Protein Kinase C Delta (PKC delta) Affects Proliferation of Insulin-Secreting Cells by Promoting Nuclear Extrusion of the Cell Cycle Inhibitor p21(Cip1/WAF1)

作者：Ranta Felicia^*; Leveringhaus Johannes; Theilig Dorothea; Schulz Raffelt Gabriele; Hennige Anita M; Hildebrand Dominic G; Handrick Rene; Jendrossek Verena; Bosch Fatima; Schulze Osthoff Klaus; Haering Hans Ulrich; Ullrich Susanne

来源：PLos One, 2011, 6(12): e28828.

DOI：10.1371/journal.pone.0028828

Background: 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.
Methodology and Principal Findings: 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(Cip1/WAF1). This nuclear extrusion was mediated by PKC delta-dependent phosphorylation of p21(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(Cip1/WAF1) was reduced, which favored its nuclear accumulation and apoptotic cell death of INS-1E cells. Human and mouse islet cells express p21(Cip1/WAF1) with strong nuclear accumulation, while in islet cells of PKC delta WT transgenic mice the inhibitor resides cytosolic.
Conclusions and Significance: These observations disclose PKC delta as negative regulator of p21(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.

• 出版日期2011-12-27