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J. Biol. Chem., Vol. 279, Issue 24, 25898-25904, June 11, 2004

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TDAG51 Mediates the Effects of Insulin-like Growth Factor I (IGF-I) on Cell Survival^*

Yuka Toyoshima, Michael Karas, Shoshana Yakar, Joelle Dupont, Lee Helman, and Derek LeRoith

From the Section on Molecular and Cellular Physiology, Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1758 and the Molecular Oncology Section, Pediatric Oncology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892-1928

Insulin-like growth factor-I (IGF-I) receptors and insulin receptors belong to the same subfamily of receptor tyrosine kinases and share a similar set of intracellular signaling pathways, despite their distinct biological actions. In the present study, we evaluated T cell death-associated gene 51 (TDAG51), which we previously identified by cDNA microarray analysis as a gene specifically induced by IGF-I. We characterized the signaling pathways by which IGF-I induces TDAG51 gene expression and the functional role of TDAG51 in IGF-I signaling in NIH-3T3 (NWTb3) cells, which overexpress the human IGF-I receptor. Treatment with IGF-I increased TDAG51 mRNA and protein levels in NWTb3 cells. This effect of IGF-I was specifically mediated by the IGF-IR, because IGF-I did not induce TDAG51 expression in NIH-3T3 cells overexpressing a dominant-negative IGF-I receptor. Through the use of specific inhibitors of various protein kinases, we found that IGF-I induced TDAG51 expression via the p38 MAPK pathway. The ERK, JNK, and phosphatidylinositol 3-kinase pathways were not involved in IGF-I-induced regulation of TDAG51. To assess the role of TDAG51 in IGF-I signaling, we used small interfering RNA (siRNA) expression vectors directed at two different target sites to reduce the level of TDAG51 protein. In cells expressing these siRNA vectors, TDAG51 protein levels were decreased by 75-80%. Furthermore, TDAG51 siRNA expression abolished the ability of IGF-I to rescue cells from serum starvation-induced apoptosis. These findings suggest that TDAG51 plays an important role in the anti-apoptotic effects of IGF-I.

Received for publication, January 20, 2004 , and in revised form, March 19, 2004.

^* 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.

To whom correspondence should be addressed: Section on Molecular and Cellular Physiology, Diabetes Branch, NIDDK, Rm. 8D12, Bldg. 10, MSC 1758, NIH, Bethesda, MD 20892-1758. Tel.: 301-496-8090; Fax: 301-480-4386; E-mail: derek{at}helix.nih.gov.

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