title: 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.
abstract: Nuclear receptor PXR is predominantly expressed in liver and intestine. Expression of PXR is observed to be dysregulated in various metabolic disorders indicating its involvement in disease development. However, information available on mechanisms of PXR self-regulation is fragmentary. The present investigation identifies some of the regulatory elements responsible for its tight regulation and low cellular expression. Here, we report that the PXR-promoter is a target for some key transcription factors like PU.1/Ets-1, Pax5, LEF-1 and c-Jun. Interestingly, we observed that PXR-promoter responsiveness to Pax5, LEF-1 and c-Jun, is considerably enhanced by Ets transcription factors (PU.1 and Ets-1). Co-transfection of cells with Ets-1, LEF-1 and c-Jun increased PXR-promoter activity by 5-fold and also induced expression of endogenous human PXR. Site-directed mutagenesis and transfection studies revealed that two Ets binding sites and two of the three LEF binding sites in the PXR-promoter are functional and have a positive effect on PXR transcription. Results suggest that expression of Ets family members, in conjunction with Pax5, LEF-1 and c-Jun, lead to coordinated up-regulation of PXR gene transcription. Insights obtained on the regulation of PXR gene have relevance in offering important cues towards normal functioning as well as development of several metabolic disorders via PXR signaling.
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Mallampati
authors.initials: M
authors.lastname: Saradhi
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Manjul
authors.initials: M
authors.lastname: Rana
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Swagata
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: IRI, CNRS USR 3078, Université de Lille-Nord de France, Parc CNRS de la Haute Borne, 50 Avenue de Halley, BP 70478, 59658 Villeneuve d'Ascq Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Aumercier
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Gauranga
authors.initials: G
authors.lastname: Mukhopadhyay
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address: rktyagi@yahoo.com.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Tyagi
mesh_terms: D001665:Binding Sites / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D051757:PAX5 Transcription Factor / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D051821:Lymphoid Enhancer-Binding Factor 1; D051757:PAX5 Transcription Factor; D000077297:Pregnane X Receptor; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494041:ETS1 protein, human; C497573:LEF1 protein, human; C497281:PAX5 protein, human
keywords: Gene regulation; Pregnane and Xenobiotic Receptor; Promoter-reporter assays; Transcription factors; cis-elements