Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis.
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.
Watnick
Randolph S
RS
Whitehead Institute for Biomedical Research, Cambridge, MA 01242, USA.
Cheng
Yi-Ning
YN
Rangarajan
Annapoorni
A
Ince
Tan A
TA
Weinberg
Robert A
RA
D002460:Cell Line; D002461:Cell Line, Transformed; D017690:Cell Transplantation; D016228:Endothelial Growth Factors / Q000378:metabolism; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008222:Lymphokines / Q000378:metabolism; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018631:ras Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008222:Lymphokines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D054460:rho-Associated Kinases