The c-Abl nonreceptor tyrosine kinase and the c-Jun NH2-terminal kina.se (JNK/stress.activated protein kinase) are activated during the injury response to the DNA-damaging agent cisplatin. Loss of DNA mis match repair activity results in resistance to cisplatin in human cancer

The c-Abl nonreceptor tyrosine kinase and the c-Jun NH2-terminal kina.se (JNK/stress.activated protein kinase) are activated during the injury response to the DNA-damaging agent cisplatin. Loss of DNA mis match repair activity results in resistance to cisplatin in human cancer cefts, suggesting that the mismatch repair proteins function as a detector for cisplatinDNA adducts.To Identifysignalingpathwaysactivatedby this detector, we investigated the effect ofthe loss ofDNA mismatch repair function on the abifity of cisplatin to activate the INK 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 mis. match 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 mecha. nism. We conclude that activation ofJNK and c-Abl by cisplatin is in part dependent upon the integrity of DNA mismatch repair function, suggest ing that these kinases are part of the signal transduction pathway acti vated when mismatch repair proteins recognize cisplatin adducts in DNA.