Xu Qihe, Konta Tsuneo, Nakayama Kenji, Furusu Akira, Moreno-Manzano Victoria, Lucio-Cazana Javier, Ishikawa Yoshihisa, Fine Leon G, Yao Jian, Kitamura Masanori
Department of Medicine, Royal Free and University College Medical School, University College London, London, England, United Kingdom.
Free Radic Biol Med. 2004 Apr 15;36(8):985-93. doi: 10.1016/j.freeradbiomed.2004.01.009.
Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is an oxidative stress-inducible gene. In this study, we investigated signaling pathways involved in oxidative stress-induced MKP-1 expression and its role in apoptosis of rat mesangial cells. Northern and Western blot analyses showed that H(2)O(2) induced expression of MKP-1 mRNA and protein in a dose-dependent manner, without affecting the stability of the transcript. H(2)O(2) induced phosphorylation of extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun N-terminal kinase and consequently activated activator protein 1 (AP-1). Selective inhibitors of individual MAP kinases or a dominant-negative mutant of c-jun significantly suppressed the expression of MKP-1 by H(2)O(2). Inhibition of MKP-1 by a protein tyrosine phosphatase inhibitor (vanadate) enhanced H(2)O(2)-triggered apoptosis. Consistently, transfection with a wild-type MKP-1, but not its catalytically inactive mutant MKP-1CS, attenuated H(2)O(2)-induced apoptosis. These data elucidate, for the first time, that induction of MKP-1 by H(2)O(2) is mediated by the MAP kinase-AP-1 pathway and that the induced MKP-1 is involved in cellular defense against oxidative stress-induced apoptosis of mesangial cells.
丝裂原活化蛋白（MAP）激酶磷酸酶-1（MKP-1）是一种氧化应激诱导基因。在本研究中，我们调查了氧化应激诱导MKP-1表达所涉及的信号通路及其在大鼠系膜细胞凋亡中的作用。Northern印迹和Western印迹分析表明，H₂O₂以剂量依赖方式诱导MKP-1 mRNA和蛋白的表达，且不影响转录本的稳定性。H₂O₂诱导细胞外信号调节激酶、p38 MAP激酶和c-Jun N末端激酶的磷酸化，从而激活活化蛋白1（AP-1）。单个MAP激酶的选择性抑制剂或c-jun的显性负突变体显著抑制H₂O₂诱导的MKP-1表达。蛋白酪氨酸磷酸酶抑制剂（钒酸盐）抑制MKP-1增强了H₂O₂触发的细胞凋亡。同样，转染野生型MKP-1而非其催化失活突变体MKP-1CS可减轻H₂O₂诱导的细胞凋亡。这些数据首次阐明，H₂O₂诱导MKP-1是由MAP激酶-AP-1途径介导的，且诱导的MKP-1参与了系膜细胞对抗氧化应激诱导凋亡的细胞防御。
