Raf-1 addiction in Ras-induced skin carcinogenesis.
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.
Ehrenreiter
Karin
K
Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.
Kern
Florian
F
Velamoor
Vanishree
V
Meissl
Katrin
K
Galabova-Kovacs
Gergana
G
Sibilia
Maria
M
Baccarini
Manuela
M
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
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