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Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis
Randolph S Watnick1, Yi-Ning Cheng, Annapoorni Rangarajan
1Whitehead Institute for Biomedical Research, Cambridge, MA 01242, USA.
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.
Insights
Tumor formation relies on repressing thrombospondin-1 (Tsp-1), an anti-angiogenic factor. Oncogenes Ras and Myc cooperate through a novel pathway to drive angiogenesis and tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Tumor angiogenesis is regulated by pro- and anti-angiogenic factors.
- Thrombospondin-1 (Tsp-1) is a critical anti-angiogenic factor.
- Understanding the regulation of Tsp-1 is key to understanding tumor formation.
Purpose of the Study:
- To investigate the role of thrombospondin-1 (Tsp-1) repression in tumor formation.
- To uncover the signaling pathway linking Ras oncogene to Tsp-1 repression.
- To elucidate the cooperative mechanism of Ras and Myc oncogenes in driving angiogenesis.
Main Methods:
- Engineering mammary epithelial and kidney cells to express oncogenes (SV40 early region proteins, hTERT, H-RasV12).
- Investigating the signaling pathway from Ras to Tsp-1 repression, including PI3 kinase, Rho, ROCK, and Myc.
- Analyzing the phosphorylation and activation of Myc in relation to Tsp-1 expression.
Main Results:
- Repression of thrombospondin-1 (Tsp-1) is essential for tumor formation in engineered cells.
- A novel signaling pathway was identified: Ras activates PI3 kinase, Rho, and ROCK.
- This pathway leads to Myc phosphorylation and subsequent repression of Tsp-1 expression.
Conclusions:
- The cooperative action of Ras and Myc oncogenes directly promotes angiogenesis and tumor formation.
- Repression of the anti-angiogenic factor Tsp-1 is a critical step mediated by this oncogenic pathway.
- This study reveals a new mechanism linking oncogene cooperation to tumor angiogenesis.