title: ATM regulates insulin-like growth factor 1-secretory clusterin (IGF-1-sCLU) expression that protects cells against senescence.
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.
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Laboratory of Molecular Cell Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Xiuquan
authors.initials: X
authors.lastname: Luo
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Laboratory of Molecular Cell Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Shanaz A
authors.initials: SA
authors.lastname: Ghandhi
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Amundson
authors.affiliation: Departments of Pharmacology and Radiation Oncology, Laboratory of Molecular Cell Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology*; D002460:Cell Line; D016922:Cellular Senescence; D051152:Clusterin / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D020935:MAP Kinase Signaling System; D013312:Stress, Physiological; D015533:Transcriptional Activation
chemical_list: C495242:CLU protein, human; D051152:Clusterin; D007334:Insulin-Like Growth Factor I; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins