Acinus: A Novel Corepressor of RAR-Regulated Gene Expression

描述（由申请人提供）：视黄酸（RA）是维生素A最有效的天然形式，在介导正常和转化细胞的生长和分化中起重要作用。RA通过维甲酸受体（RARs）和类维甲酸X受体（RXRs）对基因表达进行转录调控。三种不同但高度同源的RAR亚型被描述为RAR α， RAR β和RAR γ。RARs包含一个高度保守的DNA结合域（结构域C），一个保守良好的配体结合域（结构域E），以及另外三到四个不那么保守的结构域（结构域a、B、D和F）。关于RARs的a /B结构域功能的信息有限，但已知它含有与E结构域的配体依赖的交易活性（AF-1）协同作用的配体无关的交易活性（AF-2）。本应用程序提供的初步数据表明，Acinus是一种特异性结合RARs的b结构域并以不依赖配体的方式抑制转录的新蛋白。最近的报道表明，Acinus也可能起着剪接因子的作用。我们假设Acinus作为一种新的协同抑制蛋白，在rar调控的转录和rar调控的pre- mrna剪接的共转录调控中发挥重要作用。具体来说，我们将解决以下4个目标：(1)完成Acinus作为抑制RAR依赖性转录的RAR结合蛋白的表征；(2)研究Acinus在介导rar调控基因表达和ra依赖性P19细胞分化中的作用；(3)研究Acinus特异性丝氨酸残基磷酸化在介导其细胞定位和基因表达抑制中的作用；(4)开始阐明Acinus改变rar调控基因表达的机制。

DESCRIPTION (provided by applicant): 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.