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ATM regulates insulin-like growth factor 1-secretory clusterin (IGF-1-sCLU) expression that protects cells against senescence.

Luo X, Suzuki M, Ghandhi SA, Amundson SA, Boothman DA - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

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A model of the signaling pathway that mediates sCLU induction during senescence showing the role of sCLU in senescence compared to IGF-1/IGF-1R signaling required to prevent apoptosis.AAI and AG1024 are small molecule chemical inhibitors that inhibit ATM and ATR, and IGF-1 tyrosine kinase receptor (IGF-1R), respectively.
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pone-0099983-g006: A model of the signaling pathway that mediates sCLU induction during senescence showing the role of sCLU in senescence compared to IGF-1/IGF-1R signaling required to prevent apoptosis.AAI and AG1024 are small molecule chemical inhibitors that inhibit ATM and ATR, and IGF-1 tyrosine kinase receptor (IGF-1R), respectively.

Mentions: Here, we show that sCLU is up-regulated at a transcription level during both RS and SIPS, but is not elevated in response to oncogene-induced senescence. This is consistent with prior findings in the literature showing that sCLU was induced in WI-38 cells during RS or after H2O2-induced SIPS [19], [21]. Mechanistically, we also demonstrated that sCLU was induced during senescence through the ATM/IGF-1/IGF-1R/MAPK/Erk-1/2/Egr-1 signaling pathway, a pathway that is also stimulated and regulates sCLU induction during DDR (Figure 6). These results support the observation that cellular senescence processes share significant overlap with DDR pathways. And many key factors (e.g., ATM, p53, p21) that are involved in the DDR in human cells also play important roles in cellular senescence responses.


ATM regulates insulin-like growth factor 1-secretory clusterin (IGF-1-sCLU) expression that protects cells against senescence.

Luo X, Suzuki M, Ghandhi SA, Amundson SA, Boothman DA - PLoS ONE (2014)

A model of the signaling pathway that mediates sCLU induction during senescence showing the role of sCLU in senescence compared to IGF-1/IGF-1R signaling required to prevent apoptosis.AAI and AG1024 are small molecule chemical inhibitors that inhibit ATM and ATR, and IGF-1 tyrosine kinase receptor (IGF-1R), respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061041&req=5

pone-0099983-g006: A model of the signaling pathway that mediates sCLU induction during senescence showing the role of sCLU in senescence compared to IGF-1/IGF-1R signaling required to prevent apoptosis.AAI and AG1024 are small molecule chemical inhibitors that inhibit ATM and ATR, and IGF-1 tyrosine kinase receptor (IGF-1R), respectively.
Mentions: Here, we show that sCLU is up-regulated at a transcription level during both RS and SIPS, but is not elevated in response to oncogene-induced senescence. This is consistent with prior findings in the literature showing that sCLU was induced in WI-38 cells during RS or after H2O2-induced SIPS [19], [21]. Mechanistically, we also demonstrated that sCLU was induced during senescence through the ATM/IGF-1/IGF-1R/MAPK/Erk-1/2/Egr-1 signaling pathway, a pathway that is also stimulated and regulates sCLU induction during DDR (Figure 6). These results support the observation that cellular senescence processes share significant overlap with DDR pathways. And many key factors (e.g., ATM, p53, p21) that are involved in the DDR in human cells also play important roles in cellular senescence responses.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus