The C421A (Q141K) polymorphism enhances the 3'-untranslated region (3'-UTR)-dependent regulation of ATP-binding cassette transporter ABCG2

Biochemical Pharmacology
Anne Ripperger, Ralf A Benndorf

Abstract

The impact of the gout-causing C421A (Q141K) single nucleotide polymorphism (SNP) on ABC transporter ABCG2 expression and function has been extensively characterized. However, the influence of the C421A SNP on 3'-UTR-dependent ABCG2 regulation has not been analysed so far. To elucidate this matter, we generated vectors for expression of either the ABCG2 coding sequence (ORF) or the ABCG2 ORF fused to its 3'-UTR, inserted the C421A mutation via site-directed mutagenesis and expressed wild-type and C421A-mutated ABCG2 transcripts in HEK293-Tet-On cells. As shown previously, the C421A SNP significantly reduced ABCG2 protein levels in ABCG2 ORF-transfected HEK293-Tet-On cells. Interestingly, the presence of the 3'-UTR in the ABCG2 transcript dramatically reduced ABCG2 protein content in cells transfected with the C421A variant but not significantly in those transfected with ABCG2 wild-type sequence, whereas ABCG2 mRNA levels were similar. siRNA-mediated DICER1 knockdown to reduce cellular microRNA biogenesis and selective mutation of putative microRNA binding sites within the ABCG2 3'-UTR partially antagonized C421A-associated reduction of ABCG2 protein content but did not significantly affect wild-type ABCG2 protein levels. In add...Continue Reading

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Citations

Sep 1, 2016·Expert Opinion on Drug Metabolism & Toxicology·Takeshi HirotaIchiro Ieiri
Apr 7, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Toni Schumacher, Ralf A Benndorf
Nov 14, 2018·Clinical Chemistry and Laboratory Medicine : CCLM·Felicia Stefania FalvellaMauro Panteghini
Mar 12, 2019·Expert Opinion on Drug Metabolism & Toxicology·Zsolt SafarPeter Krajcsi
Jun 30, 2019·Cellular and Molecular Life Sciences : CMLS·Boglárka ZámbóBalázs Sarkadi
Jan 28, 2020·British Journal of Pharmacology·Robert Eckenstaler, Ralf A Benndorf
Jul 3, 2021·International Journal of Molecular Sciences·Robert Eckenstaler, Ralf A Benndorf
Jul 12, 2021·Arthritis Research & Therapy·Jana BohatáBlanka Stibůrková

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