Activating protein 1-mediated cyclooxygenase-2 expression is independent of N-terminal phosphorylation of c-Jun.
Transcriptional activation of the cyclooxygenase (COX)-2 gene is responsible for high level of prostaglandin production during inflammation and carcinogenesis. We found previously that c-Jun induction plays a crucial role in epidermal growth factor (EGF)-induced gene expression of COX-2. In this study, the functional role of c-Jun in EGF-induced transcriptional activation of COX-2 in A431 cells was investigated. We found that overexpression of c-Jun N-terminal phosphorylation site mutants had similar stimulatory effects on COX-2 promoter activity and protein expression as c-Jun wild type. TAM-67, a mutant of c-Jun that lacks the N-terminal transactivation domain of c-Jun, also enhanced COX-2 promoter activity and protein expression in cells treated with EGF. In vitro DNA affinity precipitation and reporter assays revealed that regulation of c-Jun C terminus by EGF enhanced c-Jun binding to COX-2 promoter and induced COX-2 expression. Furthermore, we demonstrated that c-Fos, which provides transactivation function in Jun/Fos heterodimer, was required for EGF-induced expression of COX-2. These results indicated that c-Jun N-terminal phosphorylation was not required for EGF-induced expression of COX-2. c-Jun, which could recruit other transcription factors such as c-Fos, was required for EGF-induced expression of COX-2 in A431 cells.
Chen
Lei-Chin
LC
Department of Pharmacology, College of Medicine, National Cheng-Kung University, No.1 Ta-Hsueh Road, Tainan 701, Taiwan.
Chen
Ben-Kuen
BK
Chang
Wen-Chang
WC
D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation / Q000502:physiology
D008565:Membrane Proteins; D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases