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Identification and characterization of novel polymorphisms in the basal promoter of the human transporter, MATE1.

ABSTRACT: Human multidrug and toxin extrusion member 1, MATE1 (SLC47A1), plays an important role in the renal and biliary excretion of endogenous and exogenous organic cations including many therapeutic drugs. In this study, we characterized the transcriptional effects of five polymorphic variants and six common haplotypes in the basal promoter region of MATE1 that were identified in 272 DNA samples from ethnically diverse US populations.We measured luciferase activities of the six common promoter haplotypes of MATE1 using in-vitro and in-vivo reporter assays.Haplotypes that contain the most common variant (mean allele frequency in four ethnic groups: 0.322), g.-66T>C, showed a significant decrease in reporter activities compared to the reference. Two transcription factors, activating protein-1 (AP-1) and activating protein-2 repressor (AP-2rep), were predicted to bind to the promoter in the region of g.-66T>C. Results from electrophoretic mobility shift assays showed that the g.-66T allele, exhibited greater binding to AP-1 than the g.-66C allele. AP-2rep inhibited the binding of AP-1 to the MATE1 basal promoter region, and the effect was considerably greater for the g.-66T>C. These data suggest that the reduced transcriptional activity of g.-66T>C results from a reduction in the binding potency of the transcriptional activator, AP-1, and an enhanced binding potency of the repressor, AP-2rep to the MATE1 basal promoter region. Consistent with the reporter assays, MATE1 mRNA expression levels were significantly lower in kidney samples from individuals who were homozygous or heterozygous for g.-66T>C in comparison with samples from individuals who were homozygous for the g.-66T allele.Our study suggests that the rate of transcription of MATE1 is regulated by AP-1 and AP-2rep and that a common promoter variant, g.-66T>C may affect the expression level of MATE1 in human kidney, and ultimately result in variation in drug disposition and response.

SUBMITTER: Ha Choi J

PROVIDER: S-EPMC2976711 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Identification and characterization of novel polymorphisms in the basal promoter of the human transporter, MATE1.

Ha Choi Ji J Wah Yee Sook S Kim Mee J MJ Nguyen Loan L Ho Lee Jeong J Kang Ji-One JO Hesselson Stephanie S Castro Richard A RA Stryke Doug D Johns Susan J SJ Kwok Pui-Yan PY Ferrin Thomas E TE Goo Lee Min M Black Brain L BL Ahituv Nadav N Giacomini Kathleen M KM

Pharmacogenetics and genomics 20091001 10

<h4>Objectives</h4>Human multidrug and toxin extrusion member 1, MATE1 (SLC47A1), plays an important role in the renal and biliary excretion of endogenous and exogenous organic cations including many therapeutic drugs. In this study, we characterized the transcriptional effects of five polymorphic variants and six common haplotypes in the basal promoter region of MATE1 that were identified in 272 DNA samples from ethnically diverse US populations.<h4>Methods</h4>We measured luciferase activities ...[more]

PMID: 19745787

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Project description:BackgroundConnective tissue growth factor (CCN2; CTGF) is a newly identified growth factor, which is involved in the regulation of wound repair and fibrosis. Because there is variation among individuals with respect to tissue response to injury, genetic factors might be involved in the final outcome of tissue repair or scarring. For example, polymorphisms in the promoter region of genes, such as those encoding transforming growth factor beta1 (TGF-beta1), interleukin 10 (IL-10), and tumour necrosis factor alpha (TNF-alpha), influence transcriptional responses and are thought to contribute to the dysregulation of these genes in pathological conditions.AimTo investigate whether the promoter region of the ccn2 (ctgf) gene contains polymorphic sequences that might account for differential expression.Materials/methodsSeventy seven human DNA samples were sequenced-45 were from healthy controls and 32 were from patients with ischaemic heart disease (IHD)-using M13 tailed sequence specific ccn2 (ctgf) primers for amplification of a 600 bp fragment upstream of the transcription start site. Amplicons were bidirectionally sequenced with a dye primer M13 forward and reverse sequencing kit.ResultsA C to G substitution was identified at position -132 in one of the patients with IHD. Moreover, in five of the 32 patients with IHD and in six of the 45 healthy controls, a G to C polymorphism was found at position -447. These substitutions at -132 and -447 are thought to lie within predicted binding domains for the transcription factors Pbx-1 and MZF1, respectively. In addition, insertions at position -43 (G), -47 (C), -71 (G) and a C to T substitution at position -198 were found in all DNA samples compared with the published ccn2 (ctgf) promoter sequence. These corrections do not involve sequences predicted to function as transcription factor binding sites.ConclusionSequence analysis of the ccn2 (ctgf) promoter of 77 human DNA samples has revealed corrections and polymorphic sites. The latter lie within putative regulatory elements.

Dataset Information

Identification and characterization of novel polymorphisms in the basal promoter of the human transporter, MATE1.

Publications

Identification and characterization of novel polymorphisms in the basal promoter of the human transporter, MATE1.

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