Down-regulation of the c-Jun N-terminal kinase (JNK) phosphatase M3/6 and activation of JNK by hydrogen peroxide and pyrrolidine dithiocarbamate
Down-regulation of the c-Jun N-terminal kinase (JNK) phosphatase M3/6 and activation of JNK by hydrogen peroxide and pyrrolidine dithiocarbamate
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DOI：
10.1038/sj.onc.1204105
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发表时间：
2001-01-18
期刊：
影响因子：
8
通讯作者：
Tan, TH
中科院分区：
文献类型：
--
作者：
Chen, YR;Shrivastava, A;Tan, TH
氧化应激激活c-Jun N-末端激酶（JNK）通路。然而，活性氧（ROS）激活JNK的确切机制尚不清楚。我们发现过氧化氢（H2 O2）诱导JNK激活的能力在不同的细胞类型中是不同的。吡咯烷二硫代氨基甲酸酯（PDTC），一种假定的抗氧化剂，诱导JNK激活本身和增强JNK激活过氧化氢在许多细胞类型，包括Jurkat，HEK 293，和LNCaP和Tsu-Prl前列腺癌细胞。PDTC对JNK的激活依赖于其对金属离子的螯合能力，最可能的是铜离子。尽管H2 O2 + PDTC具有很强的激活JNK的能力，但其对上游激酶SEK 1/MKK 4和MKK 7的激活并不显著。然而，与紫外线C（CUV-C）处理的细胞相比，H2 O2钉PDTC处理的细胞中JNK失活速率较慢。H2 O2钉PDTC处理显著降低JNK磷酸酶M3/6的表达水平（也称为hVH-5），但不包括其他磷酸酶的水平而UV-C照射并不引起M3/6的下调。这些结果表明H_2O_2和PDTC激活JNK是通过下调JNK磷酸酶的表达而实现的。我们的数据还揭示了仔细评估PDTC的药理学和生化特性的必要性。
Oxidative stress activates the c-Jun N-terminal kinase (JNK) pathway. However, the exact mechanisms by which reactive oxygen species (ROS) activate JNK are unclear. We found that the ability of hydrogen peroxide (H2O2) to induce JNK activation varied in different cell types. Pyrrolidine dithiocarbamate (PDTC), a presumed antioxidant, induced JNK activation on its own and enhanced JNK activation by H2O2 in many cell types, including Jurkat, HEK293, and LNCaP and Tsu-Prl prostate cancer cells. The activation of JNK by PDTC, in the presence or absence of exogenous H2O2, was dependent on its chelating ability to metal ions, most likely copper ions, Despite the strong JNK-activating ability, H2O2 plus PDTC did not induce significant activation of the upstream kinases, SEK1/MKK4 and MKK7. However, the JNK inactivation rate was slower in cells treated with H2O2 pins PDTC compared with the rate in cells treated with ultraviolet C CUV-C), Treatment of H2O2 pins PDTC significantly decreased the expression levels of a JNK phosphatase, M3/6 (also named hVH-5), but not the levels of other phosphatases (PP2A and PP4), In contrast, UV-C irradiation did not cause the down-regulation of M3/6, These results suggest that JNK activation by H2O2 plus PDTC resulted from the down-regulation of JNK phosphatases. Our data also reveal a necessity to carefully evaluate the pharmacological and biochemical properties of PDTC.