Regular ArticleInvolvement of Hepatocyte Nuclear Factor 4alpha in Transcriptional Regulation of the Human Pregnane X Receptor Gene in the Human Liver
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RNA interference screen identifies NAA10 as a regulator of PXR transcription
2019, Biochemical PharmacologyCitation Excerpt :Following the screening data analysis, the genes that repressed PXR mRNA after knockdown to equal to or greater than PXR siRNA controls were selected as hits from each plate (n = 115) for a confirmatory screen. Expected hits included PXR itself and HNF4A (HNF4A siRNA was indicated as a blue dot in Fig. 1B and C), a previously described regulator of PXR [13,14], thereby validating our experimental approach. To minimize false positives due to off-target effects, we assembled a new library containing pooled siRNAs, with each pool containing four individual siRNAs targeting each of the genes identified in the primary screen.
Developmental regulation of CYP3A4 and CYP3A7 in Chinese Han population
2016, Drug Metabolism and PharmacokineticsCitation Excerpt :On the other hand, HNF4A is also a key transcription factor of a coordinating nuclear receptor-mediated response to CYP3A4 through activation of the PXR gene. Iwazaki confirmed that HNF4A transactivated the PXR gene by binding to the DR1 element located at −88/−76 of the promoter and enhanced the expression level of PXR in the human liver [25]. Furthermore, during rifampin-mediated PXR activation, PXR simultaneously inhibited SHP gene transcription and subsequently promoted recruitment of transcriptional co-activators to the CYP3A4 chromatin.
Crosstalk of HNF4α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids
2016, Acta Pharmaceutica Sinica BCitation Excerpt :HNF4α is required for FXR expression in the fetal liver but not in the adult liver2. HNF4α can activate the human PXR promoter by binding to the DR1 motif in hepatoma cells64. In mice, HNF4α is essential for the expression of PXR in fetal liver by binding to the PXR promoter65.
Identification and interplay of sequence specific DNA binding proteins involved in regulation of human Pregnane and Xenobiotic Receptor gene
2015, Experimental Cell ResearchCitation Excerpt :Statistical analysis was done by two way Student's t-test and asterisks (*) signify values that differed significantly from the control experiment with p-value less than 0.05 (p<0.05 in Student's t-test). Studies from our laboratory along with others have shown that expression of PXR is driven by proximal promoter region [33,34,39,40]. In a recent report, we have identified the regulatory sequences within the 5′-proximal promoter that tightly regulate PXR expression in liver cells [34].
Pregnane and Xenobiotic Receptor gene expression in liver cells is modulated by Ets-1 in synchrony with transcription factors Pax5, LEF-1 and c-jun
2015, Experimental Cell ResearchCitation Excerpt :The human PXR-promoter homology with mouse promoter, 100 bp 5′-upstream region from the transcription initiation site of PXR gene is highly conserved in both the species [18]. From gene regulation studies, it is apparent that NR family members like glucocorticoid receptor (GR), peroxisome-proliferator activated receptor (PPARα) and hepatocyte nuclear factor (HNF4α) activate the transcription of human PXR which is predominantly mediated by its proximal promoter [17,19,20]. Because of its important physiologic and pathologic roles, understanding the mechanism of PXR gene expression is fundamental to the control of PXR expression and to the development of new therapeutic strategies for preventing drug–drug interaction or PXR-related cancer conditions.
This study was supported by a grant-in-aid from The Japan Health Sciences Foundation (Research on Health Sciences focusing on Drug Innovation) and the Ministry of Health Labor and Welfare of Japan (Research in Regulatory Science of Pharmaceutical and Medical Devices)