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Techniques to Induce and Quantify Cellular Senescence
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Techniques to Induce and Quantify Cellular Senescence

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

Xiuquan Luo1, Masatoshi Suzuki1, Shanaz A Ghandhi2

  • 1Departments 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.

Plos One
|June 18, 2014
PubMed

Insights

The ATM-IGF-1-sCLU pathway is crucial for cell survival, preventing premature senescence and promoting cell death resistance. This pathway suspends senescence by upregulating secretory clusterin (sCLU) expression in response to DNA damage.

Area of Science:

  • Cellular senescence
  • DNA damage response
  • Molecular signaling pathways

Background:

  • The decision between cellular senescence and cell death is not fully understood.
  • Senescence can be triggered by replicative stress, DNA damage, or oncogene activation.
  • Ataxia telangiectasia mutant (ATM) kinase is vital for DNA damage response and regulates senescence.

Purpose of the Study:

  • To elucidate downstream factors regulating the senescence versus cell death decision.
  • To investigate the role of secretory clusterin (sCLU) in cellular senescence.
  • To determine the involvement of the ATM kinase and insulin-like growth factor 1 (IGF-1) in senescence.

Main Methods:

  • Studied senescence in IMR-90 cells and ATM-deficient fibroblasts.
  • Utilized chemical inhibitors for ATM/ATR (AAI) and IGF-1.
  • Analyzed gene expression and signaling pathways (IGF-1R/MAPK/Egr-1).
  • Performed sCLU knockdown experiments.

Main Results:

  • Secretory clusterin (sCLU) is upregulated in replicative senescence (RS) and stress-induced premature senescence (SIPS), but not oncogene-induced senescence.
  • ATM kinase regulates IGF-1 expression, which in turn induces sCLU during senescence.
  • The IGF-1R/MAPK/Egr-1 pathway mediates sCLU induction in senescent cells, similar to DNA damage response.
  • IGF-1 signaling is essential for senescent cell survival; IGF-1 inhibition induces apoptosis.
  • sCLU knockdown accelerates senescence, indicating a protective role against premature senescence.

Conclusions:

  • The ATM-IGF-1-sCLU signaling axis is a critical pro-survival mechanism in senescent cells.
  • This pathway protects cells from death and suspends the senescence process.
  • Understanding this pathway offers insights into cellular fate decisions and potential therapeutic targets.

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