4.8 Article

Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis

Journal

NATURE CELL BIOLOGY
Volume 9, Issue 5, Pages 493-U25

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1567

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Funding

  1. NCI NIH HHS [CA105490, CA92910, CA93719, CA98371] Funding Source: Medline

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Activating Ras mutations can induce either proliferation or senescence depending on the cellular context. To determine whether Ras activation has context-dependent effects in the mammary gland, we generated doxycycline- inducible transgenic mice that permit Ras activation to be titrated. 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. In contrast, high levels of Ras activation - similar to those found in tumours bearing endogenous Kras2 mutations - induce cellular senescence that is Ink4a-Arf-dependent and irreversible following Ras downregulation. Chronic low-level Ras induction results in tumour formation, but only after the spontaneous upregulation of activated Ras and evasion of senescence checkpoints. Thus, high-level, but not low-level, Ras activation activates tumour suppressor pathways and triggers an irreversible senescent growth arrest in vivo. We suggest a three-stage model for Ras-induced tumorigenesis consisting of an initial activating Ras mutation, overexpression of the activated Ras allele and, finally, evasion of p53-Ink4a-Arf-dependent senescence checkpoints.

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