Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases

Kendra D. Martyn; Linda M. Frederick; Katharina Von Loehneysen; Mary C. Dinauer; Ulla G. Knaus

doi:10.1016/j.cellsig.2005.03.023

Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases

Kendra D. Martyn, Linda M. Frederick, Katharina Von Loehneysen, Mary C. Dinauer, Ulla G. Knaus

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618 Scopus citations

Abstract

Reactive oxygen species (ROS) are important signal transduction molecules in ligand-induced signaling, regulation of cell growth, differentiation, apoptosis and motility. Recently NADPH oxidases (Nox) homologous to Nox2 (gp91^phox) of phagocyte cytochrome b₅₅₈ have been identified, which are an enzymatic source for ROS generation in epithelial cells. This study was undertaken to delineate the requirements for ROS generation by Nox4. Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22^phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22 ^phox for ROS generation. Mutational analysis revealed structural requirements affecting expression of the p22^phox protein and Nox activity. Mechanistic insight into ROS regulation is significant for understanding fundamental cell biology and pathophysiological conditions.

Original language	English
Pages (from-to)	69-82
Number of pages	14
Journal	Cellular Signalling
Volume	18
Issue number	1
DOIs	https://doi.org/10.1016/j.cellsig.2005.03.023
State	Published - Jan 2006

Keywords

Epithelial cells
NADPH oxidase
Nox4
Rac GTPase
Reactive oxygen species
Regulation
p22

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10.1016/j.cellsig.2005.03.023

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title = "Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases",

abstract = "Reactive oxygen species (ROS) are important signal transduction molecules in ligand-induced signaling, regulation of cell growth, differentiation, apoptosis and motility. Recently NADPH oxidases (Nox) homologous to Nox2 (gp91phox) of phagocyte cytochrome b558 have been identified, which are an enzymatic source for ROS generation in epithelial cells. This study was undertaken to delineate the requirements for ROS generation by Nox4. Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22 phox for ROS generation. Mutational analysis revealed structural requirements affecting expression of the p22phox protein and Nox activity. Mechanistic insight into ROS regulation is significant for understanding fundamental cell biology and pathophysiological conditions.",

keywords = "Epithelial cells, NADPH oxidase, Nox4, Rac GTPase, Reactive oxygen species, Regulation, p22",

author = "Martyn, {Kendra D.} and Frederick, {Linda M.} and {Von Loehneysen}, Katharina and Dinauer, {Mary C.} and Knaus, {Ulla G.}",

note = "Funding Information: We thank the Lambeth laboratory for kindly providing Nox4 antibody and plasmid, Tom Leto for human NOXO1 and NOXA1 constructs, Mark Quinn, Dirk Roos, Al Jesaitis and John Curnutte for reagents, Greg Hannon for the pGEM-U6 plasmid and advice, and Marc Symons for Rac1 RNAi suggestions. We also acknowledge Katrina Schreiber for excellent administrative assistance and Dorian McGavern, Malcolm Woods, and Becky Diebold for advice and discussions. This work was supported by NIH grants GM37696, CI000095, HL45635 (M.D.), CA84138 (D.L.), US Army DAMD17-00-1-0426 and the California Cancer Research Program 00-00760V-20210.",

year = "2006",

month = jan,

doi = "10.1016/j.cellsig.2005.03.023",

language = "English",

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journal = "Cellular Signalling",

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AU - Martyn, Kendra D.

AU - Frederick, Linda M.

AU - Von Loehneysen, Katharina

AU - Dinauer, Mary C.

AU - Knaus, Ulla G.

N1 - Funding Information: We thank the Lambeth laboratory for kindly providing Nox4 antibody and plasmid, Tom Leto for human NOXO1 and NOXA1 constructs, Mark Quinn, Dirk Roos, Al Jesaitis and John Curnutte for reagents, Greg Hannon for the pGEM-U6 plasmid and advice, and Marc Symons for Rac1 RNAi suggestions. We also acknowledge Katrina Schreiber for excellent administrative assistance and Dorian McGavern, Malcolm Woods, and Becky Diebold for advice and discussions. This work was supported by NIH grants GM37696, CI000095, HL45635 (M.D.), CA84138 (D.L.), US Army DAMD17-00-1-0426 and the California Cancer Research Program 00-00760V-20210.

PY - 2006/1

Y1 - 2006/1

N2 - Reactive oxygen species (ROS) are important signal transduction molecules in ligand-induced signaling, regulation of cell growth, differentiation, apoptosis and motility. Recently NADPH oxidases (Nox) homologous to Nox2 (gp91phox) of phagocyte cytochrome b558 have been identified, which are an enzymatic source for ROS generation in epithelial cells. This study was undertaken to delineate the requirements for ROS generation by Nox4. Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22 phox for ROS generation. Mutational analysis revealed structural requirements affecting expression of the p22phox protein and Nox activity. Mechanistic insight into ROS regulation is significant for understanding fundamental cell biology and pathophysiological conditions.

AB - Reactive oxygen species (ROS) are important signal transduction molecules in ligand-induced signaling, regulation of cell growth, differentiation, apoptosis and motility. Recently NADPH oxidases (Nox) homologous to Nox2 (gp91phox) of phagocyte cytochrome b558 have been identified, which are an enzymatic source for ROS generation in epithelial cells. This study was undertaken to delineate the requirements for ROS generation by Nox4. Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22 phox for ROS generation. Mutational analysis revealed structural requirements affecting expression of the p22phox protein and Nox activity. Mechanistic insight into ROS regulation is significant for understanding fundamental cell biology and pathophysiological conditions.

KW - Epithelial cells

KW - NADPH oxidase

KW - Nox4

KW - Rac GTPase

KW - Reactive oxygen species

KW - Regulation

KW - p22

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Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases

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