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LNCaP prostate cancer cell lines overexpressing wild-type or GARRPR-mutant Bag-1L

ABSTRACT: The BF-3 pocket of the androgen receptor (AR) has been identified as an allosteric modulator of the transactivation function of the AR. We now demonstrate that a duplicated GARRPR motif at the N-terminus of the cochaperone Bag-1L functions through this BF-3 domain. Amino acid exchanges in these two motifs impair binding of Bag-1L to the AR but increase the androgen-dependent activation of a subset of AR-target genes. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the receptor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51524 | GEO | 2014/02/18

SECONDARY ACCESSION(S): PRJNA223354

REPOSITORIES: GEO

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LNCaP prostate cancer cell lines overexpressing wild-type or GARRPR-mutant Bag-1L

Project description:The BF-3 pocket of the androgen receptor (AR) has been identified as an allosteric modulator of the transactivation function of the AR. We now demonstrate that a duplicated GARRPR motif at the N-terminus of the cochaperone Bag-1L functions through this BF-3 domain. Amino acid exchanges in these two motifs impair binding of Bag-1L to the AR but increase the androgen-dependent activation of a subset of AR-target genes. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the receptor. LNCaP cells stably expressing the empty vector construct (=control), or wild-type or N-terminal GARRPR mutant Bag-1L were cultured under hormone-starvation conditions for 72 h and then treated with vehicle or 10 nM DHT for 4 h. Biological triplicate samples were analyzed for each cell line.

2014-02-18 | E-GEOD-51524 | biostudies-arrayexpress

Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [ChIP-Seq]

Project description:Targeting the activation function-1 (AF-1) at the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the BAG domain of the cochaperone Bag-1L. Mutations in this domain or loss of Bag-1L abrogates AR signaling and reduces PCa growth. Correspondingly, Bag-1L protein levels increase with progression of primary prostate tumors to castration-resistant PCa, correlating inversely with patient response to abiraterone therapy. Intriguingly, BAG domain residues important for its interaction with the AR AF-1 overlap a potentially druggable pocket of this protein. Bag-1L is therefore a putative therapeutic target for the inhibition of AR AF-1 activity.

2017-08-23 | GSE89938 | GEO

Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [RNA-Seq KO]

2017-08-23 | GSE89917 | GEO

Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [RNA-seq C-terminal mutant]

2017-08-23 | GSE102183 | GEO

Targeting the androgen receptor N-terminus via the cochaperone Bag-1L

Project description:Targeting the androgen receptor N-terminus via the cochaperone Bag-1L

| PRJNA354287 | ENA

Homo sapiens

Project description:Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [ChIP-Seq]

| PRJNA354526 | ENA

Homo sapiens

Project description:Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [RNA-Seq KO]

| PRJNA354527 | ENA

Homo sapiens

Project description:Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [RNA-seq C-terminal mutant]

| PRJNA396941 | ENA

Targeting the N-terminus of the androgen receptor for prostate cancer therapy

Project description:All current clinically approved androgen deprivation therapies for prostate cancer (PCa) target the C-terminal ligand-binding domain (LBD) of the androgen receptor (AR), although the N-terminal domain (NTD) is the main regulator of AR activity. Targeting the AR NTD directly is a challenge because of its intrinsic disordered nature and the lack of secondary structure and clefts for drugs to bind. Here, we make use of the cochaperone BAG1L that functions through the NTD to develop alternative AR inhibitors. We show that BAG1L binds to a short alpha-helical region of the AR NTD and regulates AR dynamics and the expression of AR target genes. We further show that disruption of the BAG1L-AR NTD action by a small molecule 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17) downregulates AR target gene expression and blocks proliferation of AR-positive PCa cells. Targeting a cochaperone as a surrogate to the AR NTD is therefore key to developing novel AR antagonists.

2021-07-01 | GSE159606 | GEO

Next Generation Sequencing of PD-iPSC derived midbrain dopaminergic(mDA) neurons treated with CDC (C021 dihychloride) or BAG (BAG 956)

Project description:Purpose: The goals of this study are to identify cellular pathways to recover a-syn aggregation-mediated toxicity induced in response to CDC or BAG treatment on PD-iPSC derived mDA neurons. Methods: mRNA profiles of 30-day-old PD-mDA neurons with CDC or BAG treatment for 1 day were generated by deep sequencing, in duplicate, using Illumina HiSeq. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Burrows–Wheeler Aligner (BWA) followed by ANOVA (ANOVA) and TopHat followed by Cufflinks. Conclusions: Our study represents the detailed analysis of mDA neuronal transcriptomes in response to CDC or BAG treatments, with biologic replicates, generated by RNA-seq technology. Our results show that CDC or BAG treatment could rescue the toxcity from a-syn aggregation via purine metabolism / ion transport pathways.

2021-06-30 | GSE153325 | GEO

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