Chen Ce-Belle, Ng Jowin K W, Choo Poh-Heok, Wu Wei, Porter Alan G
Division of Cancer and Developmental Cell Biology, Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore.
Biosci Rep. 2009 Sep 16;29(6):405-15. doi: 10.1042/BSR20090096.
MST3 (mammalian sterile 20-like kinase 3) is a sterile 20 kinase reported to have a role in Fas-ligation- and staurosporine-induced cell death by unknown mechanism(s). We found that MST3-deficient cells are resistant to H2O2, which was reversed by reconstituting recombinant MST3. H2O2-induced JNK (c-Jun N-terminal kinase) activation was greatly enhanced in shMST3 cells (a cell line treated with short hairpin RNA against MST3). Suppression of JNK activity by the inhibitor SP600125 or by dominant-negative JNK2 re-sensitized cells to H2O2. Furthermore, c-Jun Ser-63 phosphorylation was augmented in shMST3 cells, whereas JunAA (dominant-negative c-Jun) reduced H2O2 resistance, implicating an AP-1 (activator protein 1) pathway in H2O2-induced survival signalling. Total cytoprotective HO-1 (haem oxygenase 1) expression, which was attenuated by JunAA, was induced up to 5-fold higher in shMST3 cells compared with controls. Zinc protoporphyrin IX, a potent inhibitor of HO reversed the H2O2-resistance of shMST3 cells. Our results reveal that H2O2-induced MST3-mediated cell death involves suppressing both a JNK survival pathway and up-regulation of HO-1.
MST3（哺乳动物不育20样激酶3）是一种不育20激酶，据报道其通过未知机制在Fas连接和星形孢菌素诱导的细胞死亡中发挥作用。我们发现MST3缺陷型细胞对H2O2具有抗性，而通过重组重组MST3可逆转这种抗性。在shMST3细胞（一种用针对MST3的短发夹RNA处理的细胞系）中，H2O2诱导的JNK（c-Jun氨基末端激酶）激活大大增强。抑制剂SP600125或显性负性JNK2抑制JNK活性可使细胞对H2O2重新敏感。此外，shMST3细胞中c-Jun丝氨酸63磷酸化增强，而JunAA（显性负性c-Jun）降低了H2O2抗性，这表明AP-1（激活蛋白1）途径参与了H2O2诱导的存活信号传导。与对照相比，shMST3细胞中总的细胞保护酶HO-1（血红素加氧酶1）表达被JunAA减弱，但诱导水平高达对照的5倍。锌原卟啉IX是HO的有效抑制剂，可逆转shMST3细胞对H2O2的抗性。我们的结果表明，H2O2诱导的MST3介导的细胞死亡涉及抑制JNK存活途径和上调HO-1。
