Weak p53 permits senescence during cell cycle arrest.
Cell cycle arrest coupled with hyper-active mTOR leads to cellular senescence. While arresting cell cycle, high levels of p53 can inhibit mTOR (in some cell lines), thus causing reversible quiescence instead of senescence. Nutlin-3a-induced p53 inhibited mTOR and thus caused quiescence in WI-38 cells. In contrast, while arresting cell cycle, the DNA-damaging drug doxorubicin (DOX) did not inhibit mTOR and caused senescence. Super-induction of p53 by either nutlin-3a or high concentrations of DOX (high-DOX) prevented low-DOX-induced senescence, converting it into quiescence. This explains why in order to cause senescence, DNA damaging drugs must be used at low concentrations, which arrest cell cycle but do not induce p53 at levels sufficient to suppress mTOR. Noteworthy, very prolonged treatment with nutlin-3a also caused senescence preventable by rapamycin. In RPE cells, low concentrations of nutlin-3a caused a semi-senescent morphology. Higher concentrations of nutlin-3a inhibited mTOR and caused quiescent morphology. We conclude that low p53 levels during prolonged cell cycle arrest tend to cause senescence, whereas high levels of p53 tend to cause either quiescence or cell death.
Roswell Park Cancer Institute, Buffalo, NY, USA.
Olga V
OV
Leontieva
Andrei V
AV
Gudkov
Mikhail V
MV
Blagosklonny
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002460:Cell Line; D016922:Cellular Senescence; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D004317:Doxorubicin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases