p54nrb Is a Transcriptional Corepressor of the Progesterone Receptor that Modulates Transcription of the Labor-Associated Gene, Connexin 43 (Gja1)

The progesterone receptor (PR) plays important roles in the establishment and maintenance ofpregnancy. By dynamic interactions with coregulators, PR represses the expression of genes thatincrease the contractile activity of myometrium and contribute to the initiation of labor. We havepreviously shown that PTB-associated RNA splicing factor (PSF) can function as a PR corepressor. Inthis report, we demonstrated that the PSF heterodimer partner, p54nrb (non-POU-domain-containing,octamer binding protein), can also function as a transcription corepressor, independentof PSF. p54nrb Interacts directly with PR independent of progesterone. In contrast to PSF, p54nrbneither enhances PR protein degradation nor blocks PR binding to DNA. Rather, p54nrb recruitsmSin3A through its N terminus to the PR-DNA complex, resulting in an inhibition of PR-mediatedtransactivation of the progesterone-response element-luciferase reporter gene. PR also repressedtranscription of the connexin 43 gene (Gja1), an effect dependent on the presence of an activatorprotein 1 site within the proximal Gja1 promoter. Mutation of this site abolished PR-mediatedrepression and decreased the recruitment of PR and p54nrb onto the Gja1 promoter. Furthermore,knockdown p54nrb expression by small interfering RNA alleviated PR-mediated repression onGja1 transcription, whereas overexpression of p54nrb enhanced it. In the physiological context ofpregnancy, p54nrb protein levels decrease with the approach of labor in the rat myometrium. Weconclude that p54nrb is a transcriptional corepressor of PR. Decreased expression of p54nrb at thetime of labor may act to derepress PR-mediated inhibition on connexin 43 expression and contributeto the initiation of labor. (Molecular Endocrinology 23: 1147–1160, 2009)