Phosphorylation of mitogen-activated protein kinase is altered in neuroectodermal cells overexpressing the human amyloid precursor protein 751 isoform
Phosphorylation of mitogen-activated protein kinase is altered in neuroectodermal cells overexpressing the human amyloid precursor protein 751 isoform
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DOI：
10.1016/s0169-328x(99)00157-6
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发表时间：
1999-10-01
期刊：
影响因子：
--
通讯作者：
Cuello, AC
中科院分区：
文献类型：
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作者：
Grant, SM;Morinville, A;Cuello, AC
淀粉样前体蛋白（APP）的异常表达或加工是早老性家族性阿尔茨海默病的唯一已知遗传基础，APP和tau之间的分子联系一直令人困惑。人们的注意力集中在脯氨酸导向的丝氨酸/苏氨酸激酶介导的阿尔茨海默病的细胞骨架的修改，我们表明，APP的过表达可以影响一个候选激酶，丝裂原活化蛋白激酶（MAPK）的激活。在小鼠胚胎癌细胞稳定转染人751亚型的APP，我们观察到稳态超活化的p42（MAPK）伴随APP过度表达神经外胚层分化后3天。在更成熟的分化细胞，免疫细胞化学分析显示增强的基础体细胞和细胞核的磷酸化MAPK的免疫反应性，加上衰减的磷酸化反应生长因子刺激。我们的研究结果表明，APP可以影响MAPK信号通路，以这样一种方式，绝对和时间依赖性激活所需的歧视适当的下游反应受到损害。这种效应将对同时表达这两种蛋白质的细胞的功能产生重要影响，这种情况发生在易受阿尔茨海默病病理影响的神经元群体中。(C)1999 Elsevier Science B. V.保留所有权利。
The aberrant expression or processing of the amyloid precursor protein (APP) is the only known genetic basis for presenile familial Alzheimer's disease, and the molecular connection between APP and tau has been perplexing. Attention has focused on proline-directed serine/threonine kinases as mediating the cytoskeletal modifications of Alzheimer's disease, and we show that overexpression of APP can influence the activation of a candidate kinase, the mitogen-activated protein kinase (MAPK). In murine embryonal carcinoma cells stably transfected with the human 751 isoform of APP, we observed steady-state hyperactivation of p42(MAPK) concomitant with APP overexpression 3 days after neuroectodermal differentiation. In more mature differentiated cells, immunocytochemical analysis revealed enhanced basal somatic and nuclear immunoreactivity for phosphorylated MAPK coupled with an attenuated phosphorylation response to growth factor stimulation. Our results suggest that APP can influence the MAPK signaling pathway in such a way that the absolute and time-dependent activation required for discrimination of the appropriate downstream response are compromised. Such an effect would have important consequences for the functioning of cells coincidentally expressing both proteins, a situation that occurs in neuronal populations vulnerable to Alzheimer's disease pathology. (C) 1999 Elsevier Science B.V. All rights reserved.