title: Regulation of the human ascorbate transporter SVCT2 exon 1b gene by zinc-finger transcription factors.
abstract: The sodium-dependent vitamin C transporter (SVCT) 2 is crucial for ascorbate uptake in metabolically active and specialized tissues. This study focused on the gene regulation of SVCT2 exon 1b, which is ubiquitously expressed in human and mouse tissues. Although the human SVCT2 exon 1b promoter does not contain a classical TATA box, we found that it does contain a functional initiator that binds Yin Yang-1 (YY1) and interacts with upstream Sp1/Sp3 elements in the proximal promoter region. These elements in turn play a critical role in regulating YY1-mediated transcription of exon 1b. Formation of YY1/Sp complexes on the promoter is required for its optional function. YY1 with Sp1 or Sp3 synergistically enhanced exon 1b promoter activity as well as the endogenous SVCT2 protein expression. Further, in addition to Sp1/Sp3, both EGR-1 and EGR-2 were detected in the protein complexes that bound the three GC boxes bearing overlapping binding sites for EGR/WT1 and Sp1/3. The EGR family factors WT1 and MAZ were found to differentially regulate exon 1b promoter activity. These results show that differential occupancy of transcription factors on the GC-rich consensus sequences in the SVCT2 exon 1b promoter contributes to the regulation of cell and tissue expression of SVCT2.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232–6303, USA. huan.qiao@vanderbilt.edu
authors.forename: Huan
authors.initials: H
authors.lastname: Qiao
authors.forename: James M
authors.initials: JM
authors.lastname: May
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004331:Drosophila melanogaster; D051765:Early Growth Response Transcription Factors / Q000235:genetics / Q000378:metabolism; D005091:Exons; D020862:GC Rich Sequence; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060347:Sodium-Coupled Vitamin C Transporters; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D051765:Early Growth Response Transcription Factors; D029363:Organic Anion Transporters, Sodium-Dependent; C555163:SLC23A2 protein, human; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D016329:Sp1 Transcription Factor; D027981:Symporters; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D051705:Sp3 Transcription Factor; D001205:Ascorbic Acid