A nestin scaffold links Cdk5/p35 signaling to oxidant-induced cell death
A nestin scaffold links Cdk5/p35 signaling to oxidant-induced cell death
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DOI：
10.1038/sj.emboj.7601366
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发表时间：
2006-10-18
期刊：
影响因子：
11.4
通讯作者：
Eriksson, John E.
中科院分区：
文献类型：
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作者：
Sahlgren, Cecilia M.;Pallari, Hanna-Mari;Eriksson, John E.
中间丝蛋白，巢蛋白，已被牵连作为生存决定信号分子的组织者。当巢蛋白表达与神经前体细胞对氧化剂诱导的凋亡的敏感性相关时，巢蛋白显示出明显的细胞保护作用。神经元前体细胞中的氧化应激导致巢蛋白下调，随后激活神经系统中的关键激酶-细胞周期蛋白依赖性激酶5（Cdk 5）。巢蛋白下调是Cdk 5依赖性细胞凋亡的先决条件，因为巢蛋白的过表达有效地抑制了细胞凋亡的诱导，而通过RNA干扰耗尽巢蛋白则具有增敏作用。当分析巢蛋白和Cdk 5之间的潜在联系时，我们观察到巢蛋白作为Cdk 5的支架，其结合仅限于巢蛋白的α-螺旋结构域之后的特定区域，并且巢蛋白的存在和组织调节Cdk 5的螯合和活性，以及其调节剂p35的泛素化和营业额。我们的数据表明，巢蛋白是一种生存决定因素，其行动是基于一种新的模式Cdk 5的调节，影响Cdk 5/p35信号复合物的目标，活动和营业额。
The intermediate filament protein, nestin, has been implicated as an organizer of survival-determining signaling molecules. When nestin expression was related to the sensitivity of neural progenitor cells to oxidant-induced apoptosis, nestin displayed a distinct cytoprotective effect. Oxidative stress in neuronal precursor cells led to downregulation of nestin with subsequent activation of cyclindependent kinase 5 (Cdk5), a crucial kinase in the nervous system. Nestin downregulation was a prerequisite for the Cdk5-dependent apoptosis, as overexpression of nestin efficiently inhibited induction of apoptosis, whereas depletion of nestin by RNA interference had a sensitizing effect. When the underlying link between nestin and Cdk5 was analyzed, we observed that nestin serves as a scaffold for Cdk5, with binding restricted to a specific region following the alpha-helical domain of nestin, and that the presence and organization of nestin regulated the sequestration and activity of Cdk5, as well as the ubiquitylation and turnover of its regulator, p35. Our data imply that nestin is a survival determinant whose action is based upon a novel mode of Cdk5 regulation, affecting the targeting, activity, and turnover of the Cdk5/p35 signaling complex.