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Activation of Nuclear Factor-B by Depolarization and Ca²⁺ Influx in MIN6 Insulinoma Cells

From the Washington University School of Medicine, Division of Endocrinology, Diabetes and Metabolism, St. Louis, Missouri

The purpose of the current study was to determine whether nuclear factor-B (NF-B) activation is a component of the depolarization/Ca²⁺-dependent signaling in ß-cells. MIN6 cells were transfected with a plasmid containing five tandem repeats of NF-B binding sites linked to a luciferase reporter. The results of these experiments showed that KCl induced depolarization-activated NF-B-dependent transcription (3.8-fold at 45 mmol/l, P < 0.01) in a concentration-dependent manner. Tumor necrosis factor- (TNF-), a known inducer of NF-B signaling, activated this construct by 3.4-fold (P < 0.01). The response of NF-B to depolarization was inhibited by the Ca²⁺-channel blocker verapamil and by the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 (70 and 62%, respectively). TNF-, glucose, and KCl treatment resulted in inhibitory B degradation by Western blot analysis. TNF- treatment and depolarization activation of NF-B differed significantly in that TNF- activation was not blocked by PD98059. Transfection with PKA, MEK, and MEK kinase induced NF-B-dependent transcription by 20-, 90-, and 300-fold, respectively, suggesting that these pathways contribute to the activation in the depolarization response. These findings demonstrate that depolarization/Ca²⁺ influx, as well as TNF- treatment, can activate NF-B-dependent transcription in pancreatic ß-cells, but by different signaling pathways. The current studies show that Ca²⁺ signals in pancreatic ß-cells can activate transcription factors involved in the regulation of cell cycle and apoptosis. These findings now add NF-B to the list of depolarization-induced transcription factors in pancreatic ß-cells.

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