多种细胞周期蛋白依赖性激酶信号是体外和体内缺血/缺氧性神经元死亡的关键介质。
Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo.
作者信息
Rashidian Juliet, Iyirhiaro Grace, Aleyasin Hossein, Rios Mario, Vincent Inez, Callaghan Steven, Bland Ross J, Slack Ruth S, During Matthew J, Park David S
机构信息
Ottawa Health Research Institute, Neuroscience Group, Ottawa, ON, Canada K1H 8M5.
出版信息
Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14080-5. doi: 10.1073/pnas.0500099102. Epub 2005 Sep 15.
Abstract
The mechanisms involving neuronal death after ischemic/hypoxic insult are complex, involving both rapid (excitotoxic) and delayed (apoptotic-like) processes. Recent evidence suggests that cell cycle regulators such as cyclin-dependent kinases are abnormally activated in neuropathological conditions, including stroke. However, the function of this activation is unclear. Here, we provide evidence that inhibition of the cell cycle regulator, Cdk4, and its activator, cyclinD1, plays critical roles in the delayed death component of ischemic/hypoxic stress by regulating the tumor suppressor retinoblastoma protein. In contrast, the excitotoxic component of ischemia/hypoxia is predominately regulated by Cdk5 and its activator p35, components of a cyclin-dependent kinase complex associated with neuronal development. Hence, our data both characterize the functional significance of the cell cycle Cdk4 and neuronal Cdk5 signals as well as define the pathways and circumstances by which they act to control ischemic/hypoxic damage.
摘要
缺血/缺氧损伤后涉及神经元死亡的机制很复杂，包括快速（兴奋性毒性）和延迟（类凋亡）过程。最近的证据表明，细胞周期调节因子如细胞周期蛋白依赖性激酶在包括中风在内的神经病理状况下会异常激活。然而，这种激活的功能尚不清楚。在此，我们提供证据表明，抑制细胞周期调节因子Cdk4及其激活剂细胞周期蛋白D1，通过调节肿瘤抑制因子视网膜母细胞瘤蛋白，在缺血/缺氧应激的延迟死亡成分中起关键作用。相比之下，缺血/缺氧的兴奋性毒性成分主要由Cdk5及其激活剂p35调节，Cdk5及其激活剂p35是与神经元发育相关的细胞周期蛋白依赖性激酶复合物的组成部分。因此，我们的数据既阐明了细胞周期Cdk4和神经元Cdk5信号的功能意义，也确定了它们控制缺血/缺氧损伤的作用途径和情况。
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