Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes
Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes
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DOI：
10.1038/sj.embor.7400704
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发表时间：
2006-07-01
期刊：
影响因子：
7.7
通讯作者：
De Strooper, Bart
中科院分区：
文献类型：
--
作者：
Hebert, Sebastien S.;Serneels, Lutgarde;De Strooper, Bart
淀粉样前体蛋白（APP）的γ-分泌酶依赖性调节的膜内蛋白水解释放APP胞内结构域（AICD）。这个域是否像Notch胞内域一样参与核信号传导的问题是非常有争议的。虽然一些报告表明，AICD调节KAI 1，糖原合成酶激酶-3 β，Neprilysin和APP的表达，但我们没有发现γ-分泌酶抑制剂或γ-分泌酶复合物或APP家族中的遗传缺陷对细胞和组织中这些基因表达水平的一致影响。最后，我们证明，铁65，一个重要的AICD结合蛋白，反式激活各种不同的启动子，包括病毒猿猴病毒40启动子，独立的AICD共表达。总的来说，目前提出的四个靶基因充其量是间接和微弱的APP加工的影响。因此，抑制APP加工以减少阿尔茨海默病中A β的产生不会显著干扰这些基因的功能。
gamma-Secretase-dependent regulated intramembrane proteolysis of amyloid precursor protein (APP) releases the APP intracellular domain ( AICD). The question of whether this domain, like the Notch intracellular domain, is involved in nuclear signalling is highly controversial. Although some reports suggest that AICD regulates the expression of KAI1, glycogen synthase kinase-3 beta, Neprilysin and APP, we found no consistent effects of gamma-secretase inhibitors or of genetic deficiencies in the gamma-secretase complex or the APP family on the expression levels of these genes in cells and tissues. Finally, we demonstrate that Fe65, an important AICD-binding protein, transactivates a wide variety of different promoters, including the viral simian virus 40 promoter, independent of AICD coexpression. Overall, the four currently proposed target genes are at best indirectly and weakly influenced by APP processing. Therefore, inhibition of APP processing to decrease A beta generation in Alzheimer's disease will not interfere significantly with the function of these genes.