title: Methionine sulfoxide reductase A attenuates heme oxygenase-1 induction through inhibition of Nrf2 activation.
abstract: Methionine sulfoxide reductase A (MsrA) functions as a protein repair enzyme by catalyzing the stereospecific reduction of methionine-S-sulfoxide to methionine. We previously identified that MsrA deficiency inhibits normal cell growth via activation of the p53-p21 pathway. In this study, we report a critical role of MsrA in expression of heme oxygenase-1 (HO-1), a highly inducible enzyme that has an anti-proliferative effect mediated by up-regulation of p21. Down-regulation of MsrA induced HO-1 expression in mammalian cells with increased p21 levels, but MsrA overexpression did not affect HO-1 expression. MsrA depletion activated Nrf2 by increasing its expression and nuclear translocation. Nrf2 activation was associated with increased reactive oxygen species production. MsrA overexpression in MsrA-depleted cells led to the reduction of increased HO-1 expression, and suppressed nuclear accumulation of Nrf2. Taken together, the data suggest that MsrA attenuates HO-1 induction by inhibiting Nrf2 activation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine, Daegu 705-717, Republic of Korea.
authors.forename: Jung-Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Choi
authors.forename: Eujin
authors.initials: E
authors.lastname: Lee
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Kang
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Kim
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004790:Enzyme Induction; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051150:Methionine Sulfoxide Reductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010088:Oxidoreductases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016166:Free Radical Scavengers; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D010088:Oxidoreductases; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C491523:Hmox1 protein, rat; D051150:Methionine Sulfoxide Reductases; C488525:MsrA protein, rat; C027219:methionine sulfoxide reductase; D000111:Acetylcysteine