Differential Dependence of Hypoxia-inducible Factors 1α and 2α on mTORC1 and mTORC2

• Published in: The Journal of biological chemistry Vol. 283; no. 50; p. 34495
• Main Authors: Alfredo Toschi, Evan Lee, Noga Gadir, Michael Ohh, David A. Foster
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 12.12.2008
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C800170200

Constitutive expression of hypoxia-inducible factor (HIF) has been implicated in several proliferative disorders. Constitutive expression of HIF1α and HIF2α has been linked to a number of human cancers, especially renal cell carcinoma (RCC), in which HIF2α expression is the more important contributor. Expression of HIF1α is dependent on the mammalian target of rapamycin (mTOR) and is sensitive to rapamycin. In contrast, there have been no reports linking HIF2α expression with mTOR. mTOR exists in two complexes, mTORC1 and mTORC2, which are differentially sensitive to rapamycin. We report here that although there are clear differences in the sensitivity of HIF1α and HIF2α to rapamycin, both HIF1α and HIF2α expression is dependent on mTOR. HIF1α expression was dependent on both Raptor (a constituent of mTORC1) and Rictor (a constitutive of mTORC2). In contrast, HIF2α was dependent only on the mTORC2 constituent Rictor. These data indicate that although HIF1α is dependent on both mTORC1 and mTORC2, HIF2α is dependent only on mTORC2. We also examined the dependence of HIFα expression on the mTORC2 substrate Akt, which exists as three different isoforms, Akt1, Akt2, and Akt3. Interestingly, the expression of HIF2α was dependent on Akt2, whereas that of HIF1α was dependent on Akt3. Because HIF2α is apparently more critical in RCC, this study underscores the importance of targeting mTORC2 and perhaps Akt2 signaling in RCC and other proliferative disorders in which HIF2α has been implicated.