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Clin Sci (Lond). 2014 May;126(10):727-38. doi: 10.1042/CS20130385.

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

Author information

1
*Department of Biology, Program in Integrated Bioscience, The University of Akron, Akron, OH 44325, U.S.A.
2
†The Wistar Institute, Philadelphia, PA 19104, U.S.A.
3
‡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.
4
§Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, SP, Brazil.

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.

PMID:
24128372
PMCID:
PMC4255987
DOI:
10.1042/CS20130385
[Indexed for MEDLINE]
Free PMC Article

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