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

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.

• Authors: Lioubov G Korotchkina, Olga V Leontieva, Elena I Bukreeva, Zoya N Demidenko, Andrei V Gudkov, Mikhail V Blagosklonny
• Journal: Aging (Aging (Albany NY)) Vol. 2 Issue 6 Pg. 344-52 (Jun 2010) ISSN: 1945-4589 [Electronic] United States
• PMID: 20606252 (Publication Type: Journal Article)

Chemical References

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

Topics

• Animals
• Cellular Senescence (drug effects, 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, physiology)
• TOR Serine-Threonine Kinases
• Tumor Suppressor Protein p53 (metabolism)