Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia

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 s trains of mice, one that lacks Cdk4 expression and one that expresses a Cdk 4 molecule with an activating mutation. Embryonic fibroblasts proliferate n ormally 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 m utant Cdk4 that cannot bind the cell-cycle inhibitor p16(INK4a) display pan creatic hyperplasia due to abnormal proliferation of beta-islet cells. Thes e results establish Cdk4 as an essential regulator of specific cell types.