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

Shanmugam Panneer Selvam, Braden M. Roth, Rose Nganga, Jisun Kim, Marion A. Cooley, Kristi Helke, Charles D. Smith, Besim Ogretmen

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2 Scopus citations

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-deficient A549 lung cancer cells prevented TCF21 and caspase-3 activation and resulted in senescence in response to SphK2/S1P inhibition and telomere damage. Mechanistically, a p16 mutant with impaired caspase-3 association did not prevent telomere damage–induced apoptosis, indicating that an association between p16 and caspase-3 proteins forces senescence induction by inhibiting caspase-3 activation and apoptosis. These results suggest that p16 plays a direct role in telomere damage– dependent senescence by limiting apoptosis via binding to caspase-3, revealing a direct link between telomere damage– dependent senescence and apoptosis with regards to aging and cancer.

Original languageEnglish (US)
Pages (from-to)9784-9800
Number of pages17
JournalJournal of Biological Chemistry
Volume293
Issue number25
DOIs
StatePublished - Jun 22 2018

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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