Acinus-S' represses retinoic acid receptor (RAR)-regulated gene expression through interaction with the B domains of RARs.
The diverse biological actions of retinoic acid (RA) are mediated by RA 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 RA response element(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 RARbeta interact independently 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 domains of RARs.
Vucetic
Zivjena
Z
Department of Biochemistry, Temple University School of Medicine, 3440 N. Broad Street, Philadelphia, PA 19140, USA.
Zhang
Zhenping
Z
Zhao
Jianhua
J
Wang
Fang
F
Soprano
Kenneth J
KJ
Soprano
Dianne Robert
DR
D000107:Acetylation; D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072516:Retinoic Acid 4-Hydroxylase
C121310:ACIN1 protein, human; D006657:Histones; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase