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Release of large soluble NH2-terminal fragments of the amyloid precursor protein (APP) of Alzheimer's disease was measured in two Swiss 3T3 fibroblast cell lines (designated SF1.4 and SF3.2), overexpressing the alpha subtype of protein kinase C, and in two control cell lines (SC1 and SC2) (Eldar, H., Zisman, Y., Ullrich, A., and Livneh, E. (1990) J. Biol. Chem. 265, 13290-13296). Basal release of APP was significantly increased in SF1.4 cells, but not in SF3.2 cells, relative to controls. Phorbol 12-myristate 13-acetate, an activator of protein kinase C, elicited a concentration-dependent increase in APP release in all four cell lines. However, the estimated EC50 for this effect was lower in the two cell lines overexpressing protein kinase C-alpha (7 and 6 nM, in SF1.4 and SF3.2 cells, respectively) than in control SC1 and SC2 cells (56 and 22 nM, respectively). The absolute amount of APP released by maximal …