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

• DOI: 10.1042/cs20130385
• Publication Date: 2013-10-16T09:31:27Z
• Authors: Jeremy W. Prokop; Frank J. Rauscher; Hongzhuang Peng; Yuanjie Liu; Fabiano C. Araujo; Ingrid Watanabe; Fernando M. Reis; Amy Milsted
• Keywords: Feedback, Physiological; Models, Molecular; 0303 health sciences; Nitrosation; Kruppel-Like Transcription Factors; Nitric Oxide; Models, Biological; Proto-Oncogene Mas; Sex-Determining Region Y Protein; Protein Structure, Tertiary; Receptors, G-Protein-Coupled; 3. Good health; 03 medical and health sciences; Gene Expression Regulation; Proto-Oncogene Proteins; Animals; Humans; Tyrosine; Promoter Regions, Genetic; Protein Binding

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.