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.
- angiotensin-(1–7) [Ang-(1–7)]
- KRAB-associated protein-1 (KAP-1)
- Krüppel-associated box (KRAB)
- SRY (sex-determining region on the Y chromosome) box (SOX)
- tyrosine nitration
Abbreviations: ACE2, angiotensin-converting enzyme 2; Ang-(1–7), angiotensin-(1–7); AngII, angiotensin II; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; EBNA, Epstein–Barr nuclear antigen; ECR, evolutionary conserved region; HDAC, histone deacetylase; HMG, high-mobility group; HRP, horseradish peroxidase; hSRY, human SRY; KAP-1, KRAB-associated protein-1; KRAB, Krüppel-associated box; nKAP-1, nitrated KAP-1; NOS, nitric oxide synthase; PBS-T, PBS with 0.05% Tween 20; RAS, renin–angiotensin system; SHR, spontaneously hypertensive rat; SOX, SRY box; SP1, specificity protein 1; SRY, sex-determining region on the Y chromosome; TSS, transcriptional start site; WT, wild-type; ZN432, zinc finger protein 432; ZNF, zinc finger protein
- © The Authors Journal compilation © 2014 Biochemical Society