4.8 Article

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

Journal

CANCER CELL
Volume 3, Issue 3, Pages 219-231

Publisher

CELL PRESS
DOI: 10.1016/S1535-6108(03)00030-8

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Funding

  1. NCI NIH HHS [5 R01 CA78461] Funding Source: Medline

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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 P13 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.

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