Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb

Yong Li, Yian Wang, Eunjung Kim, Peter Beemiller, Cun Yu Wang, Joel Swanson, Ming You, Kun Liang Guan

Research output: Contribution to journalArticlepeer-review

189 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)35803-35813
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number49
DOIs
StatePublished - Dec 7 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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