Human organic anion transporter 3 gene is regulated constitutively and inducibly via a cAMP-response element.
Human organic anion transporter (OAT) 3 (SLC22A8) is localized to the basolateral membranes of renal tubular epithelial cells and plays a critical role in the excretion of anionic compounds. We previously reported that interindividual variation in the OAT3 mRNA level corresponded to interindividual differences in the rate of renal excretion of cefazolin. However, there is little information available on the molecular mechanisms regulating the gene expression of OAT3. Therefore, in the present study, we examined the transcriptional regulation of human OAT3. A deletion analysis of the OAT3 promoter suggested that the region spanning -214 to -77 base pairs was essential for basal transcriptional activity. This region contained a perfectly conserved cAMP-response element (CRE), and a mutation here led to a reduction in promoter activity. Electrophoretic mobility shift assays showed that CRE-binding protein (CREB)-1 and activating transcription factor (ATF)-1 bound to CRE. The activity of the OAT3 promoter was increased through the phosphorylation of CREB-1 and ATF-1 by treatment with 8-bromo-cAMP. This paper reports the first characterization of the human OAT3 promoter and shows that CREB-1 and ATF-1 function as constitutive and inducible transcriptional regulators of the human OAT3 gene via CRE.
Ogasawara
Ken
K
Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.
Terada
Tomohiro
T
Asaka
Jun-Ichi
J
Katsura
Toshiya
T
Inui
Ken-Ichi
K
D001483:Base Sequence; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020218:Response Elements / Q000502:physiology*; D024363:Transcription Initiation Site
D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases