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Identification and validation of the microRNA response elements in the 3'-untranslated region of the UDP glucuronosyltransferase (UGT) 2B7 and 2B15 genes by a functional genomics approach.

作者信息

Papageorgiou Ioannis, Court Michael H

机构信息

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA, USA.

出版信息

Biochem Pharmacol. 2017 Dec 15;146:199-213. doi: 10.1016/j.bcp.2017.09.013. Epub 2017 Sep 28.


DOI:10.1016/j.bcp.2017.09.013
PMID:28962835
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6188638/
Abstract

Posttranscriptional repression of UDP-glucuronosyltransferase (UGT) 2B7 and 2B15 expression by microRNAs (miRNAs) may be an important mechanism underlying inter-individual variability in drug glucuronidation. Furthermore, the UGT2B15 3'-UTR contains a common SNP (rs3100) that could influence miRNA binding. The aim of this study was to identify the complete complement of miRNAs that could regulate UGT2B7 and UGT2B15 expression through binding to the reference and/or variant 3'-UTRs. Luciferase reporter plasmids containing either the reference or variant 3'-UTRs were screened against a 2,048 human miRNA library to identify those miRNAs that decrease luciferase activity by at least 30% when co-transfected into HEK293 cells. Six novel miRNAs (miR-1293, miR-3664-3p, miR-4317, miR-513c-3p, miR-4483, and miR-142-3p) were identified that repressed the reference UGT2B7 3'-UTR, while twelve novel miRNAs (miR-770-5p, miR-103b, miR-3924, miR-376b-3p, miR-455-5p, miR-605, miR-624-3p, miR-4712-5p, miR-3675-3p, miR-6500-5p, miR-548as-3p, and miR-4292) repressed both the reference and rs3100 variant UGT2B15 3'-UTR. Deletion and mutagenesis studies confirmed the binding site location of each miRNA. Although the UGT2B15 rs3100 SNP was located within the miR-376c-3p response element, there was no effect on miRNA binding. miR-142-3p, miR-3664-3p, miR-4317, miR-455-5p, miR-376c-3p, miR-770-5p, miR-3675-3p, miR-331-5p, miR-605, and miR-376b-3p transcript levels were measured by quantitative PCR and correlated with UGT2B7 and UGT2B15 enzyme activities in 27 human liver samples. A significant negative correlation (R = -0.53; p = 0.005) was demonstrated between hepatic miR-455-5p transcript levels and UGT2B15-mediated S-oxazepam glucuronidation activities. Thus, the UGT2B7 and UGT2B15 3'-UTRs contain miRNA response elements for multiple miRNAs that may contribute to variable drug glucuronidation.

摘要

相似文献

[1]
Identification and validation of the microRNA response elements in the 3'-untranslated region of the UDP glucuronosyltransferase (UGT) 2B7 and 2B15 genes by a functional genomics approach.

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[2]
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[3]
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[5]
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[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
Identification and validation of microRNAs directly regulating the UDP-glucuronosyltransferase 1A subfamily enzymes by a functional genomics approach.

Biochem Pharmacol. 2017-8-1

[2]
Distribution of miRNA expression across human tissues.

Nucleic Acids Res. 2016-5-5

[3]
MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy.

Drug Metab Dispos. 2016-3

[4]
Epigenetic regulation of steroid inactivating UDP-glucuronosyltransferases by microRNAs in prostate cancer.

J Steroid Biochem Mol Biol. 2016-1

[5]
Regulation of Human UGT2B15 and UGT2B17 by miR-376c in Prostate Cancer Cell Lines.

J Pharmacol Exp Ther. 2015-9

[6]
Identification of microRNA biomarkers in type 2 diabetes: a meta-analysis of controlled profiling studies.

Diabetologia. 2015-2-13

[7]
Genetic variation in the 3'-UTR of CYP1A2, CYP2B6, CYP2D6, CYP3A4, NR1I2, and UGT2B7: potential effects on regulation by microRNA and pharmacogenomics relevance.

Front Genet. 2014-6-4

[8]
Identification of suitable reference genes for hepatic microRNA quantitation.

BMC Res Notes. 2014-3-7

[9]
The UDP-glucuronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A exon 5a/5b splice variant mRNA ratio, and decreased risk of unintentional acetaminophen-induced acute liver failure.

J Pharmacol Exp Ther. 2013-2-13

[10]
Differential allelic expression of c.1568C > A at UGT2B15 is due to variation in a novel cis-regulatory element in the 3'UTR.

Gene. 2011-4-13

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