title: MAS promoter regulation: a role for Sry and tyrosine nitration of the KRAB domain of ZNF274 as a feedback mechanism.
abstract: The ACE2 (angiotensin-converting enzyme 2)/Ang-(1-7) [angiotensin-(1-7)]/MAS axis of the RAS (renin-angiotensin system) has emerged as a pathway of interest in treating both cardiovascular disorders and cancer. The MAS protein is known to bind to and be activated by Ang-(1-7); however, the mechanisms of this activation are just starting to be understood. Although there are strong biochemical data regarding the regulation and activation of the AT1R (angiotensin II type 1 receptor) and the AT2R (angiotensin II type 2 receptor), with models of how AngII (angiotensin II) binds each receptor, fewer studies have characterized MAS. In the present study, we characterize the MAS promoter and provide a potential feedback mechanism that could compensate for MAS degradation following activation by Ang-(1-7). Analysis of ENCODE data for the MAS promoter revealed potential epigenetic control by KRAB (Krüppel-associated box)/KAP-1 (KRAB-associated protein-1). A proximal promoter construct for the MAS gene was repressed by the SOX [SRY (sex-determining region on the Y chromosome) box] proteins SRY, SOX2, SOX3 and SOX14, of which SRY is known to interact with the KRAB domain. The KRAB-KAP-1 complex can be tyrosine-nitrated, causing the dissociation of the KAP-1 protein and thus a potential loss of epigenetic control. Activation of MAS can lead to an increase in nitric oxide, suggesting a feedback mechanism for MAS on its own promoter. The results of the present study provide a more complete view of MAS regulation and, for the first time, suggest biochemical outcomes for nitration of the KRAB domain.
authors.affiliation: *Department of Biology, Program in Integrated Bioscience, The University of Akron, Akron, OH 44325, U.S.A.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Prokop
authors.affiliation: †The Wistar Institute, Philadelphia, PA 19104, U.S.A.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Rauscher
authors.affiliation: †The Wistar Institute, Philadelphia, PA 19104, U.S.A.
authors.forename: Hongzhuang
authors.initials: H
authors.lastname: Peng
authors.affiliation: †The Wistar Institute, Philadelphia, PA 19104, U.S.A.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: ‡National Institute of Science and Technology in Molecular Medicine and Department of Obstetrics and Gynecology, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Fabiano C
authors.initials: FC
authors.lastname: Araujo
authors.affiliation: §Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Watanabe
authors.affiliation: ‡National Institute of Science and Technology in Molecular Medicine and Department of Obstetrics and Gynecology, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Fernando M
authors.initials: FM
authors.lastname: Reis
authors.affiliation: *Department of Biology, Program in Integrated Bioscience, The University of Akron, Akron, OH 44325, U.S.A.
authors.forename: Amy
authors.initials: A
authors.lastname: Milsted
mesh_terms: D000818:Animals; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D009569:Nitric Oxide / Q000378:metabolism; D015538:Nitrosation; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D051876:Sex-Determining Region Y Protein; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D051741:Kruppel-Like Transcription Factors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; C497246:ZNF274 protein, human; D009569:Nitric Oxide; D014443:Tyrosine