Disease relevance of NOX1

• Although it has been found that this p40phox protein is defective in patients with chronic granulomatous disease (CGD) who lack p67phox, evidence to functionally relate it to the NADPH oxidase system has hitherto been lacking [1].
• Treatment of the transfected T84 cells with recombinant flagellin (rFliC) from Salmonella enteritidis further augmented the O(2)(-) release in association with the induction of Nox1 protein [2].
• Recently, NADPH oxidase (Nox) 4-mediated generation of intracellular reactive oxygen species (ROS) was proposed to confer antiapoptotic activity and thus a growth advantage to pancreatic cancer cells [3].
• Helicobacter pylori lipopolysaccharide (LPS) and Escherichia coli LPS have been shown to function as potent activators for the Mox1 oxidase [4].
• H. pylori LPS is generally accepted as having low toxicity; however, our results suggest that type I H. pylori lipid A may be a potent stimulator for innate immune responses of gastric mucosa by stimulating the TLR4 cascade and Mox1 oxidase in pit cells [4].
• We found that Nox1 protein overexpression is an early event in the development of prostate cancer using a National Cancer Institute prostate cancer tissue microarray (CPCTR) [5].

Psychiatry related information on NOX1

• Fibrillar amyloid-beta peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for Alzheimer's disease [6].
• Enhanced NADPH-oxidase activity is associated with several vascular-related diseases, including hypertension, stroke, subarachnoid haemorrhage and Alzheimer's dementia; however, the consequences of this for cerebral vascular function are controversial [7].
• Phagocyte NADPH oxidase generates O2. for defense mechanisms and cellular signaling [8].
• Smoking and erectile dysfunction: the role of NADPH oxidase [9].

High impact information on NOX1

• Killing was previously believed to be accomplished by oxygen free radicals and other reactive oxygen species generated by the NADPH oxidase, and by oxidized halides produced by myeloperoxidase [10].
• For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes [11].
• Together with the phagocyte NADPH oxidase itself (NOX2/gp91(phox)), the homologs are now referred to as the NOX family of NADPH oxidases [11].
• Activation of proteases in the phagosomes of neutrophils occurs by neutralization of the phagosomal pH by NADPH oxidase [12].
• (2006) show that dendritic cell phagosomes also recruit NADPH oxidase but with different results [12].

Chemical compound and disease context of NOX1

• The oxidases are also upregulated in vascular disease and are involved in the development of atherosclerosis and a significant part of angiotensin II-induced hypertension, possibly via nox1 and nox4 [13].
• In the present study, we examined whether NADPH oxidase serves as a source of ROS production and plays a role in glutamate-induced cell death in SH-SY5Y human neuroblastoma cells [14].
• The crucial flavin-containing catalytic subunits Nox1 and Nox4 are not present in leucocytes, but are highly expressed in vascular cells and upregulated in vascular remodeling, such as that found in hypertension and atherosclerosis [15].
• Using cultured A549 cells, we investigated the role of NAD(P)H oxidase 1 (Nox1), suggested to be a subunit of a low-output NAD(P)H oxidase complex, in hypoxia signaling [16].
• Chronic granulomatous disease (CGD) is a congenital disorder in which phagocytes cannot generate superoxide (O2-) and other microbial oxidants due to mutations in any one of four components of the O2(-)-generating complex, NADPH oxidase [17].

Biological context of NOX1

• Taken together, increased superoxide production by up-regulation of NOX1 may negatively regulate neuronal differentiation by suppressing excessive neurite outgrowth [18].
• Overexpression of mox1 in NIH3T3 cells increases superoxide generation and cell growth [19].
• The phagocyte NADPH oxidase, dormant in resting cells, is activated during phagocytosis to produce superoxide, a precursor of microbicidal oxidants [20].
• Furthermore, antisense knockdown of p22phox, a subunit of NADPH oxidase, inhibited Abeta1-42-induced neuronal apoptosis and cell death [6].
• For both Nox1 and gp91(phox), an organizer protein (NOXO1 or p47(phox)) cooperates with an activator protein (NOXA1 or p67(phox)) to regulate the catalytic subunit [21].

Anatomical context of NOX1

• Cultured rat astrocytes express mRNAs encoding for the regulatory subunit p47(phox), NOX1, 2, and 4, and the dual oxidases (DUOX)1 and 2, but not NOX3 [22].
• In this context, our data demonstrate that the NOX1 cytoplasmic domains interact efficiently with the cytoplasmic subunits of the phagocyte NADPH oxidase and identify the second cytoplasmic loop of NOX electron transporters as a crucial domain for enzyme function [23].
• These data show that endothelial cells simultaneously express NOX2, NOX4, and NOX1 [24].
• In smooth-muscle cells, platelet-derived growth factor induces mox1 mRNA production, while antisense mox1 mRNA decreases superoxide generation and serum-stimulated growth [19].
• Identification of a thermolabile component of the human neutrophil NADPH oxidase. A model for chronic granulomatous disease caused by deficiency of the p67-phox cytosolic component [25].

Associations of NOX1 with chemical compounds

• In SEG1 cells, acid treatment increased mRNA expression of NOX5-S, but not NOX1, and knockdown of NOX5 by NOX5 small interfering RNA abolished acid-induced H(2)O(2) production [26].
• We found that human umbilical vein endothelial cells treated with Ang1 produce ROS transiently, which was suppressed by NADPH oxidase inhibitor, diphenylene-iodonium chloride, and rotenone [27].
• The human neutrophil NADPH oxidase-associated H+ channel acts as a charge compensator for the electrogenic generation of superoxide (O2-.). The expression of the channel activity was found to increase in parallel with that of the stimulatable generation of O2-. in differentiated HL60 cells [28].
• We therefore conclude that the large subunit of the NADPH oxidase cytochrome b (gp91-phox) is the arachidonate activable H+ channel of human neutrophils [28].
• A potent inhibitor for NF-kappaB (pyrrolidine dithiocarbamate) significantly blocked the rFliC-primed increase in O(2)(-) production and induction of Nox1 protein [2].

Physical interactions of NOX1

• TPR domain mutants of NOXA1 that interfere with Rac1 binding were ineffective in supporting Nox1-dependent ROS generation [29].
• Attenuation of NADPH oxidase derived ROS coupled with GSH/GSSG reduction and suppression of NF-kappaB activation are highlighted as the molecular mechanisms responsible for Cox-2 inhibition [30].
• Here we show that Rac directly participates in Nox1 activation via interacting with Noxa1 [31].
• Assembly of the human neutrophil NADPH oxidase involves binding of p67phox and flavocytochrome b to a common functional domain in p47phox [32].
• The Rac target NADPH oxidase p67phox interacts preferentially with Rac2 rather than Rac1 [33].

Enzymatic interactions of NOX1

• p67phox and p47phox are phosphorylated in the course of stimulation of the NADPH oxidase in neutrophils [34].
• Furthermore, PKD localizes to the area of particle intake in the cell and phosphorylates two of the three cytosolic components of the NADPH oxidase, p40(phox) and p47(phox) [35].
• NADPH oxidase is an enzyme that catalyzes the production of superoxide from oxygen and NADPH [36].
• The resolved flavoprotein and cytochrome b appear unable to catalyze either NADH nor NADPH oxidase activities with O2, ferricyanide, or nitroblue tetrazolium salt serving as electron acceptors [37].

Regulatory relationships of NOX1

• To demonstrate that the additional regions identified were biologically significant, peptides mimicking the gp91-phox sequences F77LRGSSACCSTRVRRQL93 and E451WFADLLQLLESQ463 were synthesized and assayed for their ability to inhibit NADPH oxidase activity [38].
• Rac1(G12V) interaction with NOXA1 was enhanced by Nox1 and NOXO1, suggesting cooperative binding [29].
• When Nox1 is co-expressed along with its regulatory subunits NOXO1 and NOXA1, significant ROS generation is seen [29].
• The endothelial NADPH oxidase is activated by angiogenic factors including VEGF and angiopoietin-1 [39].
• Rac is a GTPase that in the GTP-bound state binds p67phox to activate NADPH oxidase [40].
• We showed that phosphorylation and 14-3-3 binding induce the dissociation of NoxA1 from the Nox1 complex at the plasma membrane, suggesting a mechanism for the inhibitory effect on Nox1 activity [41].

Other interactions of NOX1

• Two of the cytosolic NADPH oxidase components, p47-phox and p67-phox, translocate to the plasma membrane in normal neutrophils stimulated with phorbol myristate acetate (PMA) [42].
• Four novel mutations in the gene encoding gp91-phox of human NADPH oxidase: consequences for oxidase assembly [43].
• Decreased Rac1 expression using small interfering RNA reduced Nox1-dependent ROS [29].
• However, no functional DUOX-based NADPH oxidase has ever been reconstituted at the plasma membrane of transfected cells [44].
• Transfection of human embryonic kidney 293 cells with NOX3 revealed that it generates low levels of ROS on its own but produces high levels of ROS upon co-expression with cytoplasmic NOX subunits [45].

Analytical, diagnostic and therapeutic context of NOX1

• Immunoprecipitation of native Nox1 from human VSMC revealed co-precipitation of p22phox [46].
• Immunofluorescence staining with an anti-Nox1 antibody showed that immunoreactive materials were distributed in the whole interior of both types of cells, while they were preferentially localized in the nuclei of FIB cells [47].
• METHODS: NADPH oxidase expression in human, bovine and porcine endothelial cells was studied by RT-PCR and immunoblotting [48].
• Confocal microscopy demonstrated that NADPH oxidase assembly was disrupted, and LVS phagosomes did not acquire gp91/p22(phox) or p47/p67(phox) [49].
• Immunoelectron microscopy shows a clustered distribution of NADPH oxidase components in the human neutrophil plasma membrane [50].

References