| Autor: |
Block, Karen, Gorin, Yves, New, David D., Eid, Assaad, Chelmicki, Tomasz, Reed, Amanda, Choudhury, Goutam Ghosh, Parekh, Dipen J., Abboud, Hanna E. |
| Zdroj: |
American Journal of Pathology; May 2010, Vol. 176 Issue: 5 p2447-2455, 9p |
| Abstrakt: |
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 p22phoxinhibit Akt-dependent phosphorylation of tuberin and stabilizes tuberin protein levels in VHL-deficient renal carcinoma cells. p22phox-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 p22phoxin 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. |
| Databáze: |
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