Protein Kinase C Delta (PKCδ) Affects Proliferation of Insulin-Secreting Cells by Promoting Nuclear Extrusion of the Cell Cycle Inhibitor p21Cip1WAF1 英文参考文献.docVIP

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Protein Kinase C Delta (PKCδ) Affects Proliferation of Insulin-Secreting Cells by Promoting Nuclear Extrusion of the Cell Cycle Inhibitor p21Cip1WAF1 英文参考文献.doc

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Protein Kinase C Delta (PKCδ) Affects Proliferation of Insulin-Secreting Cells by Promoting Nuclear Extrusion of the Cell Cycle Inhibitor p21Cip1WAF1 英文参考文献

ProteinKinaseCDelta(PKCd)AffectsProliferationof Insulin-SecretingCellsbyPromotingNuclearExtrusionof theCellCycleInhibitorp21Cip1/WAF1 FeliciaRanta1,JohannesLeveringhaus1,DorotheaTheilig1,GabrieleSchulz-Raffelt1,AnitaM.Hennige1, DominicG.Hildebrand2,Rene′ Handrick3,VerenaJendrossek4,FatimaBosch5,KlausSchulze-Osthoff2, Hans-UlrichHa¨ring1,SusanneUllrich1* 1Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tu¨bingen, Tu¨bingen, Germany,2InterfacultyInstituteforBiochemistry(IFIB),UniversityofTu¨bingen,Tu¨bingen,Germany,3InstituteforPharmaceuticalBiotechnology,BiberachUniversityof AppliedSciences,Biberach,Germany,4Institute ofCellBiology, UniversityofEssen, Essen, Germany, 5Center ofAnimal BiotechnologyandGene Therapy,Universita Auto`nomaBarcelona,BellaterraandCIBERdeDiabetesyEnfermedadesMetabo′licasAsociadas(CIBERDEM),Barcelona,Spain Abstract Background:Highfatdiet-inducedhyperglycemiaandpalmitate-stimulatedapoptosiswaspreventedbyspecificinhibition ofproteinkinaseCdelta(PKCd)inb-cells.TounderstandtheroleofPKCdinmoredetailtheimpactofchangesinPKCd activityonproliferationandsurvivalofinsulin-secretingcellswasanalyzedunderstress-freeconditions. MethodologyandPrincipalFindings:Usinggeneticandpharmacologicalapproaches,theeffectofreducedandincreased PKCd activity on proliferation, apoptosis and cell cycle regulation of insulin secreting cells was examined. Proteins were analyzedbyWesternblottingandbyconfocallaserscanningmicroscopy.IncreasedexpressionofwildtypePKCd(PKCdWT) significantlystimulatedproliferationofINS-1Ecellswithconcomitantreducedexpressionandcytosolicretractionofthecell cycle inhibitor p21Cip1/WAF1. This nuclear extrusion was mediated by PKCd-dependent phosphorylation of p21Cip1/WAF1 at Ser146.InkinasedeadPKCd(PKCdKN)overexpressingcellsandafterinhibitionofendogenousPKCdactivitybyrottlerinor RNAinterferencephosphorylationofp21Cip1/WAF1 wasreduced,whichfavoreditsnucle