The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway

Aging (Albany NY). 2010 Jun;2(6):344-52. doi: 10.18632/aging.100160.

Abstract

Transient induction of p53 can cause reversible quiescence and irreversible senescence. Using nutlin-3a (a small molecule that activates p53 without causing DNA damage), we have previously identified cell lines in which nutlin-3a caused quiescence. Importantly, nutlin-3a caused quiescence by actively suppressing the senescence program (while still causing cell cycle arrest). Noteworthy, in these cells nutlin-3a inhibited the mTOR (mammalian Target of Rapamycin) pathway, which is known to be involved in the senescence program. Here we showed that shRNA-mediated knockdown of TSC2, a negative regulator of mTOR, partially converted quiescence into senescence in these nutlin-arrested cells. In accord, in melanoma cell lines and mouse embryo fibroblasts, which easily undergo senescence in response to p53 activation, nutlin-3a failed to inhibit mTOR. In these senescence-prone cells, the mTOR inhibitor rapamycin converted nutlin-3a-induced senescence into quiescence. We conclude that status of the mTOR pathway can determine, at least in part, the choice between senescence and quiescence in p53-arrested cells.

MeSH terms

  • Animals
  • Cellular Senescence / drug effects
  • Cellular Senescence / physiology*
  • Gene Knockdown Techniques
  • Humans
  • Imidazoles / pharmacology
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Piperazines / pharmacology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Imidazoles
  • Intracellular Signaling Peptides and Proteins
  • Piperazines
  • Tumor Suppressor Protein p53
  • nutlin 3
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases