Martín Javier, Hunt Sarah L, Dubus Pierre, Sotillo Rocío, Néhmé-Pélluard Fanny, Magnuson Mark A, Parlow Albert F, Malumbres Marcos, Ortega Sagrario, Barbacid Mariano
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Oncogene. 2003 Aug 14;22(34):5261-9. doi: 10.1038/sj.onc.1206506.
Lack of Cdk4 expression in mice leads to insulin-deficient diabetes and female infertility owing to a reduced number of pancreatic beta cells and prolactin-producing pituitary lactotrophs, respectively. Cdk4 null mice display also reduced body and organ size. Here, we show that Cdk4 is essential for the postnatal proliferation of pancreatic beta cells but not for embryonic neogenesis from ductal epithelial cells. Re-expression of endogenous Cdk4 in beta cells and in the pituitary gland of Cdk4 null mice restores cell proliferation and results in fertile and normoglycemic animals, thus, demonstrating that the proliferation defects in these cellular populations are cell autonomous because of the lack of Cdk4 expression. However, these mice remain small in size, indicating that this phenotype is not because of pancreatic- or pituitary-mediated endocrine defects. This phenotype is a consequence of reduced cell numbers rather than reduced cell size. Thus, mammalian Cdk4 is not only involved in controlling proliferation of specific cell types but may play a wider role in establishing homeostatic cell numbers.
小鼠中缺乏Cdk4表达会分别导致胰岛素缺乏性糖尿病和雌性不育，原因是胰腺β细胞数量减少以及垂体中分泌催乳素的促乳素细胞数量减少。Cdk4基因敲除小鼠还表现出身体和器官尺寸减小。在此，我们表明Cdk4对于出生后胰腺β细胞的增殖至关重要，但对于导管上皮细胞的胚胎新生成并非必需。在Cdk4基因敲除小鼠的β细胞和垂体中重新表达内源性Cdk4可恢复细胞增殖，并产生可育且血糖正常的动物，因此，证明这些细胞群体中的增殖缺陷是由于缺乏Cdk4表达而导致的细胞自主性缺陷。然而，这些小鼠的体型仍然较小，表明这种表型并非由胰腺或垂体介导的内分泌缺陷所致。这种表型是细胞数量减少而非细胞大小减小的结果。因此，哺乳动物的Cdk4不仅参与控制特定细胞类型的增殖，还可能在建立稳态细胞数量方面发挥更广泛的作用。
