Luo Xiuquan, Suzuki Masatoshi, Ghandhi Shanaz A, Amundson Sally A, Boothman David A
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.
Center for Radiological Research, Columbia University Medical Center, New York, New York, United States of America.
PLoS One. 2014 Jun 17;9(6):e99983. doi: 10.1371/journal.pone.0099983. eCollection 2014.
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.
调节衰老和细胞死亡之间抉择的下游因素尚未阐明。细胞通过三条途径进入衰老状态，即复制性衰老（RS）、应激诱导的早衰（SIPS）和癌基因诱导的衰老。最近的研究表明，共济失调毛细血管扩张症突变（ATM）激酶不仅是介导细胞对DNA损伤反应的关键蛋白，还调节由端粒末端暴露（在RS中）或持续性DNA损伤（在SIPS中）诱导的细胞衰老。在此，我们表明，分泌型簇蛋白（sCLU）是一种已知的促生存细胞外伴侣蛋白，其表达在RS和SIPS过程中均转录上调，但在癌基因诱导的衰老中则不然，这与DNA损伤诱导机制一致。我们证明，ATM在胰岛素样生长因子1（IGF-1）表达中起重要作用，而IGF-1反过来又调节衰老过程中sCLU的下游诱导。通过基因组突变（来自共济失调毛细血管扩张症患者的ATM缺陷成纤维细胞）或施用化学抑制剂（AAI，一种ATM和ATR的抑制剂）导致的ATM活性丧失，会阻断衰老细胞中IGF-1-sCLU的表达。在下游，衰老过程中sCLU的诱导由IGF-1R/MAPK/Egr-1信号介导，这与其在DNA损伤后的诱导相同。相反，施用IGF-1抑制剂会导致衰老细胞凋亡。因此，IGF-1信号是细胞存活所必需的，而sCLU似乎能保护细胞免于早衰，因为sCLU敲低的IMR-90细胞比对照细胞衰老得更快。因此，ATM-IGF-1-sCLU途径保护细胞免于死亡并延缓衰老。
