Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F•DP, in B-amyloid-induced neuronal death
Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F•DP, in B-amyloid-induced neuronal death
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DOI：
10.1074/jbc.274.27.19011
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发表时间：
1999-07-02
影响因子：
4.8
通讯作者：
Park, DS
中科院分区：
文献类型：
--
作者：
Giovanni, A;Wirtz-Brugger, F;Park, DS
其他人之前的证据表明，阿尔茨海默病患者大脑中多种细胞周期相关分子的表达上调。然而，这种增加的意义尚不清楚。因此，我们检查了细胞周期蛋白依赖性激酶的专性性质，并选择了这些激酶在 B-淀粉样 (AB) 蛋白引起的神经元死亡中的下游靶标。我们提供的药理学和分子生物学证据表明，细胞周期蛋白依赖性激酶，特别是 Cdk4/6，是此类神经元死亡所必需的。此外，我们证明 Cdk4/6 的底物 pRb/p107 在 AB 治疗期间被磷酸化，并且 pRb/p107 的一个靶标 E2F.DP 复合物是 AB 诱发的神经元死亡所必需的。这些结果提供了证据，表明细胞周期元件在 AB 引起的神经元死亡中发挥着必需的作用，并表明这些元件在阿尔茨海默病相关的神经元死亡中发挥着不可或缺的作用。
Previous evidence by others has indicated that a variety of cell cycle-related molecules are up-regulated in brains of Alzheimer's disease patients. The significance of this increase, however, is unclear. Accordingly, we examined the obligate nature of cyclin-dependent kinases and select downstream targets of these kinases in death of neurons evoked by B-amyloid (AB) protein. We present pharmacological and molecular biological evidence that cyclin dependent kinases, in particular Cdk4/6, are required for such neuronal death. In addition, we demonstrate that the substrate of Cdk4/6, pRb/ p107, is phosphorylated during AB treatment and that one target of pRb/p107, the E2F.DP complex, is required for AB-evoked neuronal death. These results provide evidence that cell cycle elements play a required role in death of neurons evoked by AB and suggest that these elements play an integral role in Alzheimer's disease-related neuronal death.