Acinus: A Novel Corepressor of RAR-Regulated Gene Expression

Acinus：RAR 调节基因表达的新型辅阻遏物

• 批准号: 7460659
• 负责人: DIANNE R SOPRANO
• 金额: $ 30.14万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-05 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460659
• 关键词: Acinus organ component; Address; Amino Acid Sequence; Binding; Binding Proteins; Cells; Complement component C1s; DNA Binding Domain; Data; Differentiation and Growth; Gene Expression; Genes; Genetic Transcription; Hand; Hormone Receptor; Interferon Gamma Receptor Beta Chain; Ligand Binding Domain; Ligands; Mediating; Numbers; Phosphorylation; Play; Protein Binding; Protein Isoforms; Proteins; RNA Splicing; RXR; Regulation; Reporter Genes; Reporting; Repression; Retinoic Acid Receptor; Role; Serine; Steroids; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Transactivation; Transcriptional Activation; Tretinoin; Vitamin A; cell transformation; member; novel; receptor; receptor binding; receptor function; retinoic acid receptor alpha

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.

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，在介导正常细胞和转化细胞的生长和分化中发挥着重要作用。 RA 通过视黄酸受体 (RAR) 和类视黄醇 X 受体 (RXR) 转录调节基因表达发挥作用。三种不同但高度同源的 RAR 亚型被称为 RARalpha、RARbeta 和 RARgamma。 RAR 包含一个高度保守的 DNA 结合结构域（结构域 C）、一个高度保守的配体结合结构域（结构域 E）和三个或四个不太保守的附加结构域（结构域 A、B、D 和 F）。关于 RAR 的 A/B 结构域功能的信息有限，但已知它含有配体独立的反式激活活性 (AF-1)，可与位于E域。本申请中提供的初步数据表明，Acinus 被鉴定为一种新蛋白质，它与 RAR 的 B 结构域特异性结合，并以不依赖于配体的方式抑制转录。最近的报告表明腺泡也可能起到剪接因子的作用。我们假设 Acinus 是一种新型辅阻遏蛋白，在 RAR 调节的转录的共转录调节和 RAR 调节的前 mRNAS 的剪接中发挥重要作用。具体来说，我们将实现以下 4 个目标：（1）完成 Acinus 作为 RAR 结合蛋白的表征，抑制 RAR 依赖性转录； (2)考察Acinus在介导RAR调节的基因表达和RA依赖性P19细胞分化中的作用； (3) 检查腺泡特定丝氨酸残基的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 调节的基因表达的机制。