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Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway

Oncogene volume 26, pages 7222–7230 (2007)Cite this article

Abstract

FDH (10-formyltetrahydrofolate dehydrogenase) is strongly downregulated in tumors while its elevation suppresses proliferation of cancer cells and induces p53-dependent apoptosis. We have previously shown that FDH induces phosphorylation of p53 at Ser6, which is a required step in the activation of apoptosis. In the present study, we report that FDH-induced p53 phosphorylation is carried out by JNK1 and JNK2 (c-Jun N-terminal kinases) working in concert. We have demonstrated that FDH induces phosphorylation of JNK1 and JNK2, while treatment of FDH-expressing cells with JNK inhibitor SP600125, as well as knockdown of JNK1 or JNK2 by siRNA, prevents phosphorylation of p53 at Ser6 and protects cells from apoptosis. Interestingly, the knockdown of JNK1 abolished phosphorylation of JNK2 in response to FDH, while knockdown of JNK2 did not prevent JNK1 phosphorylation. Pull-down assay with the p53-specific antibody has shown that JNK2, but not JNK1, is physically associated with p53. Our studies revealed a novel mechanism in which phosphorylation of JNK2 is mediated by JNK1 before phosphorylation of p53, and then p53 is directly phosphorylated by JNK2 at Ser6.

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Acknowledgements

We thank Dr Margaret Kelly for assistance with confocal microscopy. Confocal microscopy was performed in the Hollings Cancer Center Molecular Imaging Core Facility. This work was supported by the NIH grant CA95030.

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  1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA

    N V Oleinik, N I Krupenko & S A Krupenko

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  1. N V Oleinik
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Correspondence to S A Krupenko.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Oleinik, N., Krupenko, N. & Krupenko, S. Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. Oncogene 26, 7222–7230 (2007). https://doi.org/10.1038/sj.onc.1210526

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