Weak p53 permits senescence during cell cycle arrest

Abstract

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.

Aging hair follicles rejuvenated by transplantation to a young subcutaneous environment

“…24,25 High doses of doxorubicin and nutlin-3a, an inhibitor of the interaction between TP53 and its major negative regulator HDM2, promoted reversible quiescence, instead of irreversible senescence. 25,26 MTOR inhibitors, such as rapamycin, may be able to rejuvenate stem cells within the aging hair follicle, as well as restore the responsiveness of the aging stem cells to stimuli. 27 Future experiments will also focus on the role of stem cells in the aging hair follicle and pharmaceutical rejuvenation of this process, such as with rapamycin.…”

Inhibition of Glycolytic Enzymes Mediated by Pharmacologically Activated p53

“…Further, the small molecule nutlin3a also can act in a dose-dependent manner; a high dose of nutlin promotes p53-dependent inhibition of mTOR, whereas a lower dose does not (69). It is plausible that p53 posttranslational modifications and cofactors that associate with p53 can serve as the bars of the "bar code" that governs p53 transcriptional activity, thereby forming the underlying basis of the heterogeneity of p53 response, depending on the type and dose of stimuli as well as cell type (70).…”

The STAT3-IGFBP5 axis is critical for IL-6/gp130-induced premature senescence in human fibroblasts

“…[37][38][39][40][41] Therefore, in addition to the critical role of the STAT3-IGFBP5 axis in the IL-6-induced premature senescence, mTOR activity caused by serum growth factors and added IL-6 together with secreted factors during the course is likely to contribute to the premature senescence. However, our preliminary experiments showed that TIG3 cells with a chimeric receptor with truncated gp130 containing only the YRHQ motif, which activates only the STAT3 pathway without activating the ERK1/2 or PI3K/AKT/mTOR pathways, induced premature senescence in TIG3 cells at the extent comparable with that shown in IL-6/sIL-6R stimulation (unpublished data, Kojima H and Nakajima K).…”