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 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.
D000818:Animals; D002460:Cell Line; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D006965:Hyperplasia; D007247:Infertility, Female / Q000235:genetics; D007248:Infertility, Male / Q000235:genetics; D007328:Insulin / Q000172:deficiency*; D007515:Islets of Langerhans / Q000166:cytology / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016297:Mutagenesis, Site-Directed; D011518:Proto-Oncogene Proteins; D013091:Spermatogenesis / Q000235:genetics