Acetylation at lysine 183 of progesterone receptor by p300 accelerates DNA binding kinetics and transactivation of direct target genes

• Main Authors: Sze, Siu Kwan, Chung, Hwa Hwa, Tay, Alvin Shun Long, Lin, Valerie Chun Ling
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2015
• Subjects: DRNTU::Science::Biological sciences::Genetics
• Online Access: https://hdl.handle.net/10356/106716; http://hdl.handle.net/10220/25119
• Institution: Nanyang Technological University

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.