Functional Interplay between Androgen Receptor and novel Coactivators AATF, ZIP Kinase, and TSG101 in Transcription

雄激素受体(AR)是一种配体依赖的转录因子，在前列腺癌和前列腺癌的发育和动态平衡中起着至关重要的作用。我们已经确定转录因子AATF、ZIP激酶和泛素结合蛋白TSG101是AR的转录共激活因子。其中，AATF可能是ZIP激酶和TSG101的适配子或募集因子，也可能是辅助激活因子，ZIP激酶可能通过磷酸化来调节其他辅助激活因子的相互作用或活性，而TSG101似乎在调节AR和其他蛋白质的单泛素化和多泛素化方面发挥作用。在接下来的节目中，我们将进一步阐明上述共激活因子在AR介导的转录中的相互作用和可能的相互依赖。特别是，我们想要(1)通过单独的敲除以及随后的芯片和转录分析来研究AATF、ZIP激酶和TSG101之间的相互依赖；(2)研究AR及其共激活子在增强子和启动子上的组装和拆解的时间过程；(3)确定ZIP激酶介导其增强作用的底物。这一结果将为AR介导的转录调控提供新的见解。

The Androgen receptor (AR) is a ligand-dependent transcription factor that plays a crucial role in the development and homeostasis of the prostate and in prostate cancer. We have identified transcription factor AATF, ZIP kinase, and ubiquitin binding protein TSG101 as transcriptional coactivators of AR. Of these, AATF seems to serve as adaptor or recruitment factor for ZIP kinase and TSG101 and, presumably, additional coactivators, ZIP kinase may regulate interactions or activities of other coactivators through phosphorylation, and TSG101 seems to play a role in regulating mono- and polyubiquitination of AR and other proteins. In the following program we would like to further elucidate the interplay and possible interdependence of the above mentioned coactivators in AR-mediated transcription. In particular, we want to (1) investigate the interdependence between AATF, ZIP kinase, and TSG101 by individual knockdown and subsequent ChIP and transcription analyses; (2) study the time course of assembly and disassembly of AR and its coactivators at enhancers and promoters; (3) identify substrates of ZIP kinase mediating its enhancing effect. The results will provide new insights into the regulation of AR-mediated transcription.