SRCAP Regulation of CREB and GR-mediated Transcription

CREB ​​和 GR 介导的转录的 SRCAP 调节

• 批准号: 6589933
• 负责人: John Chrivia
• 金额: $ 10.48万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6589933
• 关键词: CHO cells; SDS polyacrylamide gel electrophoresis; acyltransferase; adenosinetriphosphatase; binding proteins; corticosteroid receptors; enkephalins; genetic promoter element; genetic regulation; genetic regulatory element; genetic transcription; helicase; immunoprecipitation; matrix assisted laser desorption ionization; oligonucleotides; oncoprotein p21; phosphoenolpyruvate carboxylase; plasmids; protein kinase A; protein protein interaction; protein structure function; reporter genes; somatostatin; transcription factor; transfection; virus protein

DESCRIPTION (provided by applicant): CREB-binding protein (CBP) functions as a coactivator for many transcription factors and is able to respond to extracellular signals to specifically regulate gene expression. Mutations within CBP have been found in patients with mental retardation and growth defects (Rubinstein-Taybi syndrome) and have been demonstrated in patients with acute myelogenous leukemia. Several viruses that cause diseases in humans (HTLV-l, HIV-1, CMV, HBV, and adenovirus) also use CBP to regulate gene expression. Regulation of transcription by CBP occurs in part through its ability to function as a histone acetylase transferase (HAT), and in part through contact with other molecules which themselves function as HATs or which function as general transcription factors such as TBP. Recent work indicates that CBP contacts a specific subset of proteins to activate transcription at different promoters. We have identified a novel protein termed SRCAP (SNF2-Related-CBP-Activator Protein) that binds to a region within CBP shown to be important for CBP to function as a coactivator for CREB. SRCAP regulates the ability of CREB and CBP to activate transcription and we have found that SRCAP regulates transcription of several promoters (PEPCK, somatostatin, and enkephalin) that utilize CREB and CBP to activate transcription. In addition, we have found that SRCAP enhances glucocorticoid receptor-mediated transcription of the MMTV-promoter. Recent studies indicate that SRCAP (like CBP) is targeted by several viral proteins. These include: the HCV core protein that inhibits CREB-mediated transcription; the HCV NS5A protein that in conjunction with SRCAP represses transcription of the p21 gene; the adenovirus protein, DBP, that blocks CBP-SRCAP interaction and inhibits transcription mediated by SRCAP; and the adenovirus protein, Ela that binds CBP and blocks binding of CBP to SRCAP. The proposed studies will determine whether interaction of CBP and SRCAP is needed for CREB-mediated transcription of endogenous genes. They will determine the mechanism(s) through which SRCAP activates CREB-mediated transcription and by which SRCAP activates GR-transcription of the MMTV promoter. These studies will also determine whether SRCAP binding proteins regulate the ATPase and transcriptional activities of SRCAP. For example, we have found that the Dead box RNA helicase protein (DBX) binds to SRCAP and represses CREB-mediated transcription. We propose to determine whether this repression of CREB-mediated transcription occurs through formation of a DBX-SRCAP complex.

描述（由申请人提供）：CREB结合蛋白（CBP）用作 共激活因子的许多转录因素，能够做出响应 细胞外信号特异性调节基因表达。突变 在患有智力障碍和成长的患者中已经发现了CBP内部 缺陷（Rubinstein-Taybi综合征），并且已在患有 急性脊髓性白血病。几种引起人类疾病的病毒 （HTLV-L，HIV-1，CMV，HBV和腺病毒）也使用CBP调节基因 表达。 CBP对转录的调节部分是通过其转录发生的 能够充当组蛋白乙酰基酶转移酶（HAT）的能力，部分 通过与其他发挥作用的分子接触或 功能充当一般转录因子，例如TBP。最近的工作表明 CBP接触特定的蛋白质子集，以激活转录 不同的启动子。我们已经确定了一种称为SRCAP的新型蛋白质 （与SNF2相关的CBP激活蛋白）与所示的CBP中的区域结合 对于CBP充当CREB的共激活因子很重要。 SRCAP调节 CREB和CBP激活转录的能力，我们发现SRCAP 调节多个启动子的转录（PEPCK，生长抑素和 使用CREB和CBP激活转录的Enkephalin）。此外， 我们发现SRCAP增强了糖皮质激素受体介导的 MMTV启动器的转录。最近的研究表明SRCAP（喜欢 CBP）由几种病毒蛋白靶向。其中包括：HCV核心蛋白 这抑制了Creb介导的转录； HCV NS5A蛋白 与SRCAP的结合抑制P21基因的转录；腺病毒 蛋白质，DBP，阻塞CBP-SRCAP相互作用并抑制转录 由SRCAP介导；和腺病毒蛋白，结合CBP和块的ELA CBP与SRCAP的结合。拟议的研究将确定是否 CBP和SRCAP的相互作用是CREB介导的转录的相互作用 内源基因。他们将确定SRCAP的机制 激活CREB介导的转录，并通过其激活SRCAP MMTV启动子的GR-转录。这些研究还将确定 SRCAP结合蛋白是否调节ATPase和转录 SRCAP的活动。例如，我们发现死盒RNA解旋酶 蛋白质（DBX）与SRCAP结合并抑制CREB介导的转录。我们 建议确定这种抑制Creb介导的转录 通过形成DBX-SRCAP复合物发生。