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

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 damagedependent 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. Further, 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 proteinsforces 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.

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

“…CASP3 was significantly increased 7d post-injury, suggesting some level of apoptosis occurring at this timepoint. Although caspase 3 is thought to be inhibited by cellular senescence [ 117 ], it paradoxically increases expression with ageing and has even been suggested as an initiating factor for cellular senescence [ 152 ].…”

Zfp217 mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation

“…The protein–protein and protein–RNA interactions were measured using an OpenSPR localized surface plasmon resonance (LSPR) biosensor (Nicoya Life Science, Inc., Kitchener, Canada), as described previously (33,34). In brief, 100 μl (1 μg/μl) of Flag-YTHDF2 was immobilized on a COOH sensor chip (Nicoya # SEN-AU-100-12-COOH) at a flow rate of 20 μl/min in 1× PBS buffer (pH = 7.4, RNase-free) and 0.1% v/v Tween 20.…”

Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response

“…Interestingly, these data also suggested to us a hypothesis that there may be crosstalk between CerS6 and SphK2 expression in T cells upon aging stress ( Figure S3D ). The loss of SphK2 almost completely prevented short-chain ceramide accumulation in the MITO of T cells isolated from A compared to Y SphK2 −/− mice ( Selvam and Ogretmen, 2013 ; Panneer Selvam et al, 2018 ) ( Figure 4A ). The loss of SphK2 expression in T cells isolated from Y SphK2 −/− mice was confirmed by western blotting ( Figure 4A , inset).…”