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

December 3rd, 2013 by Chung, H. H., Sze, S. K., Tay, A. S. L., Lin, V. C.-L.

The identification of lysine acetylation of steroid hormone receptors has previously been based on the presence of consensus motif K/RXKK. This study reports the discovery by mass spectrometry of a novel progesterone receptor acetylation site at K183 that is not in the consensus motif. In vivo acetylation and mutagenesis experiments revealed that K183 is a primary site of PR acetylation. K183 acetylation is enhanced by p300 over-expression and abrogated by p300 gene silencing, suggesting that p300 is the major acetyltransferase for K183 acetylation. Furthermore, p300 mediated K183 acetylation is associated with heightened PR activity. Accordingly, acetylation-mimicking mutant, PRB-K183Q exhibited accelerated DNA binding kinetics and greater activity compared to the wild type PRB on genes containing progesterone response element (PRE). In contrast, K183 acetylation had no influence on PR tethering effect on the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Additionally, increases of K183 acetylation by p300 overexpression or inhibition of deacetylation resulted in increases of serine (S) 294 phosphorylation levels. In conclusion, PR acetylation at K183 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 S294 phosphorylation.
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