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Regulation of AR Degradation and Function by Ubiquitylation

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Technical Report,23 Sep 2014,22 Sep 2015

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Beth Israel Deaconess Medical Center Boston United States

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The pathways that normally mediate AR ubiquitylation and degradation remain to be established. Newly synthesized AR associates with an HSP90 chaperone complex, and an HSP90 associated E3 ubiquitin ligase CHIP may mediate the polyubiquitylation and proteasome degradation of AR that fails to fold appropriately and bind ligand. However, there are clearly additional cytoplasmic andor nuclear ubiquitin ligases that regulate the normal turnover and degradation of the liganded AR. Indeed, multiple ubiquitin ligases have been reported to interact with AR and regulate its transcriptional activities andor degradation. Moreover, previous studies using overexpressed ubiquitin ligases and AR site-directed mutagenesis have implicated a number of lysines as possible sites for ubiquitylation. However, the physiological sites and corresponding ubiquitin ligase pathways that regulate AR degradation remain to be defined, and whether AR antagonists or other agents can enhance these pathway to enhance AR degradation remains to be determined. Our studies have identified sevral novel ubiquitylation sites on the AR. Moreover, functional studies of one such site. K911, indicate that ubiquitylation at this site may negatively regulate AR binding to chromatin and transcriptional activity. Studies are underway to identify how ubiquitylation at this site is regulated and its precise functional consequences.


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