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Homo sapiens

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

PROVIDER: PRJNA354526 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5027550.fastq.gz	Fastqsanger.gz
	SRR5027560.fastq.gz	Fastqsanger.gz
	SRR5027551.fastq.gz	Fastqsanger.gz
	SRR5027561.fastq.gz	Fastqsanger.gz
	SRR5027552.fastq.gz	Fastqsanger.gz

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

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

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

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

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.

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

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

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

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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

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

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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.

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

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

| PRJNA669849 | ENA