title: Protein kinase Czeta activation mediates glucagon-like peptide-1-induced pancreatic beta-cell proliferation.
abstract: Glucagon-like peptide-1 (GLP-1), an insulinotropic and glucoincretin hormone, is a potentially important therapeutic agent in the treatment of diabetes. We previously provided evidence that GLP-1 induces pancreatic beta-cell growth nonadditively with glucose in a phosphatidylinositol-3 kinase (PI-3K)-dependent manner. In the present study, we investigated the downstream effectors of PI-3K to determine the precise signal transduction pathways that mediate the action of GLP-1 on beta-cell proliferation. GLP-1 increased extracellular signal-related kinase 1/2, p38 mitogen-activated protein kinase (MAPK), and protein kinase B activities nonadditively with glucose in pancreatic beta(INS 832/13) cells. GLP-1 also caused nuclear translocation of the atypical protein kinase C (aPKC) zeta isoform in INS as well as in dissociated normal rat beta-cells as shown by immunolocalization and Western immunoblotting analysis. Tritiated thymidine incorporation measurements showed that the p38 MAPK inhibitor SB203580 suppressed GLP-1-induced beta-cell proliferation. Further investigation was performed using isoform-specific pseudosubstrates of classical (alpha, beta, and gamma) or zeta aPKC isoforms. The PKCzeta pseudosubstrate suppressed the proliferative action of GLP-1, whereas the inhibitor of classical PKC isoforms had no effect. Overexpression of a kinase-dead PKCzeta acting as a dominant negative protein suppressed GLP-1-induced proliferation. In addition, ectopic expression of a constitutively active PKCzeta mutant stimulated tritiated thymidine incorporation to the same extent as GLP-1, and the glucoincretin had no growth-promoting action under this condition. The data indicate that GLP-1-induced activation of PKCzeta is implicated in the beta-cell proliferative signal of the insulinotropic hormone. The results are consistent with a model in which GLP-1-induced PI-3K activation results in PKCzeta translocation to the nucleus, which may play a role in the pleiotropic effects (DNA synthesis, metabolic enzymes, and insulin gene expression) of the glucoincretin.
authors.affiliation: Molecular Nutrition Unit, Department of Nutrition, University of Montreal, the Centre de Recherche du CHUM and Institut du Cancer, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Buteau
authors.forename: S
authors.initials: S
authors.lastname: Foisy
authors.forename: C J
authors.initials: CJ
authors.lastname: Rhodes
authors.forename: L
authors.initials: L
authors.lastname: Carpenter
authors.forename: T J
authors.initials: TJ
authors.lastname: Biden
authors.forename: M
authors.initials: M
authors.lastname: Prentki
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D007515:Islets of Langerhans / Q000166:cytology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009154:Mutation / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta
chemical_list: D004791:Enzyme Inhibitors; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D020928:Mitogen-Activated Protein Kinases; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D011498:Protein Precursors; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta