MAS promoter regulation: a role for Sry and tyrosine nitration of the KRAB domain of ZNF274 as a feedback mechanism

• Published in: Clinical science (1979) Vol. 126; no. 10; pp. 727 - 738
• Main Authors: Prokop, Jeremy W, Rauscher, 3rd, Frank J, Peng, Hongzhuang, Liu, Yuanjie, Araujo, Fabiano C, Watanabe, Ingrid, Reis, Fernando M, Milsted, Amy
• Format: Journal Article
• Language: English
• Published: England 01.05.2014
• Subjects: Animals; Feedback, Physiological; Gene Expression Regulation; Humans; Kruppel-Like Transcription Factors - chemistry; Kruppel-Like Transcription Factors - metabolism; Models, Biological; Models, Molecular; Nitric Oxide - metabolism; Nitrosation; Promoter Regions, Genetic; Protein Binding - genetics; Protein Structure, Tertiary; Proto-Oncogene Proteins - genetics; Receptors, G-Protein-Coupled - genetics; Sex-Determining Region Y Protein; Tyrosine - metabolism
• ISSN: 0143-5221; 1470-8736
• DOI: 10.1042/CS20130385

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.