@article {Bruhnmol.119.116590, author = {Oliver Bruhn and Marie Lindsay and Friederike Wiebel and Meike Kaehler and Inga Nagel and Ruwen Bohm and Christian Roder and Ingolf Cascorbi}, title = {Alternative polyadenylation of ABC-transporters of the C-family (ABCC1, ABCC2, ABCC3) and implications on post-transcriptional micro-RNA regulation}, elocation-id = {mol.119.116590}, year = {2019}, doi = {10.1124/mol.119.116590}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {ABC-transporters represent a large group of efflux pumps being strongly involved in the pharmacokinetics of various drugs as well as of nutrient distribution. It was recently shown that 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{\textquoteright}-untranslated regions (3{\textquoteright}-UTRs) with varying lengths. Thus, length variants may result in presence or absence of miRNA binding sites for regulatory micro-RNAs with consequences on posttranscriptional control. In the present study, we report on 3{\textquoteright}-UTR variants of ABCC1, ABCC2, and ABCC3 mRNA. Applying in vitro luciferase reporter gene assays, we show that expression of short ABCC2 3{\textquoteright}-UTR variants leads to a significant loss of miR-379/ABCC2 interaction and subsequent upregulation of ABCC2 expression. Further, we show that expression of ABCC2 3{\textquoteright}-UTR lengths varies significantly between human healthy tissues, but is not directly correlated to the respective protein level in vivo. Concluding, presence of altered 3{\textquoteright}-UTR lengths in ABC-transporters could lead to functional consequences with regards to posttranscriptional gene expression potentially regulated by alternative polyadenylation. Hence, 3{\textquoteright}-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 microRNA binding to the 3’-UTR plays an important role in control of ABC-transporter mRNA degradation and translation into proteins. We disclosed various 3’-UTR length variants of ABCC1, C2 and C3 mRNA partly with loss of mRNA seed regions leading to varying and tissue-dependent interaction with miRNAs as proven by reporter gene assays. Alternative 3’-UTR length may contribute to variable ABCC-transporter expression and potentially explains inconsistent findings in microRNA studies.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2019/11/22/mol.119.116590}, eprint = {https://molpharm.aspetjournals.org/content/early/2019/11/22/mol.119.116590.full.pdf}, journal = {Molecular Pharmacology} }