ATF4 regulates γ-secretase activity during amino acid imbalance
ATF4 regulates γ-secretase activity during amino acid imbalance
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DOI：
10.1016/j.bbrc.2006.11.075
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发表时间：
2007-01-19
影响因子：
3.1
通讯作者：
Nakagawa, Toshiyuki
中科院分区：
文献类型：
--
作者：
Mitsuda, Teruhiko;Hayakawa, Yoshika;Nakagawa, Toshiyuki
淀粉样蛋白-β (Aβ) 是由淀粉样蛋白前体蛋白通过γ-分泌酶产生的，在大脑皮层中的积累是阿尔茨海默病中常见且严重的事件。具体来说，早老素是γ-分泌酶活性所必需的。然而，影响γ-分泌酶活性的早老素表达调节仍然不清楚。我们研究了控制早老素 1 (PS1) 表达和 γ 分泌酶活性的机制。我们发现 PS1 是诱导性 γ 激活转录因子 4 (ATF4)，受 GCN2 真核起始因子 2 α (eIF2 α) 激酶调节。染色质免疫沉淀分析和电泳迁移率变动分析表明 ATF4 与人 PS1 基因的调控区结合。通过敲低分析，我们观察到 Aβ (1-42) 的分泌和 γ-分泌酶辅助因子的诱导是由 ATF4 控制的。这些数据表明 ATF4 对于 γ 分泌酶活性至关重要，ATF4 mRNA 通过该酶优先翻译以响应 eIF2 α 磷酸化。 (c) 2006 Elsevier Inc. 保留所有权利。
Accumulation of amyloid-beta (A beta), which is generated from amyloid precursor protein by gamma-secretase, in cerebral cortex is common and critical incident in Alzheimer disease. Specifically, presenilin is an essential for gamma-secretase activity. However, the regulation of presenilin expression, affecting gamma-secretase activity, remains obscure. We investigated mechanism controlling the expression of presenilin-1 (PS1) and gamma-secretase activity. We showed that PS1 is induced gamma activating transcription factor 4 (ATF4), regulated by GCN2 eukaryotic initiation factor 2 alpha (eIF2 alpha) kinase. A chromatin immunoprecipitation analysis and an electrophoretic mobility shift assay demonstrated that ATF4 binds to the regulatory region of human PS1 gene. Through knockdown analysis, we observed that the secretion of A beta (1-42) and induction of gamma-secretase cofactors are controlled by ATF4. These data indicate that ATF4 is critical for gamma-secretase activity, by which ATF4 mRNA is preferentially translated in response to eIF2 alpha phosphorylation. (c) 2006 Elsevier Inc. All rights reserved.