Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis

Cancer Cell. 2003 Mar;3(3):219-31. doi: 10.1016/s1535-6108(03)00030-8.

Abstract

Tumor angiogenesis is postulated to be regulated by the balance between pro- and anti-angiogenic factors. We demonstrate that the critical step in establishing the angiogenic capability of human cells is the repression of the critical anti-angiogenic factor, thrombospondin-1 (Tsp-1). This repression is essential for tumor formation by mammary epithelial cells and kidney cells engineered to express SV40 early region proteins, hTERT, and H-RasV12. We have uncovered the signaling pathway leading from Ras to Tsp-1 repression. Ras induces the sequential activation of PI3 kinase, Rho, and ROCK, leading to activation of Myc through phosphorylation; phosphorylation of Myc via this mechanism enables it to repress Tsp-1 expression. We thus describe a novel mechanism by which the cooperative activity of the oncogenes, ras and myc, leads directly to angiogenesis and tumor formation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Retracted Publication

MeSH terms

  • Cell Line
  • Cell Line, Transformed
  • Cell Transplantation
  • Endothelial Growth Factors / metabolism
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Genes, ras
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Lymphokines / metabolism
  • Models, Biological
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / physiopathology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / metabolism*
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • ras Proteins / metabolism*
  • rho GTP-Binding Proteins / metabolism
  • rho-Associated Kinases

Substances

  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lymphokines
  • Thrombospondin 1
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • ras Proteins
  • rho GTP-Binding Proteins