Critical roles of Sp1 in gene expression of human and rat H+/organic cation antiporter MATE1

American Journal of Physiology - Renal Physiology - Tập 293 Số 5 - Trang F1564-F1570 - 2007
Moto Kajiwara1, Tomohiro Terada, Junichi Asaka, K. OGASAWARA, Toshiya Katsura, Osamu Ogawa, Atsushi Fukatsu, Toshio Doi, Ken‐ichi Inui
1Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan

Tóm tắt

A H+/organic cation antiporter (multidrug and toxin extrusion 1: MATE1/SLC47A1) plays important roles in the tubular secretion of various clinically important cationic drugs such as cimetidine. We have recently found that the regulation of this transporter greatly affects the pharmacokinetic properties of cationic drugs in vivo. No information is available about the regulatory mechanisms for the MATE1 gene. In the present study, therefore, we examined the gene regulation of human (h) and rat (r) MATE1, focusing on basal expression. A deletion analysis suggested that the regions spanning −65/−25 and −146/−38 were essential for the basal transcriptional activity of the hMATE1 and rMATE1 promoter, respectively, and that both regions contained putative Sp1-binding sites. Functional involvement of Sp1 was confirmed by Sp1 overexpression, a mutational analysis of Sp1-binding sites, mithramycin A treatment, and an electrophoretic mobility shift assay. Furthermore, we found a single nucleotide polymorphism (SNP) in the promoter region of hMATE1 (G−32A), which belongs to a Sp1-binding site. The allelic frequency of this rSNP was 3.7%, and Sp1-binding and promoter activity were significantly decreased. This is the first study to clarify the transcriptional mechanisms of the MATE1 gene and to identify a SNP affecting the promoter activity of hMATE1.

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Tài liệu tham khảo

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Thông tin xuất bản

American Journal of Physiology - Renal Physiology

Tập 293 Số 5

F1564-F1570

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