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Gene Review

CYBA  -  cytochrome b-245, alpha polypeptide

Homo sapiens

Synonyms: Cytochrome b(558) alpha chain, Cytochrome b-245 light chain, Cytochrome b558 subunit alpha, Neutrophil cytochrome b 22 kDa polypeptide, Superoxide-generating NADPH oxidase light chain subunit, ...
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Disease relevance of CYBA


High impact information on CYBA


Chemical compound and disease context of CYBA

  • We examined five polymorphisms in the CYBA gene encoding the p22 phox component of NAD(P)H oxidase, including 242C/T and 640A/G polymorphisms in 467 ESRD patients and 490 healthy individuals [3].
  • The unmasking of p47-SH3 appears to play a crucial role in the assembly of the oxidase components, because p47-SH3 binds to both p22phox and p67phox but fails to interact with a mutant p22phox carrying a Pro-156-->Gln substitution in a proline-rich region, which has been found in a patient with chronic granulomatous disease [9].
  • We studied 108 male Caucasians with angiographically documented CAD and 45 controls free of vascular disease under 60 years of age. p22 phox C242T genotypes and MDA levels were determined [10].
  • This response was attenuated by antioxidants; the flavin inhibitor diphenylene-iodonium, Clostridium difficile toxin B, which inhibits Rho GTPases, p22phox antisense oligonucleotides, or the dominant-negative RacT17N mutant [11].
  • Lack of association of eNOS(G894T) and p22phox NADPH oxidase submit (C242T) polymorphisms with systemic sclerosis in a cohort of French Caucasian patients [12].

Biological context of CYBA


Anatomical context of CYBA


Associations of CYBA with chemical compounds


Physical interactions of CYBA

  • The mapping also confirmed a previously reported binding domain on gp91-phox (E554SGPRGVHFIF564) and putative Src homology 3 domain binding sites on p22-phox (P156PRPP160 and G177GPPGGP183) [24].
  • Binding experiments using the isolated first SH3 domain also demonstrated its involvement in intramolecular interactions within p47phox and showed a requirement for five residues (residues 151 to 155) on its N-terminal boundary for binding to p22phox [25].

Co-localisations of CYBA

  • In atherosclerotic arteries, there was an additional intense area of superoxide in the plaque shoulder, which is rich in macrophages and alpha-actin-positive cells. p22phox colocalized with gp91phox mainly in macrophages, whereas Nox4 was found only in nonphagocytic vascular cells [26].

Regulatory relationships of CYBA


Other interactions of CYBA

  • On the basis of these observations we propose that while Rac2 can bind to a site distinct from either gp91phox or p22phox, it depends upon an interaction with the flavocytochrome b558 for maximal stability in the membrane [30].
  • The novel homologue p41nox interacts with p22phox via the two tandem SH3 domains, as does p47phox [31].
  • In the CYBA gene, encoding the p22phox subunit of the NADPH-oxidase, 2 polymorphisms were investigated [32].
  • Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs [33].
  • ANG II and PDGF AA both activated the redox-sensitive transcription factor AP-1, which was inhibited by p22phox antisense ODNs [18].

Analytical, diagnostic and therapeutic context of CYBA


  1. Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22(phox). Rae, J., Noack, D., Heyworth, P.G., Ellis, B.A., Curnutte, J.T., Cross, A.R. Blood (2000) [Pubmed]
  2. The C242T CYBA polymorphism of NADPH oxidase is associated with essential hypertension. Moreno, M.U., José, G.S., Fortuño, A., Beloqui, O., Díez, J., Zalba, G. J. Hypertens. (2006) [Pubmed]
  3. Haplotype analysis of NAD(P)H oxidase p22 phox polymorphisms in end-stage renal disease. Doi, K., Noiri, E., Nakao, A., Fujita, T., Kobayashi, S., Tokunaga, K. J. Hum. Genet. (2005) [Pubmed]
  4. NADPH oxidase (CYBA) and FcgammaR polymorphisms as risk factors for aggressive periodontitis: a case-control association study. Nibali, L., Parkar, M., Brett, P., Knight, J., Tonetti, M.S., Griffiths, G.S. Journal of clinical periodontology. (2006) [Pubmed]
  5. Association of NAD(P)H oxidase p22 phox gene variation with advanced carotid atherosclerosis in Japanese type 2 diabetes. Hayaishi-Okano, R., Yamasaki, Y., Kajimoto, Y., Sakamoto, K., Ohtoshi, K., Katakami, N., Kawamori, D., Miyatsuka, T., Hatazaki, M., Hazama, Y., Hori, M. Diabetes Care (2003) [Pubmed]
  6. 156Pro-->Gln substitution in the light chain of cytochrome b558 of the human NADPH oxidase (p22-phox) leads to defective translocation of the cytosolic proteins p47-phox and p67-phox. Leusen, J.H., Bolscher, B.G., Hilarius, P.M., Weening, R.S., Kaulfersch, W., Seger, R.A., Roos, D., Verhoeven, A.J. J. Exp. Med. (1994) [Pubmed]
  7. Restitution of superoxide generation in autosomal cytochrome-negative chronic granulomatous disease (A22(0) CGD)-derived B lymphocyte cell lines by transfection with p22phax cDNA. Maly, F.E., Schuerer-Maly, C.C., Quilliam, L., Cochrane, C.G., Newburger, P.E., Curnutte, J.T., Gifford, M., Dinauer, M.C. J. Exp. Med. (1993) [Pubmed]
  8. Mutations in the promoter region of the gene for gp91-phox in X-linked chronic granulomatous disease with decreased expression of cytochrome b558. Newburger, P.E., Skalnik, D.G., Hopkins, P.J., Eklund, E.A., Curnutte, J.T. J. Clin. Invest. (1994) [Pubmed]
  9. Role of Src homology 3 domains in assembly and activation of the phagocyte NADPH oxidase. Sumimoto, H., Kage, Y., Nunoi, H., Sasaki, H., Nose, T., Fukumaki, Y., Ohno, M., Minakami, S., Takeshige, K. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  10. NADH/NADPH oxidase p22 phox C242T polymorphism and lipid peroxidation in coronary artery disease. Stanger, O., Renner, W., Khoschsorur, G., Rigler, B., Wascher, T.C. Clinical physiology (Oxford, England) (2001) [Pubmed]
  11. NADPH oxidase mediates tissue factor-dependent surface procoagulant activity by thrombin in human vascular smooth muscle cells. Herkert, O., Diebold, I., Brandes, R.P., Hess, J., Busse, R., Görlach, A. Circulation (2002) [Pubmed]
  12. Lack of association of eNOS(G894T) and p22phox NADPH oxidase submit (C242T) polymorphisms with systemic sclerosis in a cohort of French Caucasian patients. Tikly, M., Gulumian, M., Marshall, S. Clin. Chim. Acta (2005) [Pubmed]
  13. Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease. Dinauer, M.C., Pierce, E.A., Bruns, G.A., Curnutte, J.T., Orkin, S.H. J. Clin. Invest. (1990) [Pubmed]
  14. Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia. El Kares, R., Barbouche, M.R., Elloumi-Zghal, H., Bejaoui, M., Chemli, J., Mellouli, F., Tebib, N., Abdelmoula, M.S., Boukthir, S., Fitouri, Z., M'rad, S., Bouslama, K., Touiri, H., Abdelhak, S., Dellagi, M.K. J. Hum. Genet. (2006) [Pubmed]
  15. C242T CYBA polymorphism of the NADPH oxidase is associated with reduced respiratory burst in human neutrophils. Wyche, K.E., Wang, S.S., Griendling, K.K., Dikalov, S.I., Austin, H., Rao, S., Fink, B., Harrison, D.G., Zafari, A.M. Hypertension (2004) [Pubmed]
  16. The arachidonate-activable, NADPH oxidase-associated H+ channel. Evidence that gp91-phox functions as an essential part of the channel. Henderson, L.M., Banting, G., Chappell, J.B. J. Biol. Chem. (1995) [Pubmed]
  17. A constitutive NADPH oxidase-like system containing gp91phox homologs in human keratinocytes. Chamulitrat, W., Stremmel, W., Kawahara, T., Rokutan, K., Fujii, H., Wingler, K., Schmidt, H.H., Schmidt, R. J. Invest. Dermatol. (2004) [Pubmed]
  18. Role of p22phox in angiotensin II and platelet-derived growth factor AA induced activator protein 1 activation in vascular smooth muscle cells. Viedt, C., Fei, J., Krieger-Brauer, H.I., Brandes, R.P., Teupser, D., Kamimura, M., Katus, H.A., Kreuzer, J. J. Mol. Med. (2004) [Pubmed]
  19. Genetic studies of three Japanese patients with p22-phox-deficient chronic granulomatous disease: detection of a possible common mutant CYBA allele in Japan and a genotype-phenotype correlation in these patients. Yamada, M., Ariga, T., Kawamura, N., Ohtsu, M., Imajoh-Ohmi, S., Ohshika, E., Tatsuzawa, O., Kobayashi, K., Sakiyama, Y. Br. J. Haematol. (2000) [Pubmed]
  20. NAD(P)H oxidase p22phox Gene C242T polymorphism and lipoprotein oxidation. Nakano, T., Matsunaga, S., Nagata, A., Maruyama, T. Clin. Chim. Acta (2003) [Pubmed]
  21. The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Vignais, P.V. Cell. Mol. Life Sci. (2002) [Pubmed]
  22. p21-activated kinase (Pak) regulates NADPH oxidase activation in human neutrophils. Martyn, K.D., Kim, M.J., Quinn, M.T., Dinauer, M.C., Knaus, U.G. Blood (2005) [Pubmed]
  23. NMR solution structure of the tandem Src homology 3 domains of p47phox complexed with a p22phox-derived proline-rich peptide. Ogura, K., Nobuhisa, I., Yuzawa, S., Takeya, R., Torikai, S., Saikawa, K., Sumimoto, H., Inagaki, F. J. Biol. Chem. (2006) [Pubmed]
  24. Mapping sites of interaction of p47-phox and flavocytochrome b with random-sequence peptide phage display libraries. DeLeo, F.R., Yu, L., Burritt, J.B., Loetterle, L.R., Bond, C.W., Jesaitis, A.J., Quinn, M.T. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  25. Specificity of p47phox SH3 domain interactions in NADPH oxidase assembly and activation. de Mendez, I., Homayounpour, N., Leto, T.L. Mol. Cell. Biol. (1997) [Pubmed]
  26. Superoxide production and expression of nox family proteins in human atherosclerosis. Sorescu, D., Weiss, D., Lassègue, B., Clempus, R.E., Szöcs, K., Sorescu, G.P., Valppu, L., Quinn, M.T., Lambeth, J.D., Vega, J.D., Taylor, W.R., Griendling, K.K. Circulation (2002) [Pubmed]
  27. The expression of the NADPH oxidase subunit p22phox is regulated by a redox-sensitive pathway in endothelial cells. Djordjevic, T., Pogrebniak, A., BelAiba, R.S., Bonello, S., Wotzlaw, C., Acker, H., Hess, J., Görlach, A. Free Radic. Biol. Med. (2005) [Pubmed]
  28. Glucocorticoids inhibit superoxide anion production and p22 phox mRNA expression in human aortic smooth muscle cells. Marumo, T., Schini-Kerth, V.B., Brandes, R.P., Busse, R. Hypertension (1998) [Pubmed]
  29. Oxidative stress in the pathogenesis of thoracic aortic aneurysm: protective role of statin and angiotensin II type 1 receptor blocker. Ejiri, J., Inoue, N., Tsukube, T., Munezane, T., Hino, Y., Kobayashi, S., Hirata, K., Kawashima, S., Imajoh-Ohmi, S., Hayashi, Y., Yokozaki, H., Okita, Y., Yokoyama, M. Cardiovasc. Res. (2003) [Pubmed]
  30. Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox. Evidence for its interaction with flavocytochrome b558. Heyworth, P.G., Bohl, B.P., Bokoch, G.M., Curnutte, J.T. J. Biol. Chem. (1994) [Pubmed]
  31. Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases. Takeya, R., Ueno, N., Kami, K., Taura, M., Kohjima, M., Izaki, T., Nunoi, H., Sumimoto, H. J. Biol. Chem. (2003) [Pubmed]
  32. Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. Mosyagin, I., Dettling, M., Roots, I., Mueller-Oerlinghausen, B., Cascorbi, I. Journal of clinical psychopharmacology. (2004) [Pubmed]
  33. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Martyn, K.D., Frederick, L.M., von Loehneysen, K., Dinauer, M.C., Knaus, U.G. Cell. Signal. (2006) [Pubmed]
  34. Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase. Ambasta, R.K., Kumar, P., Griendling, K.K., Schmidt, H.H., Busse, R., Brandes, R.P. J. Biol. Chem. (2004) [Pubmed]
  35. Expression of phagocyte NADPH oxidase components in human endothelial cells. Jones, S.A., O'Donnell, V.B., Wood, J.D., Broughton, J.P., Hughes, E.J., Jones, O.T. Am. J. Physiol. (1996) [Pubmed]
  36. Relation between development of nephropathy and the p22phox C242T and receptor for advanced glycation end product G1704T gene polymorphisms in type 2 diabetic patients. Matsunaga-Irie, S., Maruyama, T., Yamamoto, Y., Motohashi, Y., Hirose, H., Shimada, A., Murata, M., Saruta, T. Diabetes Care (2004) [Pubmed]
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