PKC ζ Enhances Insulin-like Growth Factor 1-Dependent Mitogenic Activity in the Rat Clonal β Cell Line RIN 1046-38

Protein kinase C seems to be linked to the regulation of insulin secretion as well as mitogenic signaling in pancreatic β cells. To study the impact of different PKC isoforms on insulin secretion and mitogenic activity we stably overexpressed the PKC isoforms α, β2, ε, and ζ in the rat clonal β cell line RIN 1046-38. Under basal conditions PKC α, β2, ε, and ζ were identified mainly in the cytosol. Treatment with the phorbol ester TPA caused translocation of PKC α, β2, and ϵ to the plasma membrane. Glucose- and TPA-dependent increases in insulin release were comparable in all cell lines regardless of whether PKC was overexpressed or not. While PKC isoforms α, β2, and ε had no effect on the [3H]thymidine incorporation rate, overexpression of PKC ζ specifically increased basal as well as IGF-1-dependent [3H]thymidine incorporation. Incubation with the MAP-kinase inhibitor PD98056 abolished this effect. Furthermore, treatment with IGF-1 led to activation of the β cell-specific transcription factor PDX-1 in RIN 1046-38 cells overexpressing PKC ζ. Our data suggest that PKC ζ is involved in basal as well as IGF-1-dependent mitogenesis in RIN 1046-38 cells, while none of the PKC isoforms tested seem to be related to glucose-stimulated insulin release.