Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis.
Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis.
复制标题
野生型而非阿尔茨海默突变型淀粉样前体蛋白赋予对 p53 介导的细胞凋亡的抵抗力。
DOI：
10.1073/pnas.96.13.7547
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发表时间：
1999
影响因子：
11.1
通讯作者：
Mucke,L
中科院分区：
文献类型：
--
作者：
Xu,X;Yang,D;Wyss-Coray,T;Yan,J;Gan,L;Sun,Y;Mucke,L
淀粉样前体蛋白（APP）在不同物种的多种器官和细胞类型中表达。它们在物种间的保守性和脑中的高丰度以及各种APP错义突变与家族性阿尔茨海默病（FAD）的常染色体显性形式的关联表明APP在中枢神经系统中的重要作用。然而，APP在中枢神经系统中的基本功能在很大程度上仍然未知。为了评估APP对神经元死亡和存活的潜在影响，我们用编码野生型或FAD突变型人APP的DNA构建体转染APP缺陷型大鼠神经母细胞瘤细胞（B103）。野生型，但不是FAD突变型，APP有效地保护细胞免受紫外线照射，星形孢菌素或p53诱导的细胞凋亡。野生型APP也强烈抑制p53 DNA结合活性和p53介导的基因反式激活，而FAD突变APP没有。我们得出结论，APP通过在翻译后水平控制p53激活来保护神经细胞免于凋亡。APP加工中的突变或改变破坏这一功能可能会增强神经元对二次损伤的脆弱性，并导致神经元变性。
Amyloid precursor proteins (APPs) are expressed in multiple organs and cell types in diverse species. Their conservation across species and high abundance in brain and the association of various APP missense mutations with autosomal dominant forms of familial Alzheimer’s disease (FAD) suggest important roles for APP in the central nervous system. However, the basic functions of APP in the central nervous system remain largely unknown. To assess potential effects of APP on neuronal death and survival, we transfected APP-deficient rat neuroblastoma cells (B103) with DNA constructs encoding wild-type or FAD-mutant human APP. Wild-type, but not FAD-mutant, APP effectively protected cells against apoptosis induced by ultraviolet irradiation, staurosporine, or p53. Wild-type APP also strongly inhibited p53 DNA-binding activity and p53-mediated gene transactivation, whereas FAD-mutant APP did not. We conclude that APP protects neuronal cells against apoptosis by controlling p53 activation at the post-translational level. Disruption of this function by mutations or alterations in APP processing could enhance neuronal vulnerability to secondary insults and contribute to neuronal degeneration.