title: Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver.
abstract: MiR-122 is a major hepatic microRNA, accounting for more than 70% of the total liver miRNA population. It has been shown that miR-122 is associated with liver diseases, including hepatocellular carcinoma. Mir-122 is an intergenic miRNA with its own promoter. Pri-miR-122 expression is regulated by liver-enriched transcription factors, mainly by HNF4α, which mediates the expression via the interaction with a specific DR1 site. It has been shown that phenobarbital-mediated activation of constitutive androstane receptor (CAR), xenobiotic nuclear receptor, is associated with a decrease in miR-122 in the liver. In the present study, we investigated HNF4α-CAR cross-talk in the regulation of miR-122 levels and promitogenic signalling in mouse livers. The level of miR-122 was significantly repressed by treatment with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of mouse CAR. ChIP assays demonstrated that TCPOBOP-activated CAR inhibited HNF4α transactivation by competing with HNF4α for binding to the DR1 site in the pri-miR-122 promoter. Such transcription factor replacement was strongly correlated with miR-122 down-regulation. Additionally, the decrease in miR-122 levels produced by CAR activation is accompanied by an increase in mRNA and cellular protein levels of E2f1 and its accumulation on the target cMyc gene promoter. The increase in accumulation of E2f1 on the target cMyc gene promoter is accompanied by an increase in cMyc levels and transcriptional activity. Thus, our results provide evidence to support the conclusion that CAR activation decreases miR-122 levels through suppression of HNF4α transcriptional activity and indirectly regulates the promitogenic protein cMyc. HNF4α-CAR cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments.
authors.affiliation: The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117, Russia.
authors.forename: Yuliya A
authors.initials: YA
authors.lastname: Kazantseva
authors.affiliation: The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117, Russia.
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Yarushkin
authors.affiliation: The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117, Russia.
authors.forename: Lyudmila A
authors.initials: LA
authors.lastname: Mostovich
authors.affiliation: Novosibirsk State University, Pirogova str., 2, Novosibirsk 630090, Russia.
authors.forename: Yuliya A
authors.initials: YA
authors.lastname: Pustylnyak
authors.affiliation: The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117, Russia; Novosibirsk State University, Pirogova str., 2, Novosibirsk 630090, Russia; The Institute International Tomography Center of the Russian Academy of Sciences, Institutskaya str. 3-A, Novosibirsk 630090, Russia. Electronic address: pustylnyak@ngs.ru.
authors.forename: Vladimir O
authors.initials: VO
authors.lastname: Pustylnyak
mesh_terms: D000732:Androstanols / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D049109:Cell Proliferation / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000633:toxicity*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D000732:Androstanols; D000090702:Constitutive Androstane Receptor; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene
keywords: Constitutive androstane receptor; HNF4α; Liver; MiR-122; TCPOBOP; cMyc