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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107735 | GEO | 2017/12/07

SECONDARY ACCESSION(S): PRJNA421314

REPOSITORIES: GEO

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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

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

| PRJNA421354 | ENA

Effects on the lipid metabolism of Atlantic cod (Gadus morhua) after in vivo exposure with Ppar agonists

Project description:Lipid metabolism is essential in maintaining energy homeostasis in multicellular organisms. In vertebrates, the peroxisome proliferator-activated receptors (PPARs, NR1C) regulate the expression of many genes involved in these processes. Four Ppar subtypes from Atlantic cod (Gadus morhua) were recently cloned and characterized. However, the downstream regulatory role of Ppars in cod lipid metabolism is presently not well understood or described. Here we study the involvement of Atlantic cod Ppar subtypes in systemic regulation of lipid metabolism using the model agonists WY14,643, GW501516, and tetradecylthioacetic acid, employing a multiple omics approach after an in vivo exposure situation.

2022-09-20 | PXD031739 | Pride

Fatty Acid Mimetic with Multi-Specific Actions Inhibits Diet-Induced Obesity and Non-Alcoholic Fatty Liver Disease

Project description:The peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate glucose and lipid homeostasis. Activation of PPARs has been explored for the treatment of type 2 diabetes and dyslipidemia. LDT409 is a novel fatty acid like compound that has been shown to be a pan-active PPAR agonist. This data explores the changes in the liver proteome of mice treated with LDT409 while fed either a chow or high fat diet.

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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

| PRJNA421314 | ENA

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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Genome-wide analysis of RXRa binding in mouse liver chromatin with ChIP-SEQ.

Project description:For the genome-wide analysis using ChIP-Seq on mouse liver cells, a full accounting of all RXRÎ± binding sites and of RXRa related gene regulations is expected to address the main knowledge gap around RXRÎ±. Liver tissue of wild type and hs-RXRa-del-exon4-/- mice, male and female for each genotype have been ChIP-Seq'ed for RXRa and Pol2.

2014-04-01 | E-GEOD-21696 | biostudies-arrayexpress

Next Generation Sequencing of Wild Type and RXRa-/- peritoneal cavity macrophages

Project description:The goal of this study is to compare the transcriptome profile (RNA-seq) of peritoneal cavity macrophages of RXRa-deficient and WT mice to identify genes which are controlled by the expression of the TF RXRa

2019-09-01 | GSE129095 | GEO

Phosphorylation of RXRa mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome

Project description:The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating PPARa-dependent expression of the hepatokine FGF21. Hepatocyte-specific gene ablation studies demonstrated that the Mapk9 gene (encodes JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2a and JNK2b. Here we demonstrate that Fgf21 gene expression and metabolic regulation is primarily regulated by the JNK2a isoform. To identify relevant substrates of JNK2a, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK-deficiency in hepatocytes, and mice that express only JNK2a or JNK2b in hepatocytes. We identified the JNK substrate RXRa as a protein that exhibited JNK2a-promoted phosphorylation in vivo. RXRa functions as a heterodimeric partner of PPARa and may therefore mediate the effects of JNK2a signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRa proteins. We found that the RXRa phosphorylation site Ser260 was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.

2022-10-12 | PXD034183 | Pride

A multi-omics approach to study peroxisome proliferator-activated receptor mediated regulation of lipid metabolism in Atlantic cod (Gadus morhua)

Project description:Lipid metabolism is essential in maintaining energy homeostasis in multicellular organisms. In vertebrates, a group of nuclear receptor transcription factors named peroxisome proliferator-activated receptors (PPARs, NR1C) regulate the expression of many genes involved in these processes. We have recently cloned the four Ppars in Atlantic cod (Gadus morhua), including Ppara1 and Ppara2, Pparb/d, and Pparg, and studied their tissue specific transcription and ligand activation characteristics. However, the downstream regulative role of Ppars in cod lipid metabolism is not well understood or described. In this study, activation of Atlantic cod Ppar by the fibrate drug WY-14,643 (pirinixic acid) and the performance enhancing drug GW501516 (Cardarine) were first studied using ligand-binding luciferase reporter assays in vitro. Based on the agonist activities found in vitro, juvenile Atlantic cod was injected twice over four days with WY-14,643 and GW501516 in vivo, and sampled seven days after the last injection. Using multiple omics methods, including RNA sequencing, quantitative proteomics, and lipidomics, liver and plasma samples from male cod were analyzed. The resulting multi-omics dataset provides novel insights into the systemic regulation of lipid metabolism in Atlantic cod.

2022-02-28 | MTBLS2131 | MetaboLights

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