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J. Biol. Chem., Vol. 283, Issue 42, 28265-28273, October 17, 2008

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Stress and IGF-I Differentially Control Cell Fate through Mammalian Target of Rapamycin (mTOR) and Retinoblastoma Protein (pRB)^*

Melissa Popowski, Heather A. Ferguson, Amy M. Sion, Erich Koller^¶, Erik Knudsen^||, and Carla L. Van Den Berg¹

From the College of Pharmacy, University of Texas, Austin, Texas 78712-0125, the School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, ^¶Isis Pharmaceuticals Inc., Carlsbad, California 92008, and the ^||Department of Cell Biology, The Vontz Center for Molecular Studies, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267

Significant discoveries have recently contributed to our knowledge of intracellular growth factor and nutrient signaling via mTOR (mammalian target of rapamycin). This signaling pathway is essential in cellular metabolism and cell survival by enhancing protein translation through phosphorylation of 4EBP-1 and p70S6K. Growth factors like insulin-like growth factor-I induce mTOR to prevent cell death during cellular stress. Agents targeting mTOR are of major interest as anticancer agents. We show here, using human breast cancer cells, that certain types of stress activate mTOR leading to 4E-BP1 and p70S6K phosphorylation. UV treatment increased phosphorylation of the translation inhibitor eIF2, suggesting a potential mechanism for UV activation of Akt and mTOR. c-Myc, a survival protein regulated by cap-dependent protein translation, increased with IGF-I treatment, but this response was not inhibited by rapamycin. Additionally, UV treatment potently increased c-Myc degradation, which was reduced by co-treatment with the proteasomal inhibitor, MG-132. Together, these data suggest that protein translation does not strongly mediate cell survival in these models. In contrast, the phosphorylation status of retinoblastoma protein (pRB) was mediated by mTOR through its inhibitory effects on phosphatase activity. This effect was most notable during DNA damage and rapamycin treatment. Hypophosphorylated pRB was susceptible to inactivation by caspase-mediated cleavage, resulting in cell death. Reduction of pRB expression inhibited IGF-I survival effects. Our data support an important role of phosphatases and pRB in IGF-I/mTOR-mediated cell survival. These studies provide new directions in optimizing anticancer efficacy of mTOR inhibitors when used in combination with DNA-damaging agents.

Received for publication, July 25, 2008 , and in revised form, August 11, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA 89288 and the United States Army Medical Research Grant DAMD17-99-9142 (to C. L. V. D. B.). The content of this information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. 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.

¹ To whom correspondence should be addressed: College of Pharmacy, University of Texas, 1 University Ave. A1915, Austin, TX 78712-0125. Tel.: 512-471-5199; Fax: 512-475-6088; E-mail: cvandenberg{at}mail.utexas.edu.

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