细胞周期蛋白依赖性激酶抑制剂p27（Kip1）对细胞凋亡的调节作用
Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27(Kip1).
作者信息
Hiromura K, Pippin J W, Fero M L, Roberts J M, Shankland S J
机构信息
Department of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, Washington 98195-6521, USA.
出版信息
J Clin Invest. 1999 Mar;103(5):597-604. doi: 10.1172/JCI5461.
Abstract
Proliferation and apoptosis are increased in many types of inflammatory diseases. A role for the cyclin kinase inhibitor p27(Kip1) (p27) in limiting proliferation has been shown. In this study, we show that p27(-/-) mesangial cells and fibroblasts have strikingly elevated rates of apoptosis, not proliferation, when deprived of growth factors. Apoptosis was rescued by restoration of p27 expression. Cyclin A-cyclin-dependent kinase 2 (CDK2) activity, but not cyclin E-CDK2 activity, was increased in serum-starved p27(-/-) cells, and decreasing CDK2 activity, either pharmacologically (Roscovitine) or by a dominant-negative mutant, inhibited apoptosis. Our results show that a new biological function for the CDK inhibitor p27 is protection of cells from apoptosis by constraining CDK2 activity. These results suggest that CDK inhibitors are necessary for coordinating the cell cycle and cell-death programs so that cell viability is maintained during exit from the cell cycle.
摘要
在许多类型的炎症性疾病中，细胞增殖和凋亡均会增加。细胞周期蛋白激酶抑制剂p27（Kip1）（p27）在限制细胞增殖方面的作用已得到证实。在本研究中，我们发现，当缺乏生长因子时，p27基因敲除（p27-/-）的系膜细胞和成纤维细胞的凋亡率显著升高，而非增殖率升高。通过恢复p27的表达可挽救细胞凋亡。在血清饥饿的p27-/-细胞中，细胞周期蛋白A-细胞周期蛋白依赖性激酶2（CDK2）的活性增加，但细胞周期蛋白E-CDK2的活性未增加，通过药理学方法（roscovitine）或显性负性突变体降低CDK2活性可抑制细胞凋亡。我们的结果表明，CDK抑制剂p27的一种新的生物学功能是通过抑制CDK2活性来保护细胞免于凋亡。这些结果提示，CDK抑制剂对于协调细胞周期和细胞死亡程序是必需的，以便在细胞退出细胞周期时维持细胞活力。
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