GSE107734 Bladder Cancer Associated Mutations in RXRA activate Peroxisome Proliferator-Activated Receptors to Drive Urothelial Proliferation

Contributors : Angela M Halstead ; Vivek K Arora ; Andrew SchrieferSeries Type : Genome binding/occupancy profiling by high throughput sequencingOrganism : Homo sapiensRXRA 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 tyrosin...

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