Role of SRCAP in AR-Mediated Transcription

描述(由申请人提供)： 转录激活是一个复杂的过程，需要许多蛋白质的协同作用。核受体是配体依赖的转录因子家族的一部分，这些转录因子调节许多基因的表达。雄激素受体(AR)是这个家族的一员，它为男性生殖系统的发育、生长和功能调节雄激素信号。近年来，许多与核受体转录激活有关的辅因子已被发现。这些包括改变染色质结构和/或促进RNA聚合酶II招募到靶基因启动子的辅因子。SRCAP(SNF2相关CBP激活蛋白)是一种350kD的蛋白质，其特征是在SNF2家族中发现了一个保守的ATPase结构域，在转录调控的各个方面发挥作用。在酵母双杂交试验中，SRCAP被鉴定为一种与辅活化子CBP结合的蛋白质，它增强了CBP激活转录的能力。我们以前在实验室中已经证明，SRCAP作为CREB和糖皮质激素受体(GR)介导的转录的共激活因子发挥作用。SRCAP部分地通过与p160共激活因子GRIP 1和组蛋白甲基转移酶CARM1相互作用来增强GR的转录激活。SRCAP还强烈地激活AR介导的转录，并对这种激活表现出协同作用。本研究的目的是了解SRCAP在AR介导的转录中的作用。由于AR功能在前列腺癌的发生和发展中起着关键作用，了解辅助激活蛋白如何影响其活性是很重要的。

DESCRIPTION (provided by applicant): Transcriptional activation is a complex process requiring the coordinated action of many proteins. Nuclear receptors form part of a family of ligand-dependent transcription factors that regulate the expression of many genes. The androgen receptor (AR) is a member of this family and it mediates androgen signaling for development, growth, and function of the male reproductive system. Recently many cofactors implicated in the transcriptional activation by nuclear receptors have been identified. These include cofactors that alter chromatin structure and/or facilitate recruitment of RNA polymerase II to the promoters of target genes. SRCAP (SNF2-Related CBP Activator Protein) is a 350 KD protein characterized by a conserved ATPase domain found in the SNF2 family of proteins which function in various aspects of transcriptional regulation. SRCAP was identified in a yeast two-hybrid assay as a protein that binds the coactivator CBP, and it enhances the ability of CBP to activate transcription. We have previously demonstrated in our laboratory that SRCAP functions as a coactivator for CREB and glucocorticoid receptor (GR)-mediated transcription. SRCAP enhances GR transcriptional activation in part by interacting with the p160 coactivator GRIP 1 and the histone methyl transferase CARM1. SRCAP also strongly activates AR-mediated transcription, and exhibits synergistic function for this activation. The objectives of this study are to understand the role of SRCAP in AR-mediated transcription. Since AR function plays a key role in the development and progression of prostate cancer, it is important to understand how coactivator proteins affect its activity.