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J. Biol. Chem., Vol. 279, Issue 10, 9167-9175, March 5, 2004

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Insulin Promotes Rat Retinal Neuronal Cell Survival in a p70S6K-dependent Manner^*

Xiaohua Wu, Chad E. N. Reiter, David A. Antonetti, Scot R. Kimball, Leonard S. Jefferson, and Thomas W. Gardner, The Jack and Nancy Turner Professor¶

From the Department of Ophthalmology and Ulerich Ophthalmology Research Center, the JDRF Diabetic Retinopathy Center at Pennsylvania State University and the Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

The purpose of this study was to examine the role of the ribosomal protein S6 protein kinase (p70S6K), a protein synthesis regulator, in promoting retinal neuronal cell survival. Differentiated R28 rat retinal neuronal cells were used as an experimental model. Cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% newborn calf serum, and during the period of experimentation were exposed either to the absence or presence of 10 nM insulin. Insulin treatment induced p70S6K, mTOR, and Akt phosphorylation, effects that were completely prevented by the PI3K inhibitor, LY294002. Insulin-induced phosphorylation of p70S6K and mTOR was prevented by the mTOR inhibitor, rapamycin. Apoptosis, induced by serum deprivation and evaluated by Hoechst staining, was inhibited by insulin treatment in R28 cells, but not in L6 muscle cells. This effect of insulin was also largely prevented by rapamycin. Inhibition of p70S6K activity by exogenous expression of a dominant negative mutant of p70S6K prevented insulin-induced cell survival, whereas, overexpression of wild type p70S6K or expression of a rapamycin resistant form of the kinase enhanced the effect of insulin on survival. Enhanced cell survival under the latter condition was accompanied by increased p70S6K activity and phosphorylation. Rapamycin did not inhibit insulin induced p70S6K phosphorylation and activity in cells transfected with the rapamycin-resistant mutant. Together, these results suggest that p70S6K plays a key role in insulin stimulated retinal neuronal cell survival.

Received for publication, November 12, 2003 , and in revised form, December 4, 2003.

^* This study was supported by grants from the American Diabetes Association, the JDRF Diabetic Retinopathy Center at Penn State University, Fight for Sight (to X. W.), Pennsylvania Sight Conservation and Eye Research Foundation (to X. W.), and National Institutes of Health Grants EY12021, DK13499, and DK15658. 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: Dept. of Ophthalmology, The Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17033. Tel.: 717-531-6711; Fax: 717-531-0631; E-mail: tgardner{at}psu.edu.

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