The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin

Karen Block, Yves Gorin, David D. New, Assaad Eid, Tomasz Chelmicki, Amanda Reed, Goutam Ghosh Choudhury, Dipen J. Parekh, Hanna E. Abboud

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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, p22phox-dependent Nox1 and Nox4 oxidases maintain hypoxia inducible factor-2α (HIF-2α) 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-2α stabilization. Importantly, we find that marked up-regulation of p22phox 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 p22phox-based Nox oxidases maintain HIF-2α protein expression through inactivation of tuberin and downstream activation of ribosomal protein S6 kinase 1/4E-BP1 pathway.

Original languageEnglish (US)
Pages (from-to)2447-2455
Number of pages9
JournalAmerican Journal of Pathology
Issue number5
StatePublished - May 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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