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Bladder cancer associated mutations in RXRA activate peroxisome proliferator-activated receptors

ABSTRACT: Bladder cancer associated mutations in RXRA activate peroxisome proliferator-activated receptors

PROVIDER: PRJNA421354 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6353590.fastq.gz	Fastqsanger.gz
	SRR6353610.fastq.gz	Fastqsanger.gz
	SRR6353620.fastq.gz	Fastqsanger.gz
	SRR6353591.fastq.gz	Fastqsanger.gz
	SRR6353611.fastq.gz	Fastqsanger.gz

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Bladder Cancer Associated Mutations in RXRA activate Peroxisome Proliferator-Activated Receptors to Drive Urothelial Proliferation

Project description:RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from the TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20-25% of bladder cancers. Here we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers. Structure-function studies indicate the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In urothelium, we find PPAR agonism is sufficient to drive growth factor independent growth, but only after deletion of the tumor suppressors Kdm6a and Trp53. Similarly, mutant RXRA stimulates growth factor independent growth, in a manner reversible by PPAR inhibition. These studies reveal a pro-tumorigenic interaction between loss of tumor suppressors and PPAR activation and implicate PPARs as targetable drivers of bladder cancer.

2017-12-07 | GSE107734 | GEO

Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation

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Bladder Cancer Associated Mutations in RXRA activate Peroxisome Proliferator-Activated Receptors to Drive Urothelial Proliferation

Project description:Bladder Cancer Associated Mutations in RXRA activate Peroxisome Proliferator-Activated Receptors to Drive Urothelial Proliferation

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Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation

Project description:Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation

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Bladder cancer associated mutations in RXRA activate peroxisome proliferator-activated receptors

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-12-07 | GSE107783 | GEO

Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation.

Project description:RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20-25% of human bladder cancers. Here, we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers in human bladder cancer cells. Structure-function studies indicate that the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In mouse urothelial organoids, PPAR agonism is sufficient to drive growth-factor-independent growth in the context of concurrent tumor suppressor loss. Similarly, mutant RXRA stimulates growth-factor-independent growth of Trp53/Kdm6a null bladder organoids. Mutant RXRA-driven growth of urothelium is reversible by PPAR inhibition, supporting PPARs as targetable drivers of bladder cancer.

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Proteomics coupled transcriptomics reveals lipopolysaccharide inhibiting peroxisome proliferator-activated receptors signalling pathway to reduce lipid droplets accumulation in mouse liver

Project description:Proteomics coupled transcriptomics reveals lipopolysaccharide inhibiting peroxisome proliferator-activated receptors signalling pathway to reduce lipid droplets accumulation in mouse liver

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