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Originally published In Press as doi:10.1074/jbc.M705231200 on October 10, 2007

J. Biol. Chem., Vol. 282, Issue 49, 35803-35813, December 7, 2007
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Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb*

Yong Li{ddagger}, Yian Wang§, Eunjung Kim{ddagger}, Peter Beemiller, Cun-Yu Wang||, Joel Swanson, Ming You§, and Kun-Liang Guan{ddagger}**{ddagger}{ddagger}1

From the {ddagger}Life Sciences Institute, the **Department of Biological Chemistry, the {ddagger}{ddagger}Institute of Gerontology, the Department of Microbiology and Immunology, and the ||Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109 and the §Department of Surgery and Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110

The mammalian target of rapamycin (mTOR) is a central controller of cell growth, and it regulates translation, cell size, cell viability, and cell morphology. mTOR integrates a wide range of extracellular and intracellular signals, including growth factors, nutrients, energy levels, and stress conditions. Rheb, a Ras-related small GTPase, is a key upstream activator of mTOR. In this study, we found that Bnip3, a hypoxia-inducible Bcl-2 homology 3 domain-containing protein, directly binds Rheb and inhibits the mTOR pathway. Bnip3 decreases Rheb GTP levels in a manner depending on the binding to Rheb and the presence of the N-terminal domain. Both knockdown and overexpression experiments show that Bnip3 plays an important role in mTOR inactivation in response to hypoxia. Moreover, Bnip3 inhibits cell growth in vivo by suppressing the mTOR pathway. These observations demonstrate that Bnip3 mediates the inhibition of the mTOR pathway in response to hypoxia.


Received for publication, June 26, 2007 , and in revised form, September 12, 2007.

* This work is supported by grants from National Institutes of Health and the Department of Defense (to K. L. G.). 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: Dept. of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093. E-mail: kunliang{at}umich.edu.


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