Abstract
Downstream factors that regulate the decision between senescence and cell death have not been elucidated. Cells undergo senescence through three pathways, replicative senescence (RS), stress-induced premature senescence (SIPS) and oncogene-induced senescence. Recent studies suggest that the ataxia telangiectasia mutant (ATM) kinase is not only a key protein mediating cellular responses to DNA damage, but also regulates cellular senescence induced by telomere end exposure (in RS) or persistent DNA damage (in SIPS). Here, we show that expression of secretory clusterin (sCLU), a known pro-survival extracellular chaperone, is transcriptionally up-regulated during both RS and SIPS, but not in oncogene-induced senescence, consistent with a DNA damage-inducible mechanism. We demonstrate that ATM plays an important role in insulin-like growth factor 1 (IGF-1) expression, that in turn, regulates downstream sCLU induction during senescence. Loss of ATM activity, either by genomic mutation (ATM-deficient fibroblasts from an ataxia telangiectasia patient) or by administration of a chemical inhibitor (AAI, an inhibitor of ATM and ATR), blocks IGF-1-sCLU expression in senescent cells. Downstream, sCLU induction during senescence is mediated by IGF-1R/MAPK/Egr-1 signaling, identical to its induction after DNA damage. In contrast, administration of an IGF-1 inhibitor caused apoptosis of senescent cells. Thus, IGF-1 signaling is required for survival, whereas sCLU appears to protect cells from premature senescence, as IMR-90 cells with sCLU knockdown undergo senescence faster than control cells. Thus, the ATM-IGF-1-sCLU pathway protects cells from lethality and suspends senescence.
Highlights
Senescence has long been considered an important tumor suppression mechanism
To generate cells at different ages and stimulate stress-induced premature senescence (SIPS), human normal diploid IMR-90 lung fibroblasts were continually cultured under 20% O2
This is consistent with prior findings in the literature showing that secretory clusterin (sCLU) was induced in WI38 cells during Replicative senescence (RS) or after H2O2-induced SIPS [19,21]
Summary
Senescence has long been considered an important tumor suppression mechanism. Cellular senescence is a terminal state in which cells undergo permanent growth arrest accompanied by morphological changes, e.g., an enlarged and flattened cell shape. Cells can undergo senescence through three separate pathways [1,2]: (i) Replicative senescence (RS), induced through shortening of telomeres as a result of chromosome replication; (ii) Stress induced-premature senescence (SIPS), induced by cellular stress, such as elevated oxygen levels or cytotoxic agents causing extensive DNA damage; and (iii) over-expression or hyperactivation of oncogenes, such as Ras, c-myc, or BRAF, whose mechanisms of senescence induction are poorly understood. Most cell stressors that induce SIPS are DNA damage-inducing agents, such as growth in elevated oxygen, exposure to ionizing radiation (IR), and treatment with drugs that generate DSBs [14,15,16,17,18,19] All of these agents can activate ATM, which appears to be an important mediator of SIPS [15,17]. We speculate that accumulation of IGF1 and sCLU in the media of an aging microenvironment of specific tissues could contribute to tumor promotion
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