title: Lysine acetyltransferases cyclic adenosine monophosphate response element-binding binding protein and acetyltransferase p300 attenuate transcriptional activity of the mineralocorticoid receptor through its acetylation.
abstract: Acetylation of the mineralocorticoid receptor (MR) by inhibition of lysine deacetylases attenuates MR's transcriptional activity. However, the specific lysine acetyltransferases that are responsible for acetylation of the MR remain unknown. We hypothesized that the acetyltransferases cyclic adenosine monophosphate response element-binding binding protein (CBP) and acetyltransferase p300 (p300) attenuate transcriptional activity of the MR through its acetylation. Expression of MR target genes was measured by quantitative real-time polymerase chain reaction. Recruitment of MR and RNA polymerase II (Pol II) on promoters of target genes was analysed by chromatin immunoprecipitation. Acetylation of the MR was determined by western blot with an anti-acetyl-lysine antibody after immunoprecipitation with an anti-MR antibody. In human embryonic kidney (HEK) 293 cells, overexpression of CBP or p300, but not p300/CBP-associated factor, increased MR acetylation and decreased expression of MR target genes. The downregulation of target genes coincided with a decrease in the recruitment of MR and Pol II to specific hormone response elements. These results demonstrate that overexpression of CBP or p300 attenuates the transcriptional activity of the MR through its acetylation in HEK 293 cells. Our data provide strong evidence identifying CBP and p300 as lysine acetyltransferases responsible for the regulation of MR that may provide new therapeutic targets for the treatment of hypertension.
authors.affiliation: Department of Pharmacology, Kyungpook National University School of Medicine, Daegu, Korea; Laboratory of Clinical Medicine, Dongguk University College of Medicine, Gyeongju, Korea.
authors.forename: Minchul
authors.initials: M
authors.lastname: Seo
authors.forename: Minji
authors.initials: M
authors.lastname: Song
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Seok
authors.forename: Seol Hee
authors.initials: SH
authors.lastname: Kang
authors.forename: Hae Ahm
authors.initials: HA
authors.lastname: Lee
authors.forename: Uy Dong
authors.initials: UD
authors.lastname: Sohn
authors.forename: In Kyeom
authors.initials: IK
authors.lastname: Kim
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000123:Acetyltransferases / Q000378:metabolism*; D000450:Aldosterone / Q000494:pharmacology; D001483:Base Sequence; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D000123:Acetyltransferases; D000450:Aldosterone; D017362:Cyclic AMP Response Element-Binding Protein; D012319:RNA Polymerase II; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: acetylation; lysine acetyltransferases; mineralocorticoid receptor; transcriptional regulation