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

作者：Prokop Jeremy W; Rauscher Frank J III; Peng Hongzhuang; Liu Yuanjie; Araujo Fabiano C; Watanabe Ingrid; Reis Fernando M; Milsted Amy^*

来源：Clinical Science, 2014, 126(9-10): 727-738.

DOI：10.1042/C520130385

• anglotensinii-7) [Ang-(1-7)]
• KRAB-associated protein-1 (KAP-1)
• Kruppel-associated box (KRAB)
• MAS
• SRY (sex-determining region on the Y chromosome) box (SOX)
• tyrosine nitration

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 ATiR (angiotensin ll type 1 receptor) and the AT2R (angiotensin II type 2 receptor), with models of how Angll (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 (Kruppel-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.

• 出版日期2014-5