Delayed activation of insulin-like growth factor-1 receptor/Src/ MAPK/Egr-1 signaling regulates clusterin expression, a pro-survival factor

Tracy Criswell, Meghan Beman, Shinako Araki, Konstantin Leskov, Eva Cataldo, Lindsey D. Mayo, David A. Boothman

Research output: Contribution to journalArticle

123 Scopus citations

Abstract

Secretory clusterin protein (sCLU) is a general genotoxic stress-induced, pro-survival gene product implicated in aging, obesity, heart disease, and cancer. However, the regulatory signal transduction processes that control sCLU expression remain undefined. Here, we report that induction of sCLU is delayed, peaking 72 h after low doses of ionizing radiation, and is dependent on the up-regulation of insulin-like growth factor-1 as well as phosphorylation- dependent activation of its receptor (IGF-1 and IGF-1R, respectively). Activated IGF-1R then stimulates the downstream Src-Mek-Erk signal transduction cascade to ultimately transactivate the early growth response-1 (Egr-1) transcription factor, required for sCLU expression. Thus, ionizing radiation exposure causes stress-induced activation of IGF-1R-Src-Mek-Erk-Egr-1 signaling that regulates the sCLU pro-survival cascade pathway, important for radiation resistance in cancer therapy.

Original languageEnglish (US)
Pages (from-to)14212-14221
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number14
DOIs
StatePublished - Apr 8 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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