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Differential regulation of the androgen receptor by protein phosphatase regulatory subunits

Lookup NU author(s): James Grey, Dr Dominic Jones, Dr Sirintra Nakjang, Jake Clayton, Dr Richard Temperley, Dr Luke Gaughan, Professor Craig Robson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© Grey et al. The Androgen Receptor (AR) is a key molecule in the development, maintenance and progression of prostate cancer (PC). However, the relationship between the AR and co-regulatory proteins that facilitate AR activity in castrate resistant settings remain understudied. Here we show that protein phosphatase 1 regulatory subunits, identified from a phosphatase RNAi screen, direct PP1 catalytic subunits to a varied yet significant response in AR function. As such, we have characterised the PP1ß holoenzyme, myosin phosphatase (MLCP), as a novel ligand independent regulator of the AR. Sustained MLCP activity through down-regulation of the MLCP inhibitory subunit, PPP1R14C, results in impaired AR nuclear translocation, protein stability and transcriptional activity in distinct models of PC progression, culminating in restoration of a non-malignant prostate genotype. Phenotypically, a marked reduction in cell proliferation and migration, characterised by G1 cell cycle arrest is observed, confirming PP1 holoenzyme disruption as a novel treatment approach in PC.


Publication metadata

Author(s): Grey J, Jones D, Wilson L, Nakjang S, Clayton J, Temperley R, Clark E, Gaughan L, Robson C

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2018

Volume: 9

Issue: 3

Pages: 3922-3935

Online publication date: 04/12/2017

Acceptance date: 09/11/2017

Date deposited: 22/01/2018

ISSN (electronic): 1949-2553

Publisher: Impact Journals LLC

URL: https://doi.org/10.18632/oncotarget.22883

DOI: 10.18632/oncotarget.22883


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