Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb.
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.
Li
Yong
Y
Life Sciences Institute, University of Michigan, Ann Arbor, 48109, USA.
Wang
Yian
Y
Kim
Eunjung
E
Beemiller
Peter
P
Wang
Cun-Yu
CY
Swanson
Joel
J
You
Ming
M
Guan
Kun-Liang
KL
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D048429:Cell Size; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
C090121:BNIP3 protein, human; D008565:Membrane Proteins; D009479:Neuropeptides; D011518:Proto-Oncogene Proteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins