Cyclooxygenase-1 behaves as a delayed response gene in PC12 cells differentiated by nerve growth factor

Treatment of PC12 cells with nerve growth factor (NGF) results in a differentiation program characterized by expression of immediate early and delayed response genes. In this program, morphological changes such as neurite extension are accompanied by phenotypic changes in enzyme expression, including an increased capacity for prostaglandin synthesis. Cyclooxygenase (COX), the enzyme responsible for prostanoid production, exists as two isoforms: constitutive COX-1 and inducible COX-2. We report that COX-1 behaves as a delayed response gene in PC12 cells exposed to NGF. Six hours following NGF treatment, COX-1 mRNA levels were elevated in PC12 cells, reaching nearly 5-fold above basal levels at 12 h. This increase was blocked by cycloheximide and was accompanied by concomitant increases in COX-1 protein and enzyme activity. COX-1 protein remained elevated for at least 10 days and localized to the cytoplasm and neurites of NGF-differentiated PC12 cells. Moreover, basic fibroblast growth factor, but not epidermal growth factor, caused similar increases in COX-1, which is consistent with expression characteristics of other delayed response genes in PC12 cells. This is the first example of neurotrophic factor regulation of cyclooxygenase and may have important implications for determination of the differentiated phenotype in PC12 cells.