ZIP kinase plays a crucial role in androgen receptor-mediated transcription

Abstract

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. The transcriptional activity of AR is mediated by interaction with multiple co-activators, which serve in chromatin modification or remodeling, or provide a link between specific and general transcription factors. We have identified zipper interacting protein (ZIP) kinase as a novel transcriptional co-activator of the AR. ZIP kinase enhanced expression of AR-responsive promotor/ luciferase reporter constructs in a hormone-and kinasedependent manner. Similar results were obtained for glucocorticoid receptor but not for progesterone receptor and estrogen receptor. Following hormone treatment, AR and ZIP kinase formed physical complexes and associated with the promoter and enhancer of the prostate-specific antigen gene, as revealed by chromatin immunoprecipitation. Strikingly, depletion of ZIP kinase by siRNA led to significant reduction of AR-mediated transactivation. The interaction of ZIP kinase with AR seems to be mediated in part by apoptosis antagonizing transcription factor and in part by direct binding. Interestingly, AR was not phosphorylated by ZIP kinase in vitro, suggesting that it phosphorylates other co-activators or chromatin proteins.

Zipper-interacting protein kinase is involved in regulation of ubiquitination of the androgen receptor, thereby contributing to dynamic transcription complex assembly

“…Coactivation of AR by ZIPK is dependent on the kinase activity of ZIPK but the substrate has not been identified yet. 18 The present study investigated a functional relationship between AR, AATF, TSG101 and ZIPK. ChIP analyses in combination with small interfering RNA (siRNA)-mediated knockdown revealed a cyclical association of AR and its coactivators with the PSA enhancer or promoter.…”

“…We have recently identified three novel coactivators of the AR, apoptosis-antagonizing transcription factor (AATF, also named Che-1), 16 tumor-susceptibility gene 101 (TSG101) 17 and zipperinteracting protein kinase (ZIPK, also termed Dlk, for DAP-like kinase, or DAPK3). 18 AATF was originally found as interaction partner of ZIPK. 19 It is involved in transcriptional regulation, cellcycle control, DNA-damage response and apoptosis (for review, see Passananti et al 20 ).…”

“…21,22 In the case of AR, AATF may have a role in assembly and stabilization of the AR-transcription complex. 18 TSG101 is an inactive ubiquitin conjugase and involved in different ubiquitinrelated processes such as intracellular protein sorting or virus budding (for references, see Burgdorf et al 17 ). In our studies, TSG101 was recognized as interaction partner of AATF and as coactivator of AR.…”

Development of Prostate Cancer Organoid Culture Models in Basic Medicine and Translational Research

“…Examples of these cell lines are LNCaP [41,42], PC-3 [43,44], DU145 [45,46],VCaP [47,48], NCI-H660 [49], PC346 [50], 22Rv1 [51], KUCaP [52], MDA PCa 2a and MDA PCa 2b [53,54]. Among them, DU145, PC-3, and LNCaP are the most widely used ones in PC research [55,56].…”

Mutation analysis of the AATF gene in breast cancer families

“…Its function as transcription factor or as co-activator has not yet been fully worked out. However, there seem to be different modes by which AATF cooperates with other transcription factors [16]. Based on all these observations it is reasonable to speculate that AATF may be a component of the checkpoint anticancer barrier that protects cells from DNA damage or oncogenic stress.…”