title: Acetylation at lysine 183 of progesterone receptor by p300 accelerates DNA binding kinetics and transactivation of direct target genes.
abstract: The identification of lysine acetylation of steroid hormone receptors has previously been based on the presence of consensus motif (K/R)XKK. This study reports the discovery by mass spectrometry of a novel progesterone receptor acetylation site at Lys-183 that is not in the consensus motif. In vivo acetylation and mutagenesis experiments revealed that Lys-183 is a primary site of progesterone receptor (PR) acetylation. Lys-183 acetylation is enhanced by p300 overexpression and abrogated by p300 gene silencing, suggesting that p300 is the major acetyltransferase for Lys-183 acetylation. Furthermore, p300-mediated Lys-183 acetylation is associated with heightened PR activity. Accordingly, the acetylation-mimicking mutant PRB-K183Q exhibited accelerated DNA binding kinetics and greater activity compared with the wild-type PRB on genes containing progesterone response element. In contrast, Lys-183 acetylation had no influence on PR tethering effect on the nuclear factor κ-light chain enhancer of activated B cells (NFκB). Additionally, increases of Lys-183 acetylation by p300 overexpression or inhibition of deacetylation resulted in increases of Ser-294 phosphorylation levels. In conclusion, PR acetylation at Lys-183 by p300 potentiates PR activity through accelerated binding of its direct target genes without affecting PR tethering on other transcription factors. The effect may be mediated by enhancing Ser-294 phosphorylation.
authors.affiliation: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Hwa Hwa
authors.initials: HH
authors.lastname: Chung
authors.forename: Siu Kwan
authors.initials: SK
authors.lastname: Sze
authors.forename: Alvin Shun Long
authors.initials: AS
authors.lastname: Tay
authors.forename: Valerie C-L
authors.initials: VC
authors.lastname: Lin
mesh_terms: D000107:Acetylation; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D016328:NF-kappa B; D011980:Receptors, Progesterone; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: Histone Acetylase; Hormone Receptors; Nuclear Receptors; Post-translational Modification; Transcription