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调作用。核受体是调节许多基因表达的配体依赖性转录因子家族的一部分。雄激素受体（AR）是该家族的成员，它介导雄激素信号传导，促进男性生殖系统的发育、生长和功能。最近，许多涉及核受体转录激活的辅因子已被确定。这些包括改变染色质结构和/或促进RNA聚合酶II募集到靶基因启动子的辅因子。SRCAP（SNF 2-Related CBP Activator Protein，SNF 2相关CBP激活蛋白）是一种分子量为350 KD的蛋白质，其特征在于在SNF 2蛋白家族中发现的保守ATP酶结构域，其在转录调控的各个方面发挥作用。SRCAP在酵母双杂交试验中被鉴定为结合共激活因子CBP的蛋白质，并且其增强CBP激活转录的能力。我们先前已经证明，在我们的实验室，SRCAP功能作为一个共激活CREB和糖皮质激素受体（GR）介导的转录。SRCAP部分通过与p160共激活因子GRIP 1和组蛋白甲基转移酶CARM 1相互作用来增强GR转录激活。SRCAP也强烈激活AR介导的转录，并表现出这种激活的协同作用。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展和进展中起着关键作用，因此了解辅激活蛋白如何影响其活性非常重要。

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.