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Evaluation of ß-Cell Replication in Mice Transgenic for Hepatocyte Growth Factor and Placental Lactogen

Comprehensive Characterization of the G₁/S Regulatory Proteins Reveals Unique Involvement of p21^cip

Division of Endocrinology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Irene Cozar-Castellano, PhD, Division of Endocrinology, BST E-1140, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213. E-mail: cozari{at}dom.pitt.edu

Abbreviations: CIP, cyclin inhibitory protein; HGF, hepatocyte growth factor; INK, inhibitory kinase; KIP, kinase inhibitory protein; PTHrP, parathyroid hormone–related protein; RIP, rat insulin promoter; RIP-PL, RIP-placental lactogen

We hypothesized that combined transgenic overexpression of hepatocyte growth factor (HGF) and placental lactogen in islets would lead to even greater increases in ß-cell mass and replication than either growth factor alone. This did not occur, suggesting that ß-cell replication is saturable or subject to molecular restraint. We therefore performed the first comprehensive G₁/S cell cycle survey in islets, cataloguing the broad range of kinases, cyclins, and kinase inhibitors that control the G₁/S transition in islets from normal, HGF, placental lactogen, and doubly transgenic mice. Many of the G₁/S checkpoint regulators (E2Fs; pRb; p107; p130; cyclins D₁,₂,₃, A, and E; cdk-2; cdk-4; p15; p16; p18; p19; p21; p27; MDM2; p53; c-Myc; and Egr-1) are present in the murine islet. Most of these proteins were unaltered by overexpression of HGF or placental lactogen, either alone or in combination. In contrast, p21^cip was uniquely, dramatically, and reproducibly upregulated in placental lactogen and HGF islets. p21^cip was also present in, and upregulated in, proliferating human islets, localizing specifically in ß-cells and translocating to the nucleus on mitogenic stimulation. Homozygous p21^cip loss releases islets from growth inhibition, markedly enhancing proliferation in response to HGF and placental lactogen.

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