Brewer C Trent, Chen Taosheng
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Acta Pharm Sin B. 2016 Sep;6(5):441-449. doi: 10.1016/j.apsb.2016.07.002. Epub 2016 Jul 27.
The pregnane X receptor (PXR) plays an important and diverse role in mediating xenobiotic induction of drug-metabolizing enzymes and transporters. Several protein isoforms of PXR exist, and they have differential transcriptional activity upon target genes; transcript variants 3 (PXR3) and 4 (PXR4) do not induce target gene expression, whereas transcript variants 1 (PXR1) and 2 (PXR2) respond to agonist by activating target gene expression. PXR protein variants also display differences in protein-protein interactions; PXR1 interacts with p53, whereas PXR3 does not. Furthermore, the transcript variants of PXR that encode these protein isoforms are differentially regulated by methylation and deletions in the respective promoters of the variants, and their expression differs in various human cancers and also in cancerous tissue compared to adjacent normal tissues. and mRNA are downregulated by methylation in cancerous tissue and have divergent effects on cellular proliferation when ectopically overexpressed. Additional detailed and comparative mechanistic studies are required to predict the effect of PXR transcript variant expression on carcinogenesis, therapeutic response, and the development of toxicity.
孕烷X受体（PXR）在介导异生物素诱导药物代谢酶和转运蛋白方面发挥着重要且多样的作用。PXR存在几种蛋白质异构体，它们对靶基因具有不同的转录活性；转录变体3（PXR3）和4（PXR4）不诱导靶基因表达，而转录变体1（PXR1）和2（PXR2）通过激活靶基因表达来响应激动剂。PXR蛋白质变体在蛋白质-蛋白质相互作用方面也存在差异；PXR1与p53相互作用，而PXR3则不然。此外，编码这些蛋白质异构体的PXR转录变体在各自启动子中受甲基化和缺失的差异调节，并且它们在各种人类癌症以及癌组织与相邻正常组织中的表达也有所不同。 和 mRNA在癌组织中因甲基化而下调，异位过表达时对细胞增殖有不同影响。需要进行更多详细的比较机制研究，以预测PXR转录变体表达对致癌作用、治疗反应和毒性发展的影响。
