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

B. K. Nayak, D. Feliers, S. Sudarshan, W. E. Friedrichs, R. T. Day, D. D. New, J. P. Fitzgerald, A. Eid, T. Denapoli, Dipen J Parekh, Y. Gorin, K. Block

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3147-3155
Number of pages9
JournalOncogene
Volume32
Issue number26
DOIs
StatePublished - Jun 27 2013
Externally publishedYes

Fingerprint

Protein Biosynthesis
Oxidation-Reduction
Raptors
Oxidoreductases
Eukaryotic Initiation Factor-4G
Translational Peptide Chain Initiation
Eukaryotic Initiation Factors
Gene Targeting
Sirolimus
endothelial PAS domain-containing protein 1
TOR complex 2
Renal Cell Carcinoma
Reactive Oxygen Species
Carrier Proteins
Carcinogenesis
Kidney
Messenger RNA
Neoplasms
Proteins

Keywords

  • HIF-2α
  • mTOR
  • Nox oxidase
  • p22
  • renal cancer
  • Rictor

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Nayak, B. K., Feliers, D., Sudarshan, S., Friedrichs, W. E., Day, R. T., New, D. D., ... Block, K. (2013). Stabilization of HIF-2α through redox regulation of mTORC2 activation and initiation of mRNA translation. Oncogene, 32(26), 3147-3155. https://doi.org/10.1038/onc.2012.333

Stabilization of HIF-2α through redox regulation of mTORC2 activation and initiation of mRNA translation. / Nayak, B. K.; Feliers, D.; Sudarshan, S.; Friedrichs, W. E.; Day, R. T.; New, D. D.; Fitzgerald, J. P.; Eid, A.; Denapoli, T.; Parekh, Dipen J; Gorin, Y.; Block, K.

In: Oncogene, Vol. 32, No. 26, 27.06.2013, p. 3147-3155.

Research output: Contribution to journalArticle

Nayak, BK, Feliers, D, Sudarshan, S, Friedrichs, WE, Day, RT, New, DD, Fitzgerald, JP, Eid, A, Denapoli, T, Parekh, DJ, Gorin, Y & Block, K 2013, 'Stabilization of HIF-2α through redox regulation of mTORC2 activation and initiation of mRNA translation', Oncogene, vol. 32, no. 26, pp. 3147-3155. https://doi.org/10.1038/onc.2012.333
Nayak BK, Feliers D, Sudarshan S, Friedrichs WE, Day RT, New DD et al. Stabilization of HIF-2α through redox regulation of mTORC2 activation and initiation of mRNA translation. Oncogene. 2013 Jun 27;32(26):3147-3155. https://doi.org/10.1038/onc.2012.333
Nayak, B. K. ; Feliers, D. ; Sudarshan, S. ; Friedrichs, W. E. ; Day, R. T. ; New, D. D. ; Fitzgerald, J. P. ; Eid, A. ; Denapoli, T. ; Parekh, Dipen J ; Gorin, Y. ; Block, K. / Stabilization of HIF-2α through redox regulation of mTORC2 activation and initiation of mRNA translation. In: Oncogene. 2013 ; Vol. 32, No. 26. pp. 3147-3155.
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