Expression of taurine transporter is regulated through the TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway and contributes to cytoprotection in HepG2 cells
Expression of taurine transporter is regulated through the TonE (tonicity-responsive element)/TonEBP (TonE-binding protein) pathway and contributes to cytoprotection in HepG2 cells
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DOI：
10.1042/bj20031838
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发表时间：
2004-08-15
影响因子：
4.1
通讯作者：
Azuma, J
中科院分区：
文献类型：
--
作者：
Ito, T;Fujio, Y;Azuma, J
在高渗环境中，牛磺酸通过激活牛磺酸转运体（Tau transporter，TauT）在细胞内积累，这是一种适应性调节。近年来的研究表明，TonE（tonicity-responsive element）/ TbnEBP（TonE-binding protein）通路调控着多种保护细胞免受高渗应激的分子的表达。在本研究中，我们研究了TauT表达的调控机制。在高渗条件下，TauT在HepG 2中在功能和转录水平上均上调。在TauT基因启动子区发现了TonE位点。报告基因分析表明，启动子活性增加，在高渗条件下，而缺失或突变的TonE序列取消的启动子活性的诱导响应高渗。通过使用含有TauT启动子的TonE位点的报告基因质粒（p2 xTonE-Luc），证明了TonE位点足以用于高渗介导的TauT启动子的激活。重要的是，TauT启动子基因质粒与野生型TonEBP表达载体的共转染增强了等渗条件下的启动子活性，而显性负性TonEBP废除了由高渗诱导的TauT启动子活性。最后，牛磺酸处理可防止高渗培养基诱导的HepG 2细胞死亡。这些发现表明，高渗诱导TauT介导的激活的TonE/TonEBP途径，并赋予高渗应激的抵抗力。
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)/ TbnEBP (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.