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Stabilization of HIF-2α through redox regulation of mTORC2 activation and initiation of mRNA translation

Oncogene volume 32, pages 3147–3155 (2013)Cite this article

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Abstract

Hypoxia inducible factor-2α (HIF-2α) has a critical role in renal tumorigenesis. HIF-2α is stabilized in von Hippel–Lindau (VHL)-deficient renal cell carcinoma through mechanisms that require ongoing mRNA translation. Mammalian target of rapamycin (mTOR) functions in two distinct complexes: Raptor-associated mTORC1 and Rictor-associated mTORC2. Rictor-associated mTORC2 complex has been linked to maintaining HIF-2α protein in the absence of VHL; however, the mechanisms remain to be elucidated. Although Raptor-associated mTORC1 is a known key upstream regulator of mRNA translation, initiation and elongation, the role of mTORC2 in regulating mRNA translation is not clear. Complex assembly of the mRNA cap protein, eukaryotic translation initiation factor 4 (eIF4)E, with activators (eIF4 gamma (eIF4G)) and inhibitors (eIF4E-binding protein 1 (4E-BP1)) are rate-limiting determinants of mRNA translation. Our laboratory has previously demonstrated that reactive oxygen species, mediated by p22phox-based Nox oxidases, are enhanced in VHL-deficient cells and have a role in the activation of Akt on S473, a site phosphorylated by the mTORC2 complex. In this study, we examined the role of Rictor-dependent regulation of HIF-2α through eIF4E-dependent mRNA translation and examined the effects of p22phox-based Nox oxidases on TORC2 regulation. We demonstrate for the first time that mTORC2 complex stability and activation is redox sensitive, and further defined a novel role for p22phox-based Nox oxidases in eIF4E-dependent mRNA translation through mTORC2. Furthermore, we provide the first evidence that silencing of p22phox reduces HIF-2α-dependent gene targeting in vitro and tumor formation in vivo. The clinical relevance of these studies is demonstrated.

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Acknowledgements

We acknowledge Dr Goutam Gosh-Choudhury for the HRE responsive element, Cynthia Galindo for technical contributions and Dr Hanna E. Abboud for helpful discussions and critical reading of the manuscript. This study was supported by the Veterans Administration Career Development Award and NIH R01 NCI CA131272 (KB), and NIH K08 CA138774 and Voelcker Fund Young Investigator Award (SS). This study was also supported in part by the Cancer Center Support Grant, National Cancer Institute, 5 P30 CA054174-18 (DJP).

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Authors and Affiliations

  1. Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA

    B K Nayak, D Feliers, W E Friedrichs, R T Day, D D New, A Eid, Y Gorin & K Block

  2. Department of Urology, University of Texas Health Science Center, San Antonio, TX, USA

    S Sudarshan, J P Fitzgerald & D J Parekh

  3. Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA

    T DeNapoli

  4. Audie L. Murphy Memorial Hospital Division, South Texas Veterans Health Care System, San Antonio, TX, USA

    K Block

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  1. B K Nayak
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Correspondence to K Block.

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Nayak, B., Feliers, D., Sudarshan, S. et al. Stabilization of HIF-2α through redox regulation of mTORC2 activation and initiation of mRNA translation. Oncogene 32, 3147–3155 (2013). https://doi.org/10.1038/onc.2012.333

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