Acinus-S' represses RAR-regulated gene expression through interaction with the B-domain of RARs

Department of Biochemistry, Department of Microbiology & Immunology, and Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140

^* To whom correspondence should be addressed. Email: dsoprano{at}temple.edu.

	Abstract

The diverse biological actions of retinoic acid (RA) are mediated by retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Modulation of transcription by RARs/RXRs is achieved through two activation functions, ligand-independent AF-1 and ligand-dependent AF-2, located in the A/B and E-domains, respectively. While the coregulatory proteins that interact with the E-domain are well studied, the A/B-domain interacting partners and their influence(s) on the function of RARs are poorly understood. Acinus-S' is an ubiquitous nuclear protein that has been implicated in inducing apoptotic chromatin condensation and regulating mRNA processing. Our data demonstrate that Acinus-S' can specifically repress ligand-independent and ligand-dependent expression of a DR5-RARE dependent reporter gene, and several endogenous RAR-regulated genes in a dose-dependent and gene-specific manner. Chromatin immunoprecipitation assays show that Acinus-S' associates with RAREs within the promoters of endogenous genes independent of RA treatment. Furthermore, the C-terminal end of Acinus-S' and the B domain of RAR interact independent of ligand and the C-terminal end of Acinus-S' is sufficient for the repression of RAR-regulated gene expression. Finally, histone deacetylase activity only partially accounts for the repressive effect of Acinus-S' on RAR-dependent gene expression. These findings identify Acinus-S' as a novel RAR interacting protein that regulates the expression of a subset of RAR-regulated genes through direct binding to the N-terminal B-domain of RARs.