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Escape from premature senescence is not sufficient for oncogenic transformation by Ras

D S Peeper1, J H Dannenberg, S Douma

  • 1Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Nature Cell Biology
|February 15, 2001
PubMed

Insights

Oncogenic Ras normally triggers cell cycle arrest via p19ARF and p53. Loss of Rb and p107 proteins bypasses this arrest, but surprisingly, does not lead to cancer, uncoupling senescence from transformation.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • Oncogenic Ras proteins initiate cellular transformation, typically halted by replicative growth arrest resembling senescence.
  • This Ras-induced senescence is dependent on the tumor suppressor proteins p19ARF (alternative reading frame) and p53.
  • Mutations in p19ARF or p53 allow Ras to overcome senescence and drive oncogenic transformation.

Purpose of the Study:

  • To investigate the role of Retinoblastoma protein (Rb) and p107 in Ras-induced replicative arrest and senescence.
  • To determine if the loss of Rb and p107 function affects Ras-mediated oncogenic transformation.
  • To elucidate the relationship between escaping Ras-induced senescence and oncogenic transformation.

Main Methods:

  • Utilized knockout mouse embryonic fibroblasts lacking both Rb and p107 genes (Rb-/-/p107-/-).
  • Expressed oncogenic Ras in these cells and analyzed proliferation, senescence markers, and anchorage-independent growth.
  • Assessed tumor formation in vivo using Ras-expressing Rb-/-/p107-/- fibroblasts.

Main Results:

  • Simultaneous deletion of Rb and p107 disrupted Ras-induced senescence, leading to unrestrained cell proliferation.
  • This proliferation occurred despite the activation of the p19ARF/p53 pathway by Ras.
  • Ras-expressing Rb-/-/p107-/- fibroblasts failed to exhibit anchorage-independent growth in vitro and were not tumorigenic in vivo.

Conclusions:

  • Rb and p107 are essential mediators of the antiproliferative signals triggered by the p19ARF/p53 pathway in response to oncogenic Ras.
  • Loss of Rb and p107 function confers resistance to Ras-induced premature senescence but does not promote oncogenic transformation.
  • These findings decouple the escape from Ras-induced senescence from the process of oncogenic transformation.

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