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

Nat Cell Biol. 2007 May;9(5):493-505. doi: 10.1038/ncb1567. Epub 2007 Apr 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cellular Senescence* / drug effects
  • Cellular Senescence* / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Dose-Response Relationship, Drug
  • Doxycycline / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Hyperplasia
  • Mammary Glands, Animal / drug effects
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Transgenic
  • Mutation
  • Oncogene Protein p21(ras) / genetics
  • Oncogene Protein p21(ras) / metabolism*
  • Precancerous Conditions / genetics
  • Precancerous Conditions / metabolism*
  • Precancerous Conditions / pathology
  • Promoter Regions, Genetic / drug effects
  • Protein Transport
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Signal Transduction
  • Time Factors
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation


  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Tumor Suppressor Protein p53
  • ADP-Ribosylation Factors
  • Oncogene Protein p21(ras)
  • Doxycycline