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

Abstract

The progesterone receptor (PR) plays important roles in the establishment and maintenance of pregnancy. By dynamic interactions with coregulators, PR represses the expression of genes that increase the contractile activity of myometrium and contribute to the initiation of labor. We have previously shown that PTB-associated RNA splicing factor (PSF) can function as a PR corepressor. In this report, we demonstrated that the PSF heterodimer partner, p54nrb (non-POU-domain-containing, octamer binding protein), can also function as a transcription corepressor, independent of PSF. p54nrb Interacts directly with PR independent of progesterone. In contrast to PSF, p54nrb neither enhances PR protein degradation nor blocks PR binding to DNA. Rather, p54nrb recruits mSin3A through its N terminus to the PR-DNA complex, resulting in an inhibition of PR-mediated transactivation of the progesterone-response element-luciferase reporter gene. PR also repressed transcription of the connexin 43 gene (Gja1), an effect dependent on the presence of an activator protein 1 site within the proximal Gja1 promoter. Mutation of this site abolished PR-mediated repression and decreased the recruitment of PR and p54nrb onto the Gja1 promoter. Furthermore, knockdown p54nrb expression by small interfering RNA alleviated PR-mediated repression on Gja1 transcription, whereas overexpression of p54nrb enhanced it. In the physiological context of pregnancy, p54nrb protein levels decrease with the approach of labor in the rat myometrium. We conclude that p54nrb is a transcriptional corepressor of PR. Decreased expression of p54nrb at the time of labor may act to derepress PR-mediated inhibition on connexin 43 expression and contribute to the initiation of labor.

NonO Binds to the CpG Island of oct4 Promoter and Functions as a Transcriptional Activator of oct4 Gene Expression

“…For example, NonO binds to the DNA-binding domain of steroid hormone receptors and suppresses transcriptional activity in the absence of hormone ligand. (Dong et al, 2009). In contrast to the many reported repressive effects, NonO has a transcriptional coactivator function in androgen receptor-mediated transcription (Ishitani et al, 2003;Kuwahara et al, 2006).…”

The RNA-binding protein Xp54nrb isolated from a Ca2+-dependent screen is expressed in neural structures during Xenopus laevis development

“…It has also been shown that p54nrb acts as transcriptional repressor to regulate Connexin-43 expression when it interacts with the progesterone receptor during the labour (Dong et al, 2009), or with the Malignant Inhibitor Activity (MIA) in melanoma progression (Schiffner et al, 2011). Interestingly, (Amelio et al, 2007) showed that p54nrb is implicated in transcription regulation of c-fos mediated by CREB pathway.…”

Molecular Regulation of Parturition: A Myometrial Perspective

“…On the one hand, P 4 /PRcan exert a pronounced anti-inflammatory effect, by inhibiting activation/DNA binding of the proinflammatory transcription factors, NF-kB ) and AP-1 (Dong et al 2009). Alternatively, P 4 /PR can block induction of the proinflammatory response by up-regulating expression of the NF-kB inhibitor, IkBa , and the mitogen-activated kinase (MAPK) inhibitor, MAPK phosphatase-1 (MKP-1), also known as dual specificity phosphatase 1 (DUSP1) (Chen etal.…”