Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia
Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia
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DOI：
10.1038/8751
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发表时间：
1999-05-01
期刊：
影响因子：
30.8
通讯作者：
Barbacid, M
中科院分区：
文献类型：
--
作者：
Rane, SG;Dubus, P;Barbacid, M
为了确定细胞周期蛋白依赖性激酶4（Cdk 4）在体内的作用，我们有针对性的小鼠Cdk 4基因座通过同源重组产生两种小鼠，一种缺乏Cdk 4表达和一种表达具有激活突变的Cdk 4分子。胚胎成纤维细胞在Cdk 4不存在下正常增殖，但在重新进入细胞周期时具有延迟的S期。此外，缺乏Cdk 4的小鼠是可行的，但体积小且不育。这些小鼠还由于β-胰岛胰腺细胞的减少而患上胰岛素缺乏型糖尿病。相反，表达不能结合细胞周期抑制剂p16（INK 4a）的突变Cdk 4的小鼠由于β-胰岛细胞的异常增殖而显示胰腺增生。这些结果确立了Cdk 4作为特定细胞类型的重要调节因子。
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 p16(INK4a) display pancreatic hyperplasia due to abnormal proliferation of beta-islet cells. These results establish Cdk4 as an essential regulator of specific cell types.