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

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

PROVIDER: PRJNA421314 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6353610.fastq.gz	Fastqsanger.gz
	SRR6353620.fastq.gz	Fastqsanger.gz
	SRR6353611.fastq.gz	Fastqsanger.gz
	SRR6353621.fastq.gz	Fastqsanger.gz
	SRR6353612.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

| PRJNA421310 | ENA

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

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

| PRJNA421354 | ENA

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

2017-12-07 | GSE107735 | 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.

| S-EPMC5720590 | biostudies-literature

Peroxisome Proliferator-activated Receptor Agonist IVA337 Alleviates Inflammation

Project description:Peroxisome Proliferator-activated Receptor Agonist IVA337 Alleviates Inflammation

| PRJNA1242327 | ENA

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

Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function

Project description:Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function

| PRJNA953980 | ENA

The peroxisome proliferator-activated receptor-gamma agonist pioglitazone modulates aberrant T cell responses in systemic lupus erythematosus

Project description:Previous studies indicate that peroxisome proliferator-activated receptor-gamma (PPAR-g) agonists suppress autoimmune responses and renal inflammation in murine lupus. However, the mechanisms implicated in this process remain unclear. We tested the effect of the PPAR-g agonist pioglitazone in human lupus and control PBMCs with regards to gene regulation and various functional assays. We used microarrays to analyze the effect of Pioglitazone on peripheral blood cells (PBMCs) from healthy and lupus patients.

2014-12-08 | GSE45923 | GEO

Peroxisome Proliferator-activated Receptor Agonist IVA337 Alleviates Inflammation

Project description:Metabolic dysfunction-associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by significant hepatic fibrosis and inflammation. The pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist IVA337 (lanifibranor) has demonstrated potential as an anti-MASH therapeutic, although its mechanisms of action remain incompletely understood. This study explores the effects and mechanisms of IVA337 using two distinct MASH models: 2D primary human hepatic stellate cells (HSCs) stimulated with TGFß1, and 3D liver spheroids comprising primary hepatocytes, HSCs, and nonparenchymal cells. In TGFß1-stimulated HSCs, IVA337 effectively suppressed the expression of fibrosis-related genes, including PAI1, COL1A1, and SMA, as well as the inflammatory gene IL-6. We successfully established 3D mouse and human liver spheroid models of MASH, characterized by reduced lipid content and elevated fibrotic gene expression. IVA337 treatment not only attenuated fibrotic gene expression but also restored lipid content in the MASH spheroids, as evidenced by BODIPY staining. Immunostaining further confirmed a reduction in SMA and collagen levels following IVA337 treatment. Bulk RNA sequencing and Gene Ontology (GO) analysis revealed lipid metabolism-related genes as key effectors downstream of IVA337. Additionally, IVA337 modulated multiple signaling pathways, including IL-17, TNF, NF-kappa B, PI3K-AKT, and MAPK. Collectively, these findings demonstrate that IVA337 effectively mitigates fibrosis development in both 2D and 3D MASH models by restoring lipid homeostasis and regulating crucial fibrotic and inflammatory pathways.

2025-06-18 | GSE292999 | GEO

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