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Protein Kinase C- Activation Markedly Enhances ß-Cell Proliferation

An Essential Role in Growth Factor–Mediated ß-Cell Mitogenesis

¹ Department of Medicine, Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
² Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Adolfo Garcia-Ocaña, PhD, Division of Endocrinology, University of Pittsburgh, 200 Lothrop St., BST-E1156, Pittsburgh, PA 15261. E-mail: ocana{at}dom.pitt.edu

Abbreviations: Adv-CA-PKC, adenovirus containing the cDNA of constitutively active PKC; Adv-KD-PKC, adenovirus containing the cDNA of kinase-dead PKC; Adv-LacZ, adenovirus containing the cDNA of ß-galactosidase; BrdU, 5-bromo-2'-deoxyuridine; DAG, diacylglycerol; DAPI, 4,6-diamidino-2-phenylindole; ERK, extracellular signal–regulated kinase; FBS, fetal bovine serum; GLP-1, glucagon-like peptide 1; HGF, hepatocyte growth factor; MOI, multiplicity of infection; PDK-1, phosphoinositide-dependent kinase 1; PI, phosphatidylinositol; PKC, protein kinase C; PTH1R, parathyroid hormone 1 receptor; PTHrP, parathyroid hormone–related protein; RIP, rat insulin II promoter; siRNA, small-interfering RNA

OBJECTIVE— Diabetes results from a deficiency of functional ß-cells. Previous studies have identified hepatocyte growth factor (HGF) and parathyroid hormone–related protein (PTHrP) as two potent ß-cell mitogens. The objective of this study is to determine 1) whether HGF and PTHrP have additive/synergistic effects on ß-cell growth and proliferation; 2) the signaling pathways through which these growth factors mediate ß-cell mitogenesis; and 3) whether activation of this/these signaling pathway(s) enhances human ß-cell replication.

RESEARCH DESIGN AND METHODS— We generated and phenotypically analyzed doubly transgenic mice overexpressing PTHrP and HGF in the ß-cell. INS-1 and primary mouse and human islet cells were used to identify mitogenic signaling pathways activated by HGF and/or PTHrP.

RESULTS— Combined overexpression of HGF and PTHrP in the ß-cell of doubly transgenic mice did not result in additive/synergistic effects on ß-cell growth and proliferation, suggesting potential cross-talk between signaling pathways activated by both growth factors. Examination of these signaling pathways in INS-1 cells revealed atypical protein kinase C (PKC) as a novel intracellular target activated by both HGF and PTHrP in ß-cells. Knockdown of PKC, but not PKC/, expression using specific small-interfering RNAs blocked growth factor–induced INS-1 cell proliferation. Furthermore, adenovirus-mediated delivery of kinase-dead PKC completely inhibited ß-cell proliferation in primary islet cells overexpressing PTHrP and/or HGF. Finally, adenovirus-mediated delivery of constitutively active PKC in mouse and human primary islet cells significantly enhanced ß-cell proliferation.

CONCLUSIONS— PKC is essential for PTHrP- and HGF-induced ß-cell proliferation. PKC activation could be useful in therapeutic strategies for expanding ß-cell mass in vitro and in vivo.

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