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, 22 (1), 44-52

Loss of Cdk4 Expression Causes Insulin-Deficient Diabetes and Cdk4 Activation Results in Beta-Islet Cell Hyperplasia

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Loss of Cdk4 Expression Causes Insulin-Deficient Diabetes and Cdk4 Activation Results in Beta-Islet Cell Hyperplasia

S G Rane et al. Nat Genet.

Abstract

To ascertain the role of cyclin-dependent kinase 4 (Cdk4) in vivo, we have targeted the mouse Cdk4 locus by homologous recombination to generate two strains of mice, one that lacks Cdk4 expression and one that expresses a Cdk4 molecule with an activating mutation. Embryonic fibroblasts proliferate normally in the absence of Cdk4 but have a delayed S phase on re-entry into the cell cycle. Moreover, mice devoid of Cdk4 are viable, but small in size and infertile. These mice also develop insulin-deficient diabetes due to a reduction in beta-islet pancreatic cells. In contrast, mice expressing a mutant Cdk4 that cannot bind the cell-cycle inhibitor P16INK4a display pancreatic hyperplasia due to abnormal proliferation of beta-islet cells. These results establish Cdk4 as an essential regulator of specific cell types.

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