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 journalArticle

32 Citations (Scopus)

Abstract

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
Pages (from-to)2447-2455
Number of pages9
JournalAmerican Journal of Pathology
Volume176
Issue number5
DOIs
StatePublished - May 1 2010
Externally publishedYes

Fingerprint

Tumor Suppressor Proteins
NADPH Oxidase
Phosphorylation
Oxidoreductases
Renal Cell Carcinoma
Ribosomal Protein S6 Kinases
Carrier Proteins
Proteins
Eukaryotic Initiation Factor-4E
tuberous sclerosis complex 2 protein
Small Interfering RNA
Reactive Oxygen Species
Carcinogenesis
Up-Regulation
Down-Regulation
Mutation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Block, K., Gorin, Y., New, D. D., Eid, A., Chelmicki, T., Reed, A., ... Abboud, H. E. (2010). The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin. American Journal of Pathology, 176(5), 2447-2455. https://doi.org/10.2353/ajpath.2010.090606

The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin. / Block, Karen; Gorin, Yves; New, David D.; Eid, Assaad; Chelmicki, Tomasz; Reed, Amanda; Choudhury, Goutam Ghosh; Parekh, Dipen J; Abboud, Hanna E.

In: American Journal of Pathology, Vol. 176, No. 5, 01.05.2010, p. 2447-2455.

Research output: Contribution to journalArticle

Block, K, Gorin, Y, New, DD, Eid, A, Chelmicki, T, Reed, A, Choudhury, GG, Parekh, DJ & Abboud, HE 2010, 'The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin', American Journal of Pathology, vol. 176, no. 5, pp. 2447-2455. https://doi.org/10.2353/ajpath.2010.090606
Block, Karen ; Gorin, Yves ; New, David D. ; Eid, Assaad ; Chelmicki, Tomasz ; Reed, Amanda ; Choudhury, Goutam Ghosh ; Parekh, Dipen J ; Abboud, Hanna E. / The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin. In: American Journal of Pathology. 2010 ; Vol. 176, No. 5. pp. 2447-2455.
@article{8a3764ea6e25408d8b5bea1374922a2a,
title = "The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin",
abstract = "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.",
author = "Karen Block and Yves Gorin and New, {David D.} and Assaad Eid and Tomasz Chelmicki and Amanda Reed and Choudhury, {Goutam Ghosh} and Parekh, {Dipen J} and Abboud, {Hanna E.}",
year = "2010",
month = "5",
day = "1",
doi = "10.2353/ajpath.2010.090606",
language = "English",
volume = "176",
pages = "2447--2455",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin

AU - Block, Karen

AU - Gorin, Yves

AU - New, David D.

AU - Eid, Assaad

AU - Chelmicki, Tomasz

AU - Reed, Amanda

AU - Choudhury, Goutam Ghosh

AU - Parekh, Dipen J

AU - Abboud, Hanna E.

PY - 2010/5/1

Y1 - 2010/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77952079054&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952079054&partnerID=8YFLogxK

U2 - 10.2353/ajpath.2010.090606

DO - 10.2353/ajpath.2010.090606

M3 - Article

VL - 176

SP - 2447

EP - 2455

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 5

ER -