The role of mitogen-activated protein kinase phosphatase-1 in oxidative damage-induced cell death
The role of mitogen-activated protein kinase phosphatase-1 in oxidative damage-induced cell death
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DOI：
10.1158/0008-5472.can-05-4229
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发表时间：
2006-05-01
期刊：
影响因子：
11.2
通讯作者：
Wu, Gen Sheng
中科院分区：
文献类型：
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作者：
Zhou, Jun-Ying;Liu, Yusen;Wu, Gen Sheng
丝裂原活化蛋白激酶（MAPK）磷酸酶-1（MKP-1）是MAPK磷酸酶家族的成员，其作为MAPK信号传导的负调节剂起作用。MKP-1由氧化应激诱导，但其诱导在细胞死亡中的作用尚不完全清楚。在这里，我们表明，过氧化氢（H2 O2）诱导MKP-1和激活MAPK。H2 O2对MKP-1的诱导与p38和c-Jun-NH 2-激酶（JNK）的失活相关。MKP-1的过表达增加了细胞对H2 O2诱导的死亡的抵抗力。此外，我们通过小干扰RNA沉默表明MIKP-1的下调增加了磷酸化p38和JNK以及随后由H2 O2诱导的细胞死亡。更重要的是，缺乏MKP-1的小鼠的原代胚胎成纤维细胞具有更高水平的磷酸化p38和JNK，并且与具有MKP-1的相应细胞相比，对H2 O2诱导的细胞死亡更敏感，这表明p38和JNK通路可能在H2 O2介导的细胞死亡中起重要作用。因此，这些结果表明MKP-1的活化是对抗氧化损伤的存活机制。
Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a member of the MAPK phosphatase family that functions as a negative regulator of MAPK signaling. MKP-1 is induced by oxidative stress, but the role of its induction in cell death is not fully understood. Here, we show that hydrogen peroxide (H2O2) induces MKP-1 and activates MAPKs. Induction of MKP-1 by H2O2 correlated with inactivation of p38 and c-Jun-NH2-kinase (JNK). Overexpression of MKP-1 increased cell resistance to H2O2-induced death. Furthermore, we show by small interfering RNA silencing that down-regulation of MIKP-1 increases phosphorylated p38 and JNK and subsequent cell death induced by H2O2. More importantly, primary embryonic fibroblasts from mice lacking MKP-1 had a higher level of phosphorylated p38 and JNK and were more sensitive to H2O2-induced cell death compared with corresponding cells with MKP-1, indicating that p38 and JNK pathways may play important roles in H2O2-mediated cell death. Thus, these results suggest that activation of MKP-1 is a survival mechanism against oxidative damage.