title: Identification of a novel K311 ubiquitination site critical for androgen receptor transcriptional activity.
abstract: The androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression, and the primary therapeutic target in PC. To date, two functional ubiquitination sites have been identified on AR, both located in its C-terminal ligand binding domain (LBD). Recent reports highlight the emergence of AR splice variants lacking the LBD that can arise during disease progression and contribute to castrate resistance. Here, we report a novel N-terminal ubiquitination site at lysine 311. Ubiquitination of this site plays a role in AR stability and is critical for its transcriptional activity. Inactivation of this site causes AR to accumulate on chromatin and inactivates its transcriptional function as a consequence of inability to bind to p300. Additionally, mutation at lysine 311 affects cellular transcriptome altering the expression of genes involved in chromatin organization, signaling, adhesion, motility, development and metabolism. Even though this site is present in clinically relevant AR-variants it can only be ubiquitinated in cells when AR retains LBD suggesting a role for AR C-terminus in E2/E3 substrate recognition. We report that as a consequence AR variants lacking the LBD cannot be ubiquitinated in the cellular environment and their protein turnover must be regulated via an alternate pathway.
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Urszula L
authors.initials: UL
authors.lastname: McClurg
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: David M W
authors.initials: DMW
authors.lastname: Cork
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Darby
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Ryan-Munden
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.|Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Sirintra
authors.initials: S
authors.lastname: Nakjang
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Leticia
authors.initials: L
authors.lastname: Mendes Côrtes
authors.affiliation: Newcastle University Protein and Proteome Analysis, Devonshire Building, Devonshire Terrace, Newcastle upon Tyne NE1 7RU, UK.
authors.forename: Achim
authors.initials: A
authors.lastname: Treumann
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Gaughan
authors.affiliation: Solid Tumour Target Discovery Laboratory, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D016000:Cluster Analysis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D020543:Proteome; D040901:Proteomics / Q000379:methods; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D059467:Transcriptome; D054875:Ubiquitination
chemical_list: D000596:Amino Acids; D002843:Chromatin; D020543:Proteome; D011944:Receptors, Androgen; D051736:Proto-Oncogene Proteins c-mdm2