A novel polymorphism in a forkhead box A1 (FOXA1) binding site of the human UDP glucuronosyltransferase 2B17 gene modulates promoter activity and is associated with altered levels of circulating androstane-3α,17β-diol glucuronide

Molecular Pharmacology
Dong Gui HuPeter I Mackenzie

Abstract

UDP glucuronosyltransferase 2B17 is present in the prostate, where it catalyzes the addition of glucuronic acid to testosterone and dihydrotestosterone and their metabolites androsterone and androstane-3α,17β-diol. Hence, changes in UGT2B17 gene expression may affect the capacity of the prostate to inactivate and eliminate male sex hormones. In this work, we identify a prevalent polymorphism, -155G/A, in the proximal promoter of the UGT2B17 gene. This polymorphism modulates UGT2B17 promoter activity, because luciferase-gene reporter constructs containing the -155A allele were 13-fold more active than those containing the -155G allele in prostate cancer LNCaP cells. The -155G/A polymorphism is contained within a putative binding site for the transcription factor Forkhead Box A1 (FOXA1). Using gene reporter, electromobility shift, and chromatin immunoprecipitation analyses, we show that FOXA1 binds to this site and stimulates the UGT2B17 promoter. Furthermore, down-regulation of FOXA1 in LNCaP cells substantially reduces UGT2B17 mRNA levels. The binding of FOXA1 and subsequent stimulation of the UGT2B17 promoter is greatly reduced in the presence of the -155G allele compared with the -155A allele. Consonant with its capacity to b...Continue Reading

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Citations

Mar 19, 2013·The International Journal of Biochemistry & Cell Biology·Andrew RowlandPeter I Mackenzie
Oct 27, 2012·Genetic Testing and Molecular Biomarkers·Delores J GrantStephen J Freedland
Oct 23, 2014·Drug Metabolism Reviews·Dong Gui HuPeter I Mackenzie
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Apr 14, 2017·The Journal of Pharmacology and Experimental Therapeutics·Apichaya ChanawongRobyn Meech
Jan 26, 2018·The Journal of Pharmacology and Experimental Therapeutics·Dhilushi D WijayakumaraRobyn Meech
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Sep 20, 2012·Biochemical Society Transactions·Ewa JurneczkoPerdita E Barran
Feb 11, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Chan XiangHaijian Wang

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