova-Kovacs
authors: Maria
authors: M
authors: Sibilia
authors: Manuela
authors: M
authors: Baccarini
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D017353:Gene Deletion; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020664:Son of Sevenless Proteins / Q000235:genetics; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; D020664:Son of Sevenless Proteins; C494087:Stat3 protein, mouse; D019908:Proto-Oncogene Proteins c-raf; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases