Inada Shojiro, Ikeda Yukio, Suehiro Tadashi, Takata Hiroshi, Osaki Fumiaki, Arii Kaoru, Kumon Yoshitaka, Hashimoto Kozo
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Nankoku, Kochi 783-8505, Japan.
Mol Cell Endocrinol. 2007 Jun 15;271(1-2):64-70. doi: 10.1016/j.mce.2007.04.005. Epub 2007 Apr 22.
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin receptor signal transduction pathway. We investigated the effects of glucose on PTP1B transcription in the human hepatocyte cell line Huh7. Using a reporter gene assay, we found that D-glucose dose-dependently enhanced the PTP1B promoter activity. Real-time PCR demonstrated that D-glucose also increased PTP1B mRNA expression. Protein kinase C (PKC) inhibitors partially but significantly inhibited the transactivation by D-glucose. Mithramycin, a Sp1 inhibitor, completely abrogated this transactivation. The deletion of three possible Sp1 sites in the promoter region of PTP1B significantly reduced the basal promoter activity and transactivation by D-glucose. Sp1 activation by PKC is one of the key mechanisms in the regulation of several gene expressions. Our data suggested that glucose enhanced PTP1B transcription through Sp1 activation by PKC. Increased hepatic PTP1B expression may partly explain glucose toxicity in diabetes.
蛋白酪氨酸磷酸酶1B（PTP1B）是胰岛素受体信号转导通路的负调节因子。我们研究了葡萄糖对人肝癌细胞系Huh7中PTP1B转录的影响。通过报告基因检测，我们发现D - 葡萄糖呈剂量依赖性地增强PTP1B启动子活性。实时PCR表明D - 葡萄糖也增加了PTP1B mRNA的表达。蛋白激酶C（PKC）抑制剂部分但显著地抑制了D - 葡萄糖的反式激活作用。放线菌素D，一种Sp1抑制剂，完全消除了这种反式激活作用。PTP1B启动子区域三个可能的Sp1位点的缺失显著降低了基础启动子活性以及D - 葡萄糖的反式激活作用。PKC介导的Sp1激活是几种基因表达调控的关键机制之一。我们的数据表明葡萄糖通过PKC介导的Sp1激活增强了PTP1B转录。肝脏中PTP1B表达的增加可能部分解释了糖尿病中的葡萄糖毒性。
