Raf-1 addiction in Ras-induced skin carcinogenesis

Cancer Cell. 2009 Aug 4;16(2):149-60. doi: 10.1016/j.ccr.2009.06.008.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / enzymology*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Cell Differentiation
  • Cell Proliferation
  • Gene Deletion
  • Mice
  • Mice, Transgenic
  • Phosphorylation
  • Proto-Oncogene Proteins c-myc / metabolism
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins c-raf / metabolism
  • Proto-Oncogene Proteins c-raf / physiology*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Son of Sevenless Proteins / genetics
  • rho-Associated Kinases / metabolism

Substances

  • Proto-Oncogene Proteins c-myc
  • STAT3 Transcription Factor
  • Son of Sevenless Proteins
  • Stat3 protein, mouse
  • Proto-Oncogene Proteins c-raf
  • Rock2 protein, mouse
  • rho-Associated Kinases