Protective role for c-Jun in the cellular response to DNA damage

c-Jun, a member of the activation protein 1 (AP-1) family of transcription factors, has been implicated in the regulation of many important biological processes including cell cycle progression, transformation, differentiatio n, and apoptosis. Accordingly, its expression and function are upregulated in response to diverse stimuli including mitogens and a wide range of stres ses. Transcriptional activation of the e-Jun protein is dependent on its ph osphorylation at Ser-63 and Ser-73, process mediated by c-Jun N-terminal ki nase. Active c-Jun is required for AP-1 transactivation and c-Jun-mediated transformation, but its role during stress remains unclear as both pro-apop totic and pro-survival effects of e-Jun have been observed. Here we investi gated the importance of c-Jun N-terminal phosphorylation in influencing the sensitivity of human T98G glioblastoma cells to a variety of cytotoxic age nts. Stable expression of a nonphosphorylatable dominant negative protein c -Jun(S63A,S73A) markedly inhibited the activation of AP-1-driven transcript ion and greatly increased the cytotoxic effects of DNA-damaging agents asso ciated with enhanced apoptosis. However, the same cells expressing the muta nt Jun protein did not differ from parental cells in their sensitivity to s everal non-DNA-damaging cytotoxic agents. Our results suggest that activate d e-Jun has a selective role in protecting human tumor cells from apoptosis induced by DNA damage.