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, differentiation, and apoptosis. Accordingly, its expression and function are upregulated in response to diverse stimuli including mitogens and a wide range of stresses. Transcriptional activation of the c-Jun protein is dependent on its phosphorylation at Ser-63 and Ser-73, a process mediated by c-Jun N-terminal kinase. Active c-Jun is required for AP-1 transactivation and c-Jun-mediated transformation, but its role during stress remains unclear as both pro-apoptotic and pro-survival effects of c-Jun have been observed. Here we investigated the importance of c-Jun N-terminal phosphorylation in influencing the sensitivity of human T98G glioblastoma cells to a variety of cytotoxic agents. Stable expression of a nonphosphorylatable dominant negative protein c-Jun(S63A,S73A) markedly inhibited the activation of AP-1-driven transcription and greatly increased the cytotoxic effects of DNA-damaging agents associated with enhanced apoptosis. However, the same cells expressing the mutant Jun protein did not differ from parental cells in their sensitivity to several non-DNA-damaging cytotoxic agents. Our results suggest that activated c-Jun has a selective role in protecting human tumor cells from apoptosis induced by DNA damage.
Potapova
O
O
Cell Stress and Aging Section, Laboratory of Cellular and Molecular Biology, National Institute on Aging, Baltimore, Maryland 21224, USA.
Basu
S
S
Mercola
D
D
Holbrook
N J
NJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D005434:Flow Cytometry; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009153:Mutagens; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012694:Serine / Q000737:chemistry; D013312:Stress, Physiological; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009153:Mutagens; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D012694:Serine; D015500:Chloramphenicol O-Acetyltransferase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin