mTOR favors senescence over quiescence in p53-arrested cells
| Autor: | Lioubov G. Korotchkina, Elena I. Bukreeva, Andrei V. Gudkov, Zoya N. Demidenko, Olga V. Leontieva, Mikhail V. Blagosklonny |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
p53
Senescence Aging senescence Cell cycle checkpoint Protein Serine-Threonine Kinases Biology Mice 06/22/10 accepted: 06/25/10 published on line: 06/26/10 cancer Animals Cellular Senescence PI3K/AKT/mTOR pathway rapamycin TOR Serine-Threonine Kinases RPTOR Intracellular Signaling Peptides and Proteins Cell Biology Cell cycle Cell biology Cell culture Commentary mTOR Cancer research cell cycle Tumor Suppressor Protein p53 Signal transduction Cell aging Research Article Signal Transduction |
| Zdroj: | Aging (Albany NY) |
| ISSN: | 1945-4589 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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