Cyclin-dependent kinases as a therapeutic target for stroke
Cyclin-dependent kinases as a therapeutic target for stroke
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DOI：
10.1073/pnas.170144197
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发表时间：
2000-08-29
影响因子：
11.1
通讯作者：
Park, DS
中科院分区：
文献类型：
--
作者：
Osuga, H;Osuga, S;Park, DS
细胞周期蛋白依赖性激酶（CDKs）通常被认为是调节细胞增殖的，然而，先前的报道表明，在培养的有丝分裂后神经元中，CDKs的激活是死亡而不是细胞分裂的信号。我们确定了体内局灶性脑卒中期间成熟成年神经元中是否发生CDK激活，以及该信号是否为再灌注损伤后神经元死亡所必需。卒中后Cdk4/cyclin D1水平及其底物视网膜母细胞瘤蛋白（pRb）磷酸化升高。E2F1（一种由pRb调节的转录因子）的水平也被观察到。CDK抑制剂可以阻断pRb磷酸化和E2F1水平的增加，并显著降低80%的神经元死亡，这些结果表明CDK是治疗缺血后再灌注损伤的重要治疗靶点。
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.