title: Expression of taurine transporter is regulated through the TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway and contributes to cytoprotection in HepG2 cells.
abstract: In hypertonic environment, taurine accumulates in cells via activation of TauT (taurine transporter) as an adaptive regulation. Recent studies revealed that TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway regulated the expression of various molecules which protect cells against hypertonic stress. In the present study, we investigated the osmoregulatory mechanisms of TauT expression. TauT was up-regulated at both functional and transcriptional levels in HepG2 under hypertonic condition. The TonE site was identified in the promoter region of TauT gene. Reporter gene assay revealed that promoter activity was increased under hypertonic conditions, whereas deletion or mutation of TonE sequence abolished the induction of the promoter activity in response to hypertonicity. By using the reporter gene plasmids containing a TonE site of TauT promoter (p2xTonE-Luc), it was demonstrated that a TonE site was sufficient for the hypertonicity-mediated activation of TauT promoter. Importantly, co-transfection of TauT promoter gene plasmid with wild-type TonEBP expression vector enhanced promoter activity under isotonic conditions, whereas dominant-negative TonEBP abrogated the TauT promoter activity induced by hypertonicity. Finally, treatment with taurine prevented HepG2 cells from cell death induced by hypertonic medium. These findings suggested that induction of TauT by hypertonicity is mediated by the activation of the TonE/TonEBP pathway and confers resistance to hypertonic stress.
authors.affiliation: Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.forename: Mayo
authors.initials: M
authors.lastname: Hirata
authors.forename: Tomoka
authors.initials: T
authors.lastname: Takatani
authors.forename: Takahisa
authors.initials: T
authors.lastname: Matsuda
authors.forename: Satoko
authors.initials: S
authors.lastname: Muraoka
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Junichi
authors.initials: J
authors.lastname: Azuma
mesh_terms: D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D020011:Protective Agents / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D013654:Taurine / Q000378:metabolism / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000235:genetics; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000235:genetics; D000099247:Taurine Transporters
chemical_list: D004273:DNA, Neoplasm; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D020011:Protective Agents; D012097:Repressor Proteins; D013654:Taurine; D015534:Trans-Activators; D014157:Transcription Factors; D000099247:Taurine Transporters; C118125:NFAT5 protein, human