Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 176, Issue 5, Pages 2447-2455Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2010.090606
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Funding
- National Institutes of Health [CA131272, DK078971, DK50190]
- Veterans Administration Research Service
- University of Texas Health Science Center at San Antonio Institute for Integration of Medicine and Science
- Veterans Administration
- NATIONAL CANCER INSTITUTE [R01CA131272] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK078971, R29DK050190, R01DK050190] Funding Source: NIH RePORTER
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Mutations in the von Hippel-Lindau (VHL) gene give rise to renal cell carcinoma. Reactive oxygen species, generated by Nox oxidases, are involved in tumorigenesis. We have previously demonstrated that in VHL-deficient cells, p22(phox)-dependent Nox1 and Nox4 oxidases maintain hypoxia inducible factor-2 alpha (HIF-2 alpha) protein expression through an Akt-dependent translational pathway. Phosphorylation of tuberin, by Akt, results in its inactivation. Here we show that diphenyleneiodonium chloride, an inhibitor of Nox oxidases, and small-interfering RNA-mediated down-regulation of p22(phox) inhibit Akt-dependent phosphorylation of tuberin and stabilizes tuberin protein levels in VHL-deficient renal carcinoma cells. p22(phox)-mediated inactivation of tuberin is associated with an increase in ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) phosphorylation as well as HIF-2 alpha stabilization. Importantly, we find that marked up-regulation of p22(phox) in human renal cell carcinoma correlates with increased tuberin phosphorylation, decreased tuberin protein levels, and increased phosphorylation of 4E-BP1. Our data provide the first evidence that p22(phox)-based Nox oxidases maintain HIF-2a protein expression through inactivation of tulberin and downstream activation of ribosomal protein S6 kinase 1/4E-BP1 pathway. (Am J Pathol 2010, 176:2447-2455; DOI: 10.2353/ajpath.2010.090606)
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