Disease relevance of Ncf1

• Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene [1].
• To assess the role of Ncf1 in Lyme arthritis, we introgressed Bb2Bb3 from severely arthritic C3H/He mice onto mildly arthritic C57BL/6 mice [2].
• Within this region, the Ncf1 gene of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major regulator of arthritis severity in rodent models of rheumatoid arthritis, an effect attributed to protective properties of reactive oxygen species [2].
• Genomic organization of the genes Gtf2ird1, Gtf2i, and Ncf1 at the mouse chromosome 5 region syntenic to the human chromosome 7q11.23 Williams syndrome critical region [3].
• In contrast to wild-type mice, arthritis elicited in both p47phox(-/-) and gp91(-/-) mice showed more severe joint inflammation, which developed into a granulomatous synovitis [4].

High impact information on Ncf1

• Mice genetically deficient ((-/-)) in either iNOS or the p47phox subunit of NADPH oxidase, transgenic (Tg) mice that overexpress SOD, and their respective wild-type (WT) littermates were fed dextran sulfate sodium (DSS) in drinking water for 7 days to induce colitis [5].
• The p47phox mouse knock-out model of chronic granulomatous disease [6].
• Identical to the case in human CGD, leukocytes from p47phox-/- mice produced no superoxide and killed staphylococci ineffectively. p47phox-/- mice developed lethal infections and granulomatous inflammation similar to those encountered in human CGD patients [6].
• Ang II phosphorylated p47phox, a regulatory subunit of NADPH oxidase, and induced reactive oxygen species formation via NADPH oxidase activity [7].
• After bile duct ligation, p47phox-/- mice showed attenuated liver injury and fibrosis compared with WT counterparts [7].

Chemical compound and disease context of Ncf1

• Bb2Bb3 regulation of murine Lyme arthritis is distinct from Ncf1 and independent of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase [2].
• We also show that an Arg-to-Gln mutation in the PX domain of p47phox, which is found in patients with chronic granulomatous disease, eliminates phosphoinositide binding, as does the analogous mutation in the PX domain of p40phox [8].
• Wild-type (WT) controls and p47phox-/- mice were treated with intraperitoneal (i.p.) Escherichia coli lipopolysaccharide (LPS) (5 or 20 microg/g of body weight) [9].
• Whereas the time course of parasitemia in NOS2-/- x p47phox-/- mice was nearly identical to that seen in normal control mice, allopurinol treatment of these double-KO mice also enhanced the magnitude of peak parasitemia [10].
• Effect of amphotericin B and micafungin combination on survival, histopathology, and fungal burden in experimental aspergillosis in the p47phox-/- mouse model of chronic granulomatous disease [11].

Biological context of Ncf1

• These results show that Ncf1, a gene important for oxidative burst, regulates the susceptibility and severity of both arthritis and encephalomyelitis and modulates, directly or indirectly, the level of T cell-dependent autoimmune responses [1].
• Interestingly, female Ncf1-mutated mice spontaneously developed severe arthritis during the postpartum period [1].
• A single nucleotide polymorphism was identified in the Ncf1 gene that did not influence the protein sequence or expression of Ncf1 [2].
• We have isolated and analyzed the sequence of bacterial artificial chromosome clones from the syntenic mouse chromosome 5 region that contains Gtf2ird1 and Gtf2i as well as a neighboring gene, Ncf1 [3].
• Ncf1, located downstream of Gtf2i, consists of 11 exons that extend over 8 kb [3].

Anatomical context of Ncf1

• Although polymorphonuclear leukocytes from C57BL/6 mice generated a greater oxidative burst than polymorphonuclear leukocytes from C3H/He mice, studies with the Bb2Bb3 congenic mice demonstrated this difference was not linked to Ncf1 alleles [2].
• Proteins homologous to p47phox and p67phox support superoxide production by NAD(P)H oxidase 1 in colon epithelial cells [12].
• Glucose dose-dependently increased both neonatal rat myocyte protein synthesis and the expression of p47phox protein, while apocynin (an NADPH oxidase inhibitor) blocked the enhancement of protein synthesis by high glucose [13].
• MMP-2 mRNA expression and activity were analyzed in wildtype and p47phox-deficient (p47phox-/-) murine smooth muscle cells (SMC) [14].
• Mouse peritoneal macrophages and aortic segments from aldosterone-treated mice exhibited increased superoxide anion formation by up to 155% and 69%, respectively, and this effect was probably mediated by NADPH oxidase activation, because increased translocation of its cytosolic component p47phox to the macrophage plasma membrane was observed [15].

Associations of Ncf1 with chemical compounds

• Next, we used ECs obtained from p47phox-/- mice (MAE-p47-/-), which do not produce ROS in response to OS, to determine the role of NADPH oxidases [16].
• VSMC from p47phox-/- mice showed markedly reduced ROS generation and NF-kappaB activation in response to Ang II and AT1-AA [17].
• CD95L induced within 1 min ceramide formation and serine phosphorylation of p47phox, which was sensitive to inhibitors of sphingomyelinase and protein kinase Czeta (PKCzeta) [18].
• Like p47phox, p41 contains an amino-terminal Phox homology domain, two SH3 domains, and a conserved carboxyl-terminal, proline-rich motif [12].
• Voglibose treatment decreased the myocardial expression of an NADPH oxidase subunit (p47phox) [13].

Physical interactions of Ncf1

• LPS-induced NF-kappaB binding activity and accumulation of RelA in nuclear protein extracts of lung tissue were markedly increased in WT compared to p47phox-/- mice 90 min after treatment with 20 but not 5 microg of i.p. LPS per g [9].

Enzymatic interactions of Ncf1

• However, p47-phox phosphorylated by calyculin A treatment lost its ability to activate NADPH oxidase [19].

Other interactions of Ncf1

• Furthermore, Lyme arthritis severity was not altered in mice lacking either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex [2].
• Both iNOS-/- and p47phox-/- mice were attenuated in the ability to control C. burnetii infection compared to wild-type mice [20].
• Here we describe two proteins, p41 and p51, with significant homology to two cytosolic components of the phagocytic oxidase, p47phox and p67phox [12].
• p47phox deficiency impairs NF-kappa B activation and host defense in Pseudomonas pneumonia [21].
• In both control and gp91phox(-/-) animals, reactive oxygen species (ROS) production and MMP induction was enhanced by AVF, whereas in p47phox(-/-) and eNOS(-/-) mice such response was negligible [22].

Analytical, diagnostic and therapeutic context of Ncf1

• We found that the mutated Ncf1 led to a more severe and chronic relapsing collagen-induced arthritis [1].
• The use of linkage analysis and positional cloning of genes in animal models for RA resulted in the identification of one of the genes regulating severity of arthritis in rats and mice, the Ncf1 gene [23].
• Western blotting of BPAECs and immunocytochemistry of BPAECs and rat and mouse lungs showed the presence of p47phox, a cytoplasmic component of NADPH oxidase and the putative target for PR-39 inhibition [24].
• Immunoprecipitation and Western blotting analysis demonstrated that arsenic stimulation induced serine phosphorylation of p47phox, a key component of NADPH oxidase, indicating that arsenic induces O2* formation through NADPH oxidase activation [25].
• Northern blot analysis was used to assess induction of mRNAs encoding gp91-phox, and the myeloid oxidase cytosolic components, p47 and p67 [26].

References