Alternative Polyadenylation of ABC Transporters of the C-Family (ABCC1, ABCC2, ABCC3) and Implications on Posttranscriptional Micro-RNA Regulation.

Autor:	Bruhn O; Institute of Experimental and Clinical Pharmacology (O.B., M.L., F.W., M.K., I.N., R.B., I.C.) and Institute for Experimental Cancer Research (C.R.), University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Lindsay M; Institute of Experimental and Clinical Pharmacology (O.B., M.L., F.W., M.K., I.N., R.B., I.C.) and Institute for Experimental Cancer Research (C.R.), University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Wiebel F; Institute of Experimental and Clinical Pharmacology (O.B., M.L., F.W., M.K., I.N., R.B., I.C.) and Institute for Experimental Cancer Research (C.R.), University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Kaehler M; Institute of Experimental and Clinical Pharmacology (O.B., M.L., F.W., M.K., I.N., R.B., I.C.) and Institute for Experimental Cancer Research (C.R.), University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Nagel I; Institute of Experimental and Clinical Pharmacology (O.B., M.L., F.W., M.K., I.N., R.B., I.C.) and Institute for Experimental Cancer Research (C.R.), University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Böhm R; Institute of Experimental and Clinical Pharmacology (O.B., M.L., F.W., M.K., I.N., R.B., I.C.) and Institute for Experimental Cancer Research (C.R.), University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Röder C; Institute of Experimental and Clinical Pharmacology (O.B., M.L., F.W., M.K., I.N., R.B., I.C.) and Institute for Experimental Cancer Research (C.R.), University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany., Cascorbi I; Institute of Experimental and Clinical Pharmacology (O.B., M.L., F.W., M.K., I.N., R.B., I.C.) and Institute for Experimental Cancer Research (C.R.), University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany cascorbi@pharmakologie.uni-kiel.de.
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2020 Feb; Vol. 97 (2), pp. 112-122. Date of Electronic Publication: 2019 Nov 22.
DOI:	10.1124/mol.119.116590
Abstrakt:	ATP-binding cassette (ABC) transporters represent a large group of efflux pumps that are strongly involved in the pharmacokinetics of various drugs and nutrient distribution. It was recently shown that micro-RNAs (miRNAs) may significantly alter their expression as proven, e.g., for miR-379 and ABCC2 However, alternative mRNA polyadenylation may result in expression of 3'-untranslated regions (3'-UTRs) with varying lengths. Thus, length variants may result in presence or absence of miRNA binding sites for regulatory miRNAs with consequences on posttranscriptional control. In the present study, we report on 3'-UTR variants of ABCC1 , ABCC2 , and ABCC3 mRNA. Applying in vitro luciferase reporter gene assays, we show that expression of short ABCC2 3'-UTR variants leads to a significant loss of miR-379/ ABCC2 interaction and subsequent upregulation of ABCC2 expression. Furthermore, we show that expression of ABCC2 3'-UTR lengths varies significantly between human healthy tissues but is not directly correlated to the respective protein level in vivo. In conclusion, the presence of altered 3'-UTR lengths in ABC transporters could lead to functional consequences regarding posttranscriptional gene expression, potentially regulated by alternative polyadenylation. Hence, 3'-UTR length variability may be considered as a further mechanism contributing to variability of ABCC transporter expression and subsequent drug variation in drug response. SIGNIFICANCE STATEMENT: micro-RNA (miRNA) binding to 3'-untranslated region (3'-UTR) plays an important role in the control of ATP-binding cassette (ABC)-transporter mRNA degradation and translation into proteins. We disclosed various 3'-UTR length variants of ABCC1, C2, and C3 mRNA, with loss of mRNA seed regions partly leading to varying and tissue-dependent interaction with miRNAs, as proven by reporter gene assays. Alternative 3'-UTR lengths may contribute to variable ABCC transporter expression and potentially explains inconsistent findings in miRNA studies. (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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