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Down-regulation of the c-Jun N-terminal kinase (JNK) phosphatase M3/6 and activation of JNK by hydrogen peroxide and pyrrolidine dithiocarbamate

Oncogene volume 20, pages 367–374 (2001)Cite this article

Abstract

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-Pr1 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 plus PDTC compared with the rate in cells treated with ultraviolet C (UV-C). Treatment of H2O2 plus 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.

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Abbreviations

BCS:

bathocuproinedisulfonic acid

HEK293 cells:

human embryonic kidney 293 cells

GSH:

glutathione

GST:

glutathione S-transferase

JNK:

c-Jun N-terminal kinase

PDTC:

pyrrolidine dithiocarbamate

PP2A:

protein phosphatase 2A

PP4:

protein phosphatase 4

redox:

reduction-oxidation

ROS:

reactive oxygen species

SEK1:

SAPK/ERK kinase 1

UV-C:

ultraviolet C

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Acknowledgements

We thank Drs A Ashworth, J Chen, KE Davis, RJ Davis, M Karin, N Rodrigues, A Smith, A Theodosiou, D Templeton, B Yao and L Zon for generous gifts, members of Tan laboratory for their helpful discussions and critical reading of this manuscript, A Ashtari for technical assistance and S Robertson for secretarial assistance. This work was supported by the National Institutes of Health grants R01-AI38649, R01-AI42532, and P50-CA58204 (to T-H Tan) and Postdoctoral Fellowship DAMD17-99-1-9507 from the Prostate Cancer Research Program, Department of Defense (to Y-R Chen). T-H Tan is a Scholar of the Leukemia & Lymphoma Society (formerly the Leukemia Society of America).

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  1. Department of Immunology, Baylor College of Medicine, Houston, 77030, Texas, TX, USA

    Yi-Rong Chen, Anju Shrivastava & Tse-Hua Tan

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Chen, YR., Shrivastava, A. & Tan, TH. Down-regulation of the c-Jun N-terminal kinase (JNK) phosphatase M3/6 and activation of JNK by hydrogen peroxide and pyrrolidine dithiocarbamate. Oncogene 20, 367–374 (2001). https://doi.org/10.1038/sj.onc.1204105

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