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Cyclin D2 Protein Stability Is Regulated in Pancreatic β-Cells

Division of Endocrinology and Diabetes (L.M.H., D.J.S., M.T., M.M.R., S.Y.L., J.A.K.), Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Division of Endocrinology (L.M.O.-A.), Children’s Hospital, Boston, Harvard Medical School, Boston, Massachusetts 02115; and Abramson Family Cancer Research Institute (J.A.D.), Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Jake A. Kushner M.D., Division of Endocrinology, Children’s Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104. E-mail:kushnerj{at}mail.med.upenn.edu.

The molecular determinants of β-cell mass expansion remain poorly understood. Cyclin D2 is the major D-type cyclin expressed in β-cells, essential for adult β-cell growth. We hypothesized that cyclin D2 could be actively regulated in β-cells, which could allow mitogenic stimuli to influence β-cell expansion. Cyclin D2 protein was sharply increased after partial pancreatectomy, but cyclin D2 mRNA was unchanged, suggesting posttranscriptional regulatory mechanisms influence cyclin D2 expression in β-cells. Consistent with this hypothesis, cyclin D2 protein stability is powerfully regulated in fibroblasts. Threonine 280 of cyclin D2 is phosphorylated, and this residue critically limits D2 stability. We derived transgenic (tg) mice with threonine 280 of cyclin D2 mutated to alanine (T280A) or wild-type cyclin D2 under the control of the insulin promoter. Cyclin D2 T280A protein was expressed at much higher levels than wild-type cyclin D2 protein in β-cells, despite equivalent expression of tg mRNAs. Cyclin D2 T280A tg mice exhibited a constitutively nuclear cyclin D2 localization in β-cells, and increased cyclin D2 stability in islets. Interestingly, threonine 280-mutant cyclin D2 tg mice had greatly reduced β-cell apoptosis, with suppressed expression of proapoptotic genes. Suppressed β-cell apoptosis in threonine 280-mutant cyclin D2 tg mice resulted in greatly increased β-cell area in aged mice. Taken together, these data indicate that cyclin D2 is regulated by protein stability in pancreatic β-cells, that signals that act upon threonine 280 limit cyclin D2 stability in β-cells, and that threonine 280-mutant cyclin D2 overexpression prolongs β-cell survival and augments β-cell mass expansion.