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 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.

RXRA与其他14种核受体（包括过氧化物酶体增殖物激活受体（PPAR））一起作为异二聚体的一部分来调节转录。TCGA的分析提出了由于PPARγ基因扩增或RXRA热点突变（S427F / Y）引起的PPAR信号过度活跃可能驱动20-25％的人类膀胱癌的可能性。在这里，我们表征突变体RXRA，证明它在人膀胱癌细胞中的RXRA / PPAR异二聚体的背景下诱导增强子/启动子活性。结构功能研究表明，RXRA取代通过与PPAR中存在的末端酪氨酸的芳香相互作用而变构地调节PPAR AF2域。在小鼠尿路上皮类器官中，PPAR激动作用足以在肿瘤抑制因子同时消失的情况下促进生长因子非依赖性生长。相似地，Trp53 / Kdm6a无效的膀胱类器官。突变的RXRA驱动的尿道上皮细胞的生长可通过PPAR抑制来逆转，从而支持PPARs作为膀胱癌的靶向驱动器。