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

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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.