The Jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin.

摘要: We have studied the role of Jun/stress-activated protein kinase (JNK/SAPK) pathway in DNA repair and cisplatin resistance T98G glioblastoma cells. JUN/SAPK is activated by damage phosphorylates serines 63 73 N-terminal domain c-Jun, which known to increase its transactivation properties. show that treatment cells with but not transplatin isomer activates JNK/SAPK about 10-fold. cells, are highly resistent (IC50 = 140 +/- 13 microM), modified express a nonphosphorylatable dominant negative c-Jun (termed dnJun) exhibit decreased viability following cisplatin, transplatin, proportion (rPearson 0.98) level dnJun expressed leading 7-fold IC50. Similar effects observed U87 PC-3 MCF-7 as well TAM-67, inhibitor function. In contrast, no sensitization effect was wild-type c-Jun. Furthermore, through quantitative polymerase chain reaction-stop assays, we expressing were inhibited adducts (p 0.55), whereas readily detectable 0.003) parental These observations indicate cisplatin-induced this response required for treatment. Regulation genotoxic stress may be normal physiological pathway.