Osuga H, Osuga S, Wang F, Fetni R, Hogan M J, Slack R S, Hakim A M, Ikeda J E, Park D S
Department of Molecular Neuroscience, Institute of Medical Sciences, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, Japan 259-1193.
Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10254-9. doi: 10.1073/pnas.170144197.
Cyclin-dependent kinases (CDKs) are commonly known to regulate cell proliferation. However, previous reports suggest that in cultured postmitotic neurons, activation of CDKs is a signal for death rather than cell division. We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury. Cdk4/cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke. Deregulated levels of E2F1, a transcription factor regulated by pRb, are also observed. Administration of a CDK inhibitor blocks pRb phosphorylation and the increase in E2F1 levels and dramatically reduces neuronal death by 80%. These results indicate that CDKs are an important therapeutic target for the treatment of reperfusion injury after ischemia.
细胞周期蛋白依赖性激酶（CDKs）通常被认为可调节细胞增殖。然而，先前的报告表明，在培养的有丝分裂后神经元中，CDKs的激活是死亡信号而非细胞分裂信号。我们确定了在体内局灶性中风期间成熟成年神经元中是否发生CDK激活，以及该信号是否是再灌注损伤后神经元死亡所必需的。中风后Cdk4/细胞周期蛋白D1水平及其底物视网膜母细胞瘤蛋白（pRb）的磷酸化增加。还观察到由pRb调节的转录因子E2F1水平失调。给予CDK抑制剂可阻断pRb磷酸化和E2F1水平的增加，并显著减少80%的神经元死亡。这些结果表明，CDKs是治疗缺血后再灌注损伤的重要治疗靶点。
