Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis (Nat Cell Biol, 2007, 9:493-505)

報告日期: 2007/09/28
報告時間: 16:00/16:50
報告學生: 卓建宇
講評老師: 曾大千
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Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis

Sarkisian CJ et al. Nat Cell Biol. 2007. 9(5):493-505.

 

Speaker: 卓建宇 

Commentator: 曾大千 博士 

Time: 16:00-17:00, Sep. 28, 2007

Place: Room 602

 

Abstract:

Mutations in Ras family members promote both proliferation and tumorigenesis in mammalian cells and occur in approximately 30% of human cancers. Recently, conflicting reports have shown that oncogene activation may induce either proliferation or senescence. In the absence of cooperating oncogenic mutations, Ras induces a permanent growth arrest through the p53 and Ink4a–Arf pathways and resembles replicative senescence in cultured primary cells. The decision to undergo senescence or proliferation in response to oncogenic Ras may depend upon the intensity of Ras activation. To test this hypothesis, transgenic mice were generated that inducibly express oncogenic Ras in the mammary gland in a titratable, doxycycline-dependent manner. They observed that high-level Ras activation, similar to that found in tumours bearing activated Kras2 alleles, induces a senescent growth arrest that is Ink4aArf- dependent and irreversible following Ras downregulation in mammary epithelial cells. In contrast, low levels of Ras activation, similar to those found in non-transformed mouse tissues expressing endogenous oncogenic Kras2, stimulate cellular proliferation and mammary epithelial hyperplasias. The authers observations suggest that Ras-induced tumorigenesis requires at least three distinct oncogenic events: an initial activating Ras mutation that results in low levels of oncogene activation sufficient to stimulate proliferation; spontaneous upregulation of activated Ras to levels that are unavoidably associated with the induction of senescence; and evasion of Ink4aArf and p53-dependent senescence checkpoints that must be inactivated for tumour progression to occur.

 

Reference:

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2. Lin, A. W. & Lowe, S. W. Oncogenic ras activates the ARF–p53 pathway to suppress epithelial cell transformation. Proc. Natl Acad. Sci. USA 98, 5025–5030 (2001).