Paradoxical suppression of cellular senescence by p53.
The tumor suppressor p53 is a canonical inducer of cellular senescence (irreversible loss of proliferative potential and senescent morphology). p53 can also cause reversible arrest without senescent morphology, which has usually been interpreted as failure of p53 to induce senescence. Here we demonstrate that p53-induced quiescence actually results from suppression of senescence by p53. In previous studies, suppression of senescence by p53 was masked by p53-induced cell cycle arrest. Here, we separated these two activities by inducing senescence through overexpression of p21 and then testing the effect of p53 on senescence. We found that in p21-arrested cells, p53 converted senescence into quiescence. Suppression of senescence by p53 required its transactivation function. Like rapamycin, which is known to suppress senescence, p53 inhibited the mTOR pathway. We suggest that, while inducing cell cycle arrest, p53 may simultaneously suppress the senescence program, thus causing quiescence and that suppression of senescence and induction of cell cycle arrest are distinct functions of p53. Thus, in spite of its ability to induce cell cycle arrest, p53 can act as a suppressor of cellular senescence.
Demidenko
Zoya N
ZN
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Korotchkina
Lioubov G
LG
Gudkov
Andrei V
AV
Blagosklonny
Mikhail V
MV
D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases
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