Balance between senescence and apoptosis is regulated by telomere damage-induced association between p16 and caspase-3

The Journal of Biological Chemistry
Shanmugam Panneer SelvamBesim Ogretmen

Abstract

Telomerase activation protects cells from telomere damage by delaying senescence and inducing cell immortalization, whereas telomerase inhibition mediates rapid senescence or apoptosis. However, the cellular mechanisms that determine telomere damage-dependent senescence versus apoptosis induction are largely unknown. Here, we demonstrate that telomerase instability mediated by silencing of sphingosine kinase 2 (SPHK2) and sphingosine 1-phosphate (S1P), which binds and stabilizes telomerase, induces telomere damage-dependent caspase-3 activation and apoptosis, but not senescence, in p16-deficient lung cancer cells or tumors. These outcomes were prevented by knockdown of a tumor-suppressor protein, transcription factor 21 (TCF21), or by ectopic expression of WT human telomerase reverse transcriptase (hTERT) but not mutant hTERT with altered S1P binding. Interestingly, SphK2-deficient mice exhibited accelerated aging and telomerase instability that increased telomere damage and senescence via p16 activation especially in testes tissues, but not in apoptosis. Moreover, p16 silencing in SphK2-/- mouse embryonic fibroblasts activated caspase-3 and apoptosis without inducing senescence. Furthermore, ectopic WT p16 expression in p16-de...Continue Reading

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Citations

Mar 7, 2019·Annals of the New York Academy of Sciences·Sandro ArgüellesAntonio Ayala
Nov 10, 2020·International Journal of Biological Macromolecules·Valentina PirotaDaniela Montesarchio
Feb 27, 2021·Frontiers in Endocrinology·Yanfei QiPu Xia
May 10, 2021·Acta Neuropathologica Communications·Nicole SchwabLili-Naz Hazrati

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