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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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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 | GSE107735 | GEO

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

2017-12-07 | GSE107734 | GEO

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 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

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: Not available

| S-EPMC5720590 | biostudies-literature

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

Project description:Lipid droplets (LDs) are multifunctional organelles consisting of a central compartment of non-polar lipids shielded from the cytoplasm by a phospholipid monolayer. The excessive accumulation of lipid droplets in cells is closely related to the development and progression of many diseases in humans and animals, such as liver-related and cardiovascular diseases. Thus, regulating the LDs size and abundance is necessary to maintain metabolic homeostasis. In this study, we found that LPS stimulation reduced the LDs content in the mouse liver. We tried to explain the possible molecular mechanisms at the broad protein and mRNA levels, finding that inhibition of the peroxisome proliferator-activated receptors (PPAR) signalling pathway by LPS may be a critical factor in reducing LDs content.

2023-02-02 | GSE224012 | GEO

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

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

2014-12-08 | E-GEOD-45923 | biostudies-arrayexpress

Peroxisome proliferator activated receptor gamma controls mature brown adipocyte inducibility through glycerol kinase

Project description:Peroxisome proliferator‑activated receptors (PPARs) have been suggested as the master regulators of adipose tissue formation, however their role in regulating brown fat functionality has not been resolved. To address this question, we generated inducible brown fat specific mouse models for PPARa, b/d and g, respectively. Interestingly, we found that both PPARa and b/d are dispensable for brown fat function. In contrast, we could show that ablation of PPARg in vitro as well in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARgfunction, and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARg mediated regulation of brown fat function and activation by β-adrenergic signaling.

2018-01-16 | GSE103474 | GEO

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