Constitutive NADPH Oxidase 4 Activity Resides in the Composition of the B-loop and the Penultimate C Terminus

Löhneysen, Katharina von; Noack, Deborah; Hayes, Patti; Friedman, Jeffrey S.; Knaus, Ulla G.

doi:10.1074/jbc.m111.332494

Cited by 45 publications

(36 citation statements)

References 24 publications

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“…Among the NOX/DUOX homologs belonging to this gene family, NOX4 is unique in that it is primarily regulated at the level of gene transcription with the apparent dispensability of cytosolic factors and/or calcium to activate the enzyme (5–7). Thus, uncovering mechanisms that control NOX4 gene transcription are critical to understanding its regulation in health and disease.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike other NOX family enzymes, NOX4 does not require the assembly of an active enzymatic complex by recruitment of cytoplasmic regulator proteins that are critical for the activation of other NOX family members, NOX1-3, or calcium-dependent activation (NOX5, DUOX1, 2). Thus, NOX4 is a unique member of this enzyme family in that it is regulated primarily at the level of gene expression (5,6), and has thus been termed a “constitutive” enzyme (7). Despite this distinctive property, mechanisms that regulate NOX4 gene expression are not well understood.…”

Section: Introductionmentioning

confidence: 99%

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A far-upstream AP-1/Smad binding box regulates human NOX4 promoter activation by transforming growth factor-β

Bai

Hock

Logsdon

et al. 2014

Gene

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NADPH oxidase 4 (NOX4) is a member of the NADPH oxidase gene family that regulates cellular differentiation, innate immunity and tissue fibrosis. Transforming growth factor-β (TGF-β1) is known to induce expression of NOX4 mRNA in mesenchymal cells. However, the mechanisms of transcriptional regulation of NOX4 are not well understood. In this study, we examined the transcriptional regulation of NOX4 in human lung fibroblasts by TGF-β1. Five promoter-reporter constructs containing DNA fragments of 0.74 kb, 1.35 kb, 1.84 kb, 3.97 kb and 4.76 kb upstream from the transcriptional start site (TSS) of the human NOX4 gene were generated and their relative responsiveness to TGF-β1 analyzed. TGF-β1-induced NOX4 gene promoter activation requires a region between −3.97 kb and −4.76 kb. Bioinformatics analysis revealed a 15 bp AP-1/Smad binding element in this region. Mutation or deletion of either the AP-1 or the Smad element attenuated TGF-β1 responsiveness of the −4.76 kb NOX4 promoter. Furthermore, insertion of this AP-1/Smad box conferred TGF-β1 inducibility to the non-responsive −3.97 kb NOX4 promoter construct. Chromatin immunoprecipitation analysis indicated phospho-Smad3 and cJun associate with this element in a TGF-β1-inducible manner. These results demonstrate that the AP-1/Smad box located between 3.97 kb and 4.76 kb upstream of the TSS site of the NOX4 promoter is essential for NOX4 gene transcription induced by TGF-β1 in human lung fibroblasts. Our study provides insights into the molecular mechanisms of NOX4 gene expression, informing novel therapeutic approaches to interfere with upregulation of NOX4 in diseases characterized by activation of the TGF-β1/NOX4 pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A far-upstream AP-1/Smad binding box regulates human NOX4 promoter activation by transforming growth factor-β

Bai

Hock

Logsdon

et al. 2014

Gene

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“…Le turnover de Nox4 est cependant 50 à 100 fois inférieur à celui de l'activité oxydase induite de Nox2 (130 à 150 s -1 ) [23,31,32]. Le caractère constitutif des activités oxydase et diaphorase de Nox4 est lié à la présence, dans sa structure, de 22 acides aminés stratégiques en position carboxyterminale, avec deux résidus essentiels, H557 et E571 [31,33]. Certains dérivés de la famille des quinones centres redox de Nox2 via le FAD qui est réduit successivement en FADH • , puis en FADH 2 ( Figure 3A).…”

Section: Mécanismes De Régulation Des Autres Noxunclassified

Les NADPH oxydases, Nox

et al. 2015

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“…Nox 4 was long thought to be the only constitutively active member of the Nox family, under regulation by transcription factors at the level of mRNA rather than relying on cytosolic organiser and activator subunits (Von Löhneysen et al, 2012;Serrander et al, 2007). However, it has recently been proposed that Nox 4 requires the stabilising presence of p22phox with which it forms a heterodimer at the plasma membrane (Ambasta et al, 2004), and that this association is dependent on the polymerase delta-interacting protein (Poldip2) (Lyle et al, 2009).…”

Section: Elmentioning

confidence: 99%

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

Corcoran

Cotter

2012

Free Radical Research

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Access to the full text of the published version may require a subscription. and ideas for this work, and who supported and believed in me throughout -I am grateful to have had the opportunity to learn from the best. I must also give a huge thank you to Kate Cotter, who made me feel at home from day one, and who has continued to be a tireless source of energy and assistance. RightsI was fortunate to interact with a vibrant, dynamic group in the Cotter Lab and I owe a huge thanks to every single member, past-Claire, Ruth, Carolyn, Chris, Ashley, To all the friends that I have made in U.C.C. and beyond during this process, as well as those friends lucky enough not to be involved but who still got to listen to all that whingeing-thank you! Lastly, I am most indebted to those closest to me. My mam -who is always ready to listen, comfort and reassure, and as a result probably knows more than she ever wanted to about cells and reactive oxygen species! My dad, a real scientist, who never stops teaching and never stops learning, and is still the person I turn to with my "homework" questions! I am so grateful to you both for your wisdom, encouragement and patience; truly I could not have achieved this without you. ToSinead and Dara, for all the much needed distractions and laughs, and for even being interested! And to John, for being there throughout, for the joy and the inspiration. To everyone still waiting for good news or the right medicine 'Happy is he who gets to know the reasons for things.' -Virgil DeclarationThis thesis has not been submitted in whole or in part to this or any other university for any degree and is, unless otherwise stated, the original work of the author. pathway may allow for combination therapies to be used to impede the emergence of resistance. However, the intracellular signal transduction pathway of FLT3 is relatively obscure. The objective of this study is to further elucidate this pathway, with particular focus on the redox signalling element which is thought to be involved. Signalling via reactive oxygen species is becoming increasingly recognised as a crucial aspect of physiological and pathological processes within the cell. The first part of this study examined the effects of NADPH oxidase-derived reactive oxygen species on the tyrosine phosphorylation levels of acute myeloid leukaemia cell lines. Using two-dimensional phosphotyrosine immunoblotting, a range of proteins were identified as undergoing tyrosine phosphorylation in response to iii NADPH oxidase activity. Ezrin, a cytoskeletal regulatory protein and substrate of Src kinase, was selected for further study.The next part of this study established that NADPH oxidase is subject to regulation by FLT3. Both wild type and oncogenic FLT3 signalling were shown to affect the expression of a key NADPH oxidase subunit, p22phox, and FLT3 was also demonstrated to drive intracellular reactive oxygen species production. The NADPH oxidase target protein, Ezrin, undergoes phosphorylation on two tyrosine residues downstream of FLT3 signalli...

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Constitutive NADPH Oxidase 4 Activity Resides in the Composition of the B-loop and the Penultimate C Terminus

Cited by 45 publications

References 24 publications

A far-upstream AP-1/Smad binding box regulates human NOX4 promoter activation by transforming growth factor-β

A far-upstream AP-1/Smad binding box regulates human NOX4 promoter activation by transforming growth factor-β

Les NADPH oxydases, Nox

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

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