The c-Abl nonreceptor tyrosine kinase and the c-Jun NH2-terminal kinase (JNK/stress-activated protein kinase) are activated during the injury response to the DNA-damaging agent cisplatin. Loss of DNA mismatch repair activity results in resistance to cisplatin in human cancer cells, suggesting that the mismatch repair proteins function as a detector for cisplatin DNA adducts. To identify signaling pathways activated by this detector, we investigated the effect of the loss of DNA mismatch repair function on the ability of cisplatin to activate the JNK and c-Abl kinases. The results demonstrate that cisplatin activates JNK kinase 3.8 ± 0.2-fold more efficiently in DNA mismatch repair-proficient than repair-deficient cells, and that activation of c-Abl is completely absent in the DNA mismatch repair-deficient cells. Furthermore, the results show that cisplatin-induced activation of JNK occurs through a stress-activated protein kinase/extracellular signal-regulated kinase kinase 1-independent mechanism. We conclude that activation of JNK and c-Abl by cisplatin is in part dependent upon the integrity of DNA mismatch repair function, suggesting that these kinases are part of the signal transduction pathway activated when mismatch repair proteins recognize cisplatin adducts in DNA.


This work was supported by Grant 4154 from the Council for Tobacco Research, grants from CaP CURE, the Association for the Cure of Cancer of the Prostate, and the National Institute of Environmental Health Science, a program project grant from the National Cancer Institute, and grants from the Swiss National Science Foundation, Ciba Geigy Jubiläumsstiftung, Krebsliga beider Basel, Schweizerische Stiftung für Biologisch Medizinische Stipendien, EMDO Stiftung Zürich, Holderbank Stiftung, and the Ernst Schering Research Foundation, Berlin. This work was conducted in part by the Clayton Foundation for Research-California Division. R. D. C. and S. B. H. are Clayton Foundation Investigators.

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