Cdc42 Regulates Arsenic-induced NADPH Oxidase Activation and Cell Migration through Actin Filament Reorganization

Qian, Yong; Liu, Ke Jian; Chen, Yan; Flynn, Daniel C.; Castranova, Vince; Shi, Xianglin

doi:10.1074/jbc.m403788200

Cited by 77 publications

(64 citation statements)

References 44 publications

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“…Thus, p38 kinase may be a downstream target of RhoA/ROCK in As 2 O 3 -treated macrophages; this idea is concordant with recent demonstrations of RhoA/ROCK-dependent activation of p38 kinase in different cell types, including macrophages (37)(38)(39). Interestingly, Cdc42, another small GTP-binding protein, was found to promote p47 phox phosphorylation in iAstreated vascular endothelial cells (16). Cdc42 is thought to activate NADPH oxidase by triggering actin filament reorganization (16).…”

Section: Discussionsupporting

confidence: 73%

“…Interestingly, Cdc42, another small GTP-binding protein, was found to promote p47 phox phosphorylation in iAstreated vascular endothelial cells (16). Cdc42 is thought to activate NADPH oxidase by triggering actin filament reorganization (16). In As 2 O 3 -treated macrophages, neither the actin stabilizer jasplakinolide nor the actin disruptor cytochalasin D could prevent ROS production (A. Lemarie, unpublished data); thus, involvement of actin dynamic in metalloid activation of macrophagic NADPH oxidase is unlikely.…”

Section: Discussionmentioning

confidence: 99%

“…Besides phagocytic NADPH oxidase, iAs can also stimulate nonphagocytic NADPH oxidase in endothelial cells (16,34), vascular smooth muscle cells (35), and in the human promyelocytic NB4 cell line (15); however, molecular mechanisms mediating its activation remain poorly understood. Chou et al (15) have shown that prolonged treatment of NB4 cells (9 days) with 0.75 M As 2 O 3 markedly up-regulate mRNA levels and membrane expression of p47 phox .…”

Section: Discussionmentioning

confidence: 99%

“…Cellular effects of iAs are frequently related to the increased production of reactive oxygen species (ROS) (4,14); recent studies have reported that NADPH oxidase could, in part, mediate ROS formation in iAs-treated cells (15,16). Interestingly, NADPH oxidase is a major superoxide-generating enzymatic system, first described in monocytes/macrophages (17).…”

Section: Norganic Arsenic (Ias)mentioning

confidence: 99%

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Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Lemarié

Bourdonnay

Morzadec

et al. 2008

The Journal of Immunology

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Inorganic arsenic is an immunotoxic environmental contaminant to which millions of humans are chronically exposed. We recently demonstrated that human primary macrophages constituted a critical target for arsenic trioxide (As2O3), an inorganic trivalent form. To specify the effects of arsenic on macrophage phenotype, we investigated in the present study whether As2O3 could regulate the activity of NADPH oxidase, a major superoxide-generating enzymatic system in human phagocytes. Our results show that superoxide levels were significantly increased in a time-dependent manner in blood monocyte-derived macrophages treated with 1 μM As2O3 for 72 h. Concomitantly, As2O3 induced phosphorylation and membrane translocation of the NADPH oxidase subunit p47phox and it also increased translocation of Rac1 and p67phox. Apocynin, a selective inhibitor of NADPH oxidases, prevented both p47phox translocation and superoxide production. NADPH oxidase activation was preceded by phosphorylation of p38-kinase in As2O3-treated macrophages. The p38-kinase inhibitor SB-203580 prevented phosphorylation and translocation of p47phox and subsequent superoxide production. Pretreatment of macrophages with the Rho-kinase inhibitor Y-27632 was found to mimic inhibitory effects of SB-203580 and to prevent As2O3-induced phosphorylation of p38 kinase. Treatment with As2O3 also resulted in an increased secretion of the proinflammatory chemokine CCL18 that was fully inhibited by both apocynin and SB-203580. Taken together, our results demonstrate that As2O3 induced a marked activation of NADPH oxidase in human macrophages, likely through stimulation of a Rho-kinase/p38-kinase pathway, and which may contribute to some of the deleterious effects of inorganic arsenic on macrophage phenotype.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Norganic Arsenic (Ias)mentioning

confidence: 99%

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Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Lemarié

Bourdonnay

Morzadec

et al. 2008

The Journal of Immunology

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“…Actin cytoskeleton and other cytoskeletal proteins may play a role in phagocytic and non-phagocytic assembly and the activation of NADPH oxidase (23)(24)(25)(26)(27). In phorbol ester-stimulated neutrophils, oxidase activity has been shown to co-sediment with the heavy plasma membrane fraction that contains actin and fodrin; furthermore, the labile oxidase can be stabilized by chemical cross-linking and is not extractable by Triton X-100, suggesting that an interaction occurs between the NADPH oxidase complex and actin filaments (28,29).…”

mentioning

confidence: 99%

Regulation of Hyperoxia-induced NADPH Oxidase Activation in Human Lung Endothelial Cells by the Actin Cytoskeleton and Cortactin

Usatyuk

Romer

et al. 2007

Journal of Biological Chemistry

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Although the actin cytoskeleton has been implicated in the control of NADPH oxidase in phagocytosis, very little is known about the cytoskeletal regulation of endothelial NADPH oxidase assembly and activation. Here, we report a role for cortactin and the tyrosine phosphorylation of cortactin in hyperoxiainduced NADPH oxidase activation and ROS production in human pulmonary artery ECs (HPAECs). Exposure of HPAECs to hyperoxia for 3 h induced NADPH oxidase activation, as demonstrated by enhanced superoxide production. Hyperoxia also caused a thickening of the subcortical dense peripheral F-actin band and increased the localization of cortactin in the cortical regions and lamellipodia at cell-cell borders that protruded under neighboring cells. Pretreatment of HPAECs with the actin-stabilizing agent phallacidin attenuated hyperoxia-induced cortical actin thickening and ROS production, whereas cytochalasin D and latrunculin A enhanced basal and hyperoxia-induced ROS formation. In HPAECs, a 3-h hyperoxic exposure enhanced the tyrosine phosphorylation of cortactin and interaction between cortactin and p47 phox , a subcomponent of the EC NADPH oxidase, when compared with normoxic cells. Furthermore, transfection of HPAECs with cortactin small interfering RNA or myristoylated cortactin Src homology domain 3 blocking peptide attenuated ROS production and the hyperoxia-induced translocation of p47 phox to the cell periphery. Similarly, down-regulation of Src with Src small interfering RNA attenuated the hyperoxia-mediated phosphorylation of cortactin tyrosines and blocked the association of cortactin with actin and p47phox . In addition, the hyperoxia-induced generation of ROS was significantly lower in ECs expressing a tyrosine-deficient mutant of cortactin than in vector control or wild-type cells. These data demonstrate a novel function for cortactin and actin in hyperoxiainduced activation of NADPH oxidase and ROS generation in human lung endothelial cells. production that is dependent on NADPH oxidase activation and independent of the mitochondrial electron transport or xanthine/xanthine oxidase systems (10). The mechanisms of NADPH oxidase activation are complex. In phagocytes, activation of NADPH oxidase requires serine phosphorylation of the cytosolic p47 phox , p67 phox , and p40 phox components, assembly of the phosphorylated subunits with Rac2, and translocation to the phagosomes for association with cytochrome b 558. Here, one-electron reduction of molecular O 2 to O 2 . occurs with NADPH as the electron donor (7). In leukocytes, formyl-Met-Leu-Phe-OH or phorbol ester stimulates phosphorylation of p47 phox at multiple serine residues through reactions involving several protein kinases such as protein kinase C, protein kinase A, and mitogen-activated protein kinases (14 -17). In HPAECs, tumor necrosis factor-␣-medi-*This work was supported by National Institutes of Health Grants RO1 HL 69909 (to V. N.), PO1 HL 58064 (to V. N. and J. G. N. G.) and DE13079-01 and AI061042 (to L. H. R.). The costs of publication...

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Use of Histology in Nutrition

Garla

2022

Biomarkers in Disease: Methods, Discoveries and Applications

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Cdc42 Regulates Arsenic-induced NADPH Oxidase Activation and Cell Migration through Actin Filament Reorganization

Cited by 77 publications

References 44 publications

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Regulation of Hyperoxia-induced NADPH Oxidase Activation in Human Lung Endothelial Cells by the Actin Cytoskeleton and Cortactin

Use of Histology in Nutrition

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