Secretory clusterin (sCLU) is a hallmark sensor of DNA damage, cell stress, and cellular senescence: Evidence for similar regulation of sCLU expression after cellular stress and replicative senescence

Masatoshi Suzuki, Eva C. Goetz, Giorgio Veneziano, Bhavani Shankar, Yonglong Zou, Julio Morales, David A. Boothman

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

As the molecular processes in signal transduction during cell stress and senescence (aging), and cancer progression are elucidated, it is clear that certain elements are common amongst these cellular events. Our working hypothesis is that specific cell stress processes activated during the stress of cellular replicative senescence become permanently expressed during early carcinogenic initiation events. Many of these responses to stress are pro-survival and are important to understand. Our data strongly suggest that the signal transduction processes involved in induction of secretory clusterin (sCLU) expression after ionizing radiation (IR) exposure and during cellular replicative senescence are identical. This pathway involves the formation of DNA double-strand breaks and activation of ataxia telengiectasia mutated (ATM). ATM, in turn, stimulates production of insulin-like growth factor (IGF)-1 ligand synthesis by an unknown mechanism. Increased IGF-1 then activates the IGF-1R/c-Src/MAPK/Egr-1 pathway and promotes Egr-1 binding to the CLU promoter to induce expression. The induction of sCLU is complicated by the presence of an inhibitory process involving p53. By elucidating the molecular events and signal transduction in the induction of sCLU, during cell stress (e.g., low-dose IR exposure), replicative senescence, and tumorigenesis, we theorize that we have found a common stress response pathway.

Original languageEnglish (US)
Pages (from-to)150-157
Number of pages8
JournalInternational Congress Series
Volume1299
DOIs
StatePublished - Feb 1 2007

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Keywords

  • ATM
  • Cellular senescence
  • Clusterin
  • Ionizing radiation
  • Src/MAPK/Egr-1

ASJC Scopus subject areas

  • Medicine(all)

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