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Induction of ß-Cell Proliferation and Retinoblastoma Protein Phosphorylation in Rat and Human Islets Using Adenovirus-Mediated Transfer of Cyclin-Dependent Kinase-4 and Cyclin D₁

¹ Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
² Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh, Rangos Research Center
³ Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

The major regulator of the gap-1/synthesis phase (G₁/S) cell cycle checkpoint is the retinoblastoma protein (pRb), and this is regulated in part by the activities of cyclin-dependent kinase (cdk)-4 and the D cyclins. Surprisingly, given the potential importance of ß-cell replication for islet replacement therapy, pRb presence, phosphorylation status, and function have not been explored in ß-cells. Here, adenoviruses expressing cdk-4 and cyclin D₁ were used to explore rat and human pRb phosphorylation and ß-cell cycle control. pRb is present in rat and human islets, and overexpression of cyclin D₁/cdk-4 led to strikingly enhanced pRb phosphorylation in both species. Combined overexpression of both cdk-4 and cyclin D₁ caused a threefold increase in [³H]thymidine incorporation. This increase in proliferation was confirmed independently using insulin and bromodeoxyuridine immunohistochemistry, where human ß-cell replication rates were increased 10-fold. Cdk-4 or cyclin D₁ overexpression did not adversely effect ß-cell differentiation or function. The key cell cycle regulatory protein, pRb, can be harnessed to advantage using cyclin D₁/cdk-4 for the induction of human and rodent ß-cell replication, enhancing replication without adversely affecting function or differentiation. This approach will allow detailed molecular study of the cellular mechanisms regulating the cell cycle in ß-cells, ß-cell lines, and stem cell-derived ß-cells.

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