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J. Biol. Chem., Vol. 280, Issue 14, 14212-14221, April 8, 2005

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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¶, and David A. Boothman||

From the Department of Radiation Oncology and Program in Molecular and Cellular Basis of Disease, Laboratory of Molecular Stress Responses, Case Comprehensive Cancer Center, Cleveland, Ohio 44106-7285

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.

Received for publication, November 8, 2004 , and in revised form, January 10, 2005.

^* This work was supported by Department of Energy Grant DE-FG02-99EQ62724 (to D. A. B.) and United States Army Department of Defense Breast Cancer Post- and Predoctoral Fellowships DAMD17-01-1-0196 (to K. L.) and DAMD17-01-1-0194 (T. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1S and 2S.

¶ To whom correspondence may be addressed: Dept. of Radiation Oncology, 10900 Euclid Ave., WRB-3, Case Comprehensive Cancer Center, Cleveland, OH 44106-7285. E-mail: lindsey.mayo{at}case.edu. || To whom correspondence may be addressed: Dept. of Radiation Oncology, 10900 Euclid Ave., WRB-3, Case Comprehensive Cancer Center, Cleveland, OH 44106-7285. E-mail: david.boothman{at}case.edu.

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