Protein Kinase C Delta

High fat diet-induced hyperglycemia and palmitate-stimulated apoptosis was prevented by specific inhibition of protein kinase C delta (PKC[delta]) in [beta]-cells. To understand the role of PKC[delta] in more detail the impact of changes in PKC[delta] activity on proliferation and survival of insuli...

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Published in:PloS one 2011-12, Vol.6 (12), p.e28828
Main Authors: Ranta, Felicia, Leveringhaus, Johannes, Theilig, Dorothea, Schulz-Raffelt, Gabriele, Hennige, Anita M, Hildebrand, Dominic G, Handrick, René, Jendrossek, Verena, Bosch, Fatima, Schulze-Osthoff, Klaus, Häring, Hans-Ulrich, Ullrich, Susanne
Format: Article
Language:English
Subjects:
Analysis
Apoptosis
Cell cycle
Genetic engineering
Hyperglycemia
Insulin
Pancreatic beta cells
Protein kinases
Proteins
Type 2 diabetes
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Summary:High fat diet-induced hyperglycemia and palmitate-stimulated apoptosis was prevented by specific inhibition of protein kinase C delta (PKC[delta]) in [beta]-cells. To understand the role of PKC[delta] in more detail the impact of changes in PKC[delta] activity on proliferation and survival of insulin-secreting cells was analyzed under stress-free conditions. Using genetic and pharmacological approaches, the effect of reduced and increased PKC[delta] activity on proliferation, apoptosis and cell cycle regulation of insulin secreting cells was examined. Proteins were analyzed by Western blotting and by confocal laser scanning microscopy. Increased expression of wild type PKC[delta] (PKC[delta]WT) significantly stimulated proliferation of INS-1E cells with concomitant reduced expression and cytosolic retraction of the cell cycle inhibitor p21.sup.Cip1/WAF1 . This nuclear extrusion was mediated by PKC[delta]-dependent phosphorylation of p21.sup.Cip1/WAF1 at Ser146. In kinase dead PKC[delta] (PKC[delta]KN) overexpressing cells and after inhibition of endogenous PKC[delta] activity by rottlerin or RNA interference phosphorylation of p21.sup.Cip1/WAF1 was reduced, which favored its nuclear accumulation and apoptotic cell death of INS-1E cells. Human and mouse islet cells express p21.sup.Cip1/WAF1 with strong nuclear accumulation, while in islet cells of PKC[delta]WT transgenic mice the inhibitor resides cytosolic. These observations disclose PKC[delta] as negative regulator of p21.sup.Cip1/WAF1, which facilitates proliferation of insulin secreting cells under stress-free conditions and suggest that additional stress-induced changes push PKC[delta] into its known pro-apoptotic role.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0028828