Identification of a novel K311 ubiquitination site critical for androgen receptor transcriptional activity

McClurg, U, Cork, DM, Darby, Steven, Ryan-Munden, CA, Nakjang, S, Mendes-Côrtes, L, Treumann, A, Gaughan, L and Robson, CN (2016) Identification of a novel K311 ubiquitination site critical for androgen receptor transcriptional activity. Nucleic Acids Research, 45 (4). pp. 1793-1804. ISSN 0305-1048

[img]
Preview
PDF
NAR Paper.pdf - Published Version
Available under License Creative Commons Attribution.

Download (3MB) | Preview

Search Google Scholar

Abstract

The androgen receptor (AR) is the main driver ofprostate cancer (PC) development and progression,and the primary therapeutic target in PC. To date,two functional ubiquitination sites have been iden-tified on AR, both located in its C-terminal ligandbinding domain (LBD). Recent reports highlight theemergence of AR splice variants lacking the LBD thatcan arise during disease progression and contributeto castrate resistance. Here, we report a novel N-terminal ubiquitination site at lysine 311. Ubiquitina-tion of this site plays a role in AR stability and is crit-ical for its transcriptional activity. Inactivation of thissite causes AR to accumulate on chromatin and inac-tivates its transcriptional function as a consequenceof inability to bind to p300. Additionally, mutation atlysine 311 affects cellular transcriptome altering theexpression of genes involved in chromatin organiza-tion, signaling, adhesion, motility, development andmetabolism. Even though this site is present in clini-cally relevant AR-variants it can only be ubiquitinatedin cells when AR retains LBD suggesting a role for ARC-terminus in E2/E3 substrate recognition. We reportthat as a consequence AR variants lacking the LBDcannot be ubiquitinated in the cellular environmentand their protein turnover must be regulated via analternate pathway.

Item Type: Article
Subjects: Sciences > Biomedical Sciences
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences
Related URLs:
Depositing User: Steven Darby
Date Deposited: 11 Apr 2017 13:52
Last Modified: 06 Feb 2020 14:45
URI: http://sure.sunderland.ac.uk/id/eprint/7148
ORCID for Steven Darby: ORCID iD orcid.org/0000-0002-7226-8634

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year