PMID- 31757862 OWN - NLM STAT- MEDLINE DCOM- 20200512 LR - 20211204 IS - 1521-0111 (Electronic) IS - 0026-895X (Linking) VI - 97 IP - 2 DP - 2020 Feb TI - Alternative Polyadenylation of ABC Transporters of the C-Family (ABCC1, ABCC2, ABCC3) and Implications on Posttranscriptional Micro-RNA Regulation. PG - 112-122 LID - 10.1124/mol.119.116590 [doi] AB - 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. CI - Copyright (c) 2020 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Bruhn, Oliver AU - Bruhn O AD - 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. FAU - Lindsay, Marie AU - Lindsay M AD - 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. FAU - Wiebel, Friederike AU - Wiebel F AD - 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. FAU - Kaehler, Meike AU - Kaehler M AD - 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. FAU - Nagel, Inga AU - Nagel I AD - 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. FAU - Bohm, Ruwen AU - Bohm R AD - 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. FAU - Roder, Christian AU - Roder C AD - 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. FAU - Cascorbi, Ingolf AU - Cascorbi I AUID- ORCID: 0000-0002-2182-9534 AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191122 PL - United States TA - Mol Pharmacol JT - Molecular pharmacology JID - 0035623 RN - 0 (3' Untranslated Regions) RN - 0 (ABCC2 protein, human) RN - 0 (MIRN379 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Multidrug Resistance-Associated Protein 2) RN - 0 (Multidrug Resistance-Associated Proteins) RN - 0 (RNA, Messenger) RN - 1YV0492L5Z (multidrug resistance-associated protein 3) RN - Y49M64GZ4Q (multidrug resistance-associated protein 1) SB - IM MH - 3' Untranslated Regions MH - Aged MH - Aged, 80 and over MH - Caco-2 Cells MH - Colon/metabolism MH - Female MH - Gallbladder/metabolism MH - Gene Expression Regulation MH - Hep G2 Cells MH - Humans MH - Liver/metabolism MH - Male MH - MicroRNAs/*metabolism MH - Middle Aged MH - Multidrug Resistance-Associated Protein 2 MH - Multidrug Resistance-Associated Proteins/*genetics/metabolism MH - Polyadenylation MH - RNA, Messenger/*metabolism EDAT- 2019/11/24 06:00 MHDA- 2020/05/13 06:00 CRDT- 2019/11/24 06:00 PHST- 2019/03/02 00:00 [received] PHST- 2019/11/12 00:00 [accepted] PHST- 2019/11/24 06:00 [pubmed] PHST- 2020/05/13 06:00 [medline] PHST- 2019/11/24 06:00 [entrez] AID - mol.119.116590 [pii] AID - 10.1124/mol.119.116590 [doi] PST - ppublish SO - Mol Pharmacol. 2020 Feb;97(2):112-122. doi: 10.1124/mol.119.116590. Epub 2019 Nov 22.