title: NADPH oxidase 4 regulates cardiomyocyte differentiation via redox activation of c-Jun protein and the cis-regulation of GATA-4 gene transcription.
abstract: NADPH oxidase 4 (Nox4) generates reactive oxygen species (ROS) that can modulate cellular phenotype and function in part through the redox modulation of the activity of transcription factors. We demonstrate here the potential of Nox4 to drive cardiomyocyte differentiation in pluripotent embryonal carcinoma cells, and we show that this involves the redox activation of c-Jun. This in turn acts to up-regulate GATA-4 expression, one of the earliest markers of cardiotypic differentiation, through a defined and highly conserved cis-acting motif within the GATA-4 promoter. These data therefore suggest a mechanism whereby ROS act in pluripotential cells in vivo to regulate the initial transcription of critical tissue-restricted determinant(s) of the cardiomyocyte phenotype, including GATA-4. The ROS-dependent activation, mediated by Nox4, of widely expressed redox-regulated transcription factors, such as c-Jun, is fundamental to this process.
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, London SE5 9NU, United Kingdom.
authors.forename: Thomas V A
authors.initials: TV
authors.lastname: Murray
authors.forename: Ioannis
authors.initials: I
authors.lastname: Smyrnias
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Alison C
authors.initials: AC
authors.lastname: Brewer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D050991:GATA4 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D050991:GATA4 Transcription Factor; D009124:Muscle Proteins; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: AP-1 Transcription Factor; Cardiac Development; Cardiogenesis; Nox; Nox4; Reactive Oxygen Species (ROS); Redox Regulation