Department of Pediatrics, University of Tennessee Health Science Center, and the Children's Foundation Research Center at Le Bonheur Children's Medical Center, Memphis, Tennessee, USA.
J Biomed Sci. 2010 Aug 24;17 Suppl 1(Suppl 1):S28. doi: 10.1186/1423-0127-17-S1-S28.
Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity. We have demonstrated that cisplatin down-regulates the expression of the taurine transporter gene (TauT) in renal cells and that forced overexpression of TauT protects against cisplatin-induced apoptosis in renal cells in vitro and in vivo. In the present study, we have investigated how TauT is regulated by p53 and c-Jun and its role during acute kidney injury (AKI).
Regulation of TauT by p53 and c-Jun was determined by reporter gene assay, DNA binding, Western blot analysis, and immunohistochemistry.
TauT was down-regulated by p53 and up-regulated by c-Jun. Two potential binding sites for c-Jun were identified in the promoter region of TauT. Inhibition of c-Jun N-terminal kinase (JNK) enhanced TauT promoter activity. Overexpression of TauT protects against cisplatin-induced kidney injury in a TauT transgenic mouse model.
Our findings suggest that TauT plays a critical role in renal function. Expression of TauT is negatively regulated by p53 and positively regulated by c-Jun, which is mediated by the JNK signaling pathway. The outcome level of TauT may determine the fate of renal cells during stress-induced AKI.
顺铂是一种常用的化疗药物，但由于其肾毒性而存在很大的局限性。我们已经证明，顺铂下调肾细胞中牛磺酸转运体基因（TauT）的表达，而强制过表达 TauT 可在体外和体内保护肾细胞免受顺铂诱导的凋亡。在本研究中，我们研究了 TauT 如何受 p53 和 c-Jun 调节及其在急性肾损伤（AKI）期间的作用。
通过报告基因测定、DNA 结合、Western blot 分析和免疫组织化学来确定 TauT 受 p53 和 c-Jun 的调节。
TauT 受 p53 下调，受 c-Jun 上调。在 TauT 启动子区域鉴定出两个潜在的 c-Jun 结合位点。抑制 c-Jun N 端激酶（JNK）增强 TauT 启动子活性。过表达 TauT 可在 TauT 转基因小鼠模型中保护顺铂诱导的肾损伤。
我们的研究结果表明，TauT 在肾功能中起着关键作用。TauT 的表达受 p53 负调控，受 c-Jun 正调控，这是由 JNK 信号通路介导的。TauT 的表达水平可能决定应激诱导的 AKI 期间肾细胞的命运。
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