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J. Biol. Chem., Vol. 278, Issue 32, 29655-29660, August 8, 2003
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¶
From the
Committee on Genetics, University of
Chicago, Chicago, Illinois 60615 and Abramson
Family Cancer Research Institute and Howard Hughes Medical Institute,
University of Pennsylvania, Philadelphia, Pennsylvania 19104
Hypoxia triggers a reversible inhibition of protein synthesis thought to be important for energy conservation in O2-deficient environments. The mammalian target of rapamycin (mTOR) pathway integrates multiple environmental cues to regulate translation in response to nutrient availability and stress, suggesting it as a candidate for O2 regulation. We show here that hypoxia rapidly and reversibly triggers hypophosphorylation of mTOR and its effectors 4E-BP1, p70S6K, rpS6, and eukaryotic initiation factor 4G. Hypoxic regulation of these translational control proteins is dominant to activation via multiple distinct signaling pathways such as insulin, amino acids, phorbol esters, and serum and is independent of Akt/protein kinase B and AMP-activated protein kinase phosphorylation, ATP levels, ATP:ADP ratios, and hypoxia-inducible factor-1 (HIF-1). Finally, hypoxia appears to repress phosphorylation of translational control proteins in a manner analogous to rapamycin and independent of phosphatase 2A (PP2A) activity. These data demonstrate a new mode of regulation of the mTOR pathway and position this pathway as a powerful point of control by O2 of cellular metabolism and energetics.
Received for publication, December 16, 2002 , and in revised form, May 29, 2003.
* This work was supported by a National Science Foundation Graduate Research Fellowship, the Howard Hughes Medical Institute, National Institutes of Health Grant 66310, and the Abramson Family Cancer Research Institute. 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: 438 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-746-5532; Fax: 215-746-5511; E-mail: celeste2{at}mail.med.upenn.edu.
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