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Chemotherapeutic DNA-damaging Drugs Activate Interferon Regulatory Factor-7 by the Mitogen-activated Protein Kinase Kinase-4-c-Jun NH₂-Terminal Kinase Pathway¹

National Creative Research Initiative Center for Genetic Reprogramming, Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea [T. K. K., T. K., T. Y. K., J. K.], and Institute of Chemistry and Cell Biology, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 [T. K. K., W. G. L.]

Chemotherapeutic drugs and energy-rich radiation cause DNA damage, inducing signaling pathways for apoptotic cell death or cell growth arrest. The tumor suppressor gene p53 plays the critical role in the regulation of these DNA damage responses. Human tumor cells can become resistant to chemotherapy through functional inactivation of p53. Thus, it is important to identify p53-independent DNA damage signaling pathways. Here, treatment of cells with chemotherapeutic drugs or UV irradiation potentiated the transcriptional activity of IFN regulatory factor-7 (IRF7), inducing its phosphorylation and its nuclear translocation. Furthermore, IRF7 was activated by the c-Jun NH₂-terminal kinase (JNK) in response to DNA-damaging agents. Activation of JNK by mitogen-activated protein kinase kinase-4 stimulated the transcriptional activity of IRF7 and induced its translocation into the nucleus. Thus, activation of IRF7 through the JNK signaling pathway may play a role in the transcriptional regulation of genes in response to DNA-damaging agents.

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