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  • Title: Selective activation by bryostatin-1 demonstrates unique roles for PKC epsilon in neurite extension and tau phosphorylation.
    Author: Ekinci FJ, Shea TB.
    Journal: Int J Dev Neurosci; 1997 Nov; 15(7):867-74. PubMed ID: 9568534.
    Abstract:
    Phorbol esters such as 12-O-tetradeonyl phorbol-13 acetate (TPA) induce a time-dependent biphasic effect on protein kinase C (PKC)-mediated events by fostering translocation of cytosolic (latent) PKC to the plasma membrane (where it is activated). Continued treatment, however, depletes the cell's entire PKC complement and induces a functional stake of PKC inhibition. Previous studies from several laboratories have demonstrated that long-term TPA treatment, like treatment with PKC inhibitors, induces neuronal differentiation. Bryostatin-1 also induces translocation and overall downregulation of PKC following long-term treatment, yet, unlike TPA or PKC inhibitors, does not induce neuronal differentiation, promoting controversy regarding the role of PKC inhibition in neuronal differentiation. We demonstrate herein that, despite overall downregulation in human neuroblastoma cells, membrane-associated levels of one PKC isoform (PKC epsilon) are actually increased following long-term bryostatin-1 treatment. Since previous studies have implicated this PKC isoform in phosphorylation of the microtubule-associated protein tau and in neuritogenesis, we examined the consequences of long-term bryostatin treatment on these phenomena. Treatment with 25 n-100 M bryostatin-1 for 72 h increased tau phosphorylation and inhibited neuritogenesis. By contrast, treatment with either TPA or the PKC inhibitor staurosporine did not induce tau phosphorylation and induced neurite elaboration. Bryostatin-1 antagonized neurite induction by staurosporine. These findings provide additional evidence for a unique role of PKC epsilon in the regulation of tau phosphorylation and neuronal differentiation, and demonstrate that bryostatin-1 can function under certain conditions as a selective PKC epsilon activator even following long-term treatment.
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