期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2001
卷号：98
期号：26
页码：14979-14984
DOI：10.1073/pnas.261463298
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Sequential processing of the amyloid precursor protein (APP) by {beta}- and {gamma}-secretases generates the A{beta} peptide, a major constituent of the senile plaques observed in Alzheimer's disease. The cleavage by {gamma}-secretase also results in the cytoplasmic release of a 59- or 57-residue-long C-terminal fragment (C{gamma}). This processing resembles regulated intramembrane proteolysis of transmembrane proteins such as Notch, where the released cytoplasmic fragments enter the nucleus and modulate gene expression. Here, we examined whether the analogous C{gamma} fragments of APP also exert effects in the nucleus. We find that ectopically expressed C{gamma} is present both in the cytoplasm and in the nucleus. Interestingly, expression of C{gamma}59 causes disappearance of PAT1, a protein that interacts with the APP cytoplasmic domain, from the nucleus and induces its proteosomal degradation. Treatment of cells with lactacystin prevents PAT1 degradation and retains its nuclear localization. By contrast, C{gamma}57, a minor product of {gamma}-cleavage, is only marginally effective in PAT1 degradation. Furthermore, C{gamma}59 but not C{gamma}57 potently represses retinoic acid-responsive gene expression. Thus, our studies provide the evidence that, as predicted by the regulated intramembrane proteolysis mechanism, C{gamma} seems to function in the nucleus.
