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Originally published In Press as doi:10.1074/jbc.M111142200 on February 27, 2002

J. Biol. Chem., Vol. 277, Issue 18, 15600-15606, May 3, 2002
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Insulin-like Growth Factor I Induces MDM2-dependent Degradation of p53 via the p38 MAPK Pathway in Response to DNA Damage*

Lisa Héron-Milhavet and Derek LeRoithDagger

From the Section on Cellular and Molecular Physiology, Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1758

In many tissues, the insulin-like growth factor I (IGF-I) receptor (IGF-IR) is known to functionally oppose apoptosis. Recently, we demonstrated a direct role for the IGF-IR in the rescue of DNA-damaged fibroblasts by activating a DNA repair pathway (Héron-Milhavet, L., Karas, M., Goldsmith, C. M., Baum, B. J., and LeRoith, D. (2001) J. Biol. Chem. 276, 18185-18192). p53 is a nuclear transcription factor that can block progression of the cell cycle, modulate DNA repair, and trigger apoptosis. In this work, we tested the effect of IGF-I on the regulation of the p53 signaling cascade. The DNA-damaging agent 4-nitroquinoline 1-oxide was applied to NIH-3T3 cells overexpressing normal IGF-IRs (NWTb3 cells). We showed that after 4-nitroquinoline 1-oxide-induced DNA damage, IGF-I induced exclusion of the p53 protein from the nucleus and led to its degradation in the cytoplasm, whereas p53 mRNA was unaffected. Degradation of the p53 protein was associated with an increase in MDM2, an upstream modulator of the half-life and activity of the p53 protein. p53 degradation was also associated with down-regulation of p21. We further showed that the effects of IGF-I on mdm2 transcription and on MDM2/p19 ARF association were mediated by the p38 MAPK pathway. In conclusion, we describe a novel role for IGF-I in the regulation of the MDM2/p53/p21 signaling pathway during DNA damage.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: CEB, NIDDK, NIH, Bldg. 10, Rm. 8D12, Bethesda, MD 20892-1758. Tel.: 301-496-8090; Fax: 301-480-4386; E-mail: Derek@helix.nih.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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