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

Christopher J. Sarkisian, Blaine A. Keister, Douglas Stairs, Robert B. Boxer, Susan E. Moody, Lewis A. Chodosh

Research output: Contribution to journalArticle

300 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)493-505
Number of pages13
JournalNature Cell Biology
Volume9
Issue number5
DOIs
StatePublished - May 1 2007

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Sarkisian, C. J., Keister, B. A., Stairs, D., Boxer, R. B., Moody, S. E., & Chodosh, L. A. (2007). Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nature Cell Biology, 9(5), 493-505. https://doi.org/10.1038/ncb1567