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

Randolph S. Watnick, Yi Ning Cheng, Annapoorni Rangarajan, Tan Ince, Robert A. Weinberg

Research output: Contribution to journalArticle

277 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)219-231
Number of pages13
JournalCancer Cell
Volume3
Issue number3
DOIs
StatePublished - Mar 1 2003
Externally publishedYes

Fingerprint

Thrombospondin 1
Angiogenesis Inducing Agents
Phosphorylation
Neoplasms
myc Genes
ras Genes
Phosphatidylinositol 3-Kinases
Breast
Epithelial Cells
Kidney
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. / Watnick, Randolph S.; Cheng, Yi Ning; Rangarajan, Annapoorni; Ince, Tan; Weinberg, Robert A.

In: Cancer Cell, Vol. 3, No. 3, 01.03.2003, p. 219-231.

Research output: Contribution to journalArticle

Watnick, Randolph S. ; Cheng, Yi Ning ; Rangarajan, Annapoorni ; Ince, Tan ; Weinberg, Robert A. / Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. In: Cancer Cell. 2003 ; Vol. 3, No. 3. pp. 219-231.
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