Retinoic acid (RA), the most potent natural form of vitamin A, plays an important role in mediating the growth and differentiation of both normal and transformed cells. RA functions by transcriptionally regulating gene expression via retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Three distinct but highly homologous RAR subtypes have been described termed RARalpha, RARbeta and RARgamma. RARs contain a highly conserved DNA binding domain (domain C), a well conserved ligand binding domain (domain E), and three or four additional domains that are not as well conserved (domains A, B, D and F). There is a limited amount of information concerning the function of the A/B domains of RARs however it is known to contain ligand-independent transactivation activity (AF-1) that synergizes with the ligand- dependent transactivation activity (AF-2) located in the E domain. Preliminary data presented in this application demonstrate the identification of Acinus as a new protein that binds specifically to the B-domain of RARs and represses transcription in a ligand-independent fashion. Recently reports suggest that Acinus may also function as a splicing factor. We hypothesize that Acinus functions as a novel corepressor protein that plans an important role in the cotranscriptional regulation of both RAR-regulated transcription and the splicing of RAR-regulated pre-mRNAS. Specifically we will address the following 4 aims: (1) Complete the characterization of Acinus as a RAR binding protein that represses RAR-dependent transcription;(2) Examine the role of Acinus in mediating both RAR-regulated gene expression and RA-dependent differentiation of P19 cells;(3) Examine the role of phosphorylation of specific serine residues of Acinus in mediating its cellular localization and repression of gene expression;and (4) Begin to elucidate the mechanism by which Acinus alters RAR-regulated gene expression.
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