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A genome wide analysis of ubiquitin ligases in APP processing identifies a novel regulator of BACE1 mRNA levels

被引：25
作者：
Espeseth, Amy S.
Huang, Qian
Gates, Adam
Xu, Min
Yu, Yuanjiang
Simon, Adam J.
Shi, Xiao-Ping
Zhang, Xiaohua
Hodor, Paul
Stone, David J.
Burchard, Julja
Cavet, Guy
Bartz, Steven
Linsley, Peter
Ray, William J.
Hazuda, Daria
机构：
[1] Merck Res Labs, Virus & Cell Biol, West Point, PA 19486 USA
[2] Rosetta Inpharmat, Dept Biol, Seattle, WA 98019 USA
[3] Rosetta Inpharmat, Dept Mol Profiling, Seattle, WA 98019 USA
[4] Merck Res Labs, Mol Profiling, West Point, PA 19486 USA
[5] Merck Res Labs, Biometr Res, West Point, PA 19486 USA
[6] Merck Res Labs, Alzheimers Res, West Point, PA 19486 USA
[7] Merck Res Labs, Dept Mol & Cellular Technol, West Point, PA 19486 USA
来源：
MOLECULAR AND CELLULAR NEUROSCIENCE | 2006年 / 33卷 / 03期
关键词：
Alzheimer's; BACE1; regulation; PPIL2; hCyp-60; siRNA screen;
D O I：
10.1016/j.mcn.2006.07.003
中图分类号：
Q189 [神经科学];
学科分类号：
071006 [神经生物学];
摘要：
Proteolysis of beta-amyloid precursor protein (APP) into amyloid beta peptide (A beta) by beta- and gamma-secretases is a critical step in the pathogenesis of Alzheimer's Disease (AD), but the pathways regulating secretases are not fully characterized. Ubiquitinylation, which is dysregulated in AD, may affect APP processing. Here, we describe a screen for APP processing modulators using an siRNA library targeting 532 predicted ubiquitin ligases. Seven siRNA pools diminished A beta production. Of these, siRNAs targeting PPIL2 (hCyp-60) suppressed beta-site cleavage. Knockdown of PPIL2 mRNA decreased BACE1 mRNA, while overexpression of PPIL2 cDNA enhanced BACE1 mRNA levels. Microarray analysis of PPIL2 or BACE1 knockdown indicated that genes affected by BACE1 knockdown are a subset of those dependent upon PPIL2; suggesting that BACE1 expression is downstream of PPIL2. The association of PPIL2 with BACE expression and its requirement for AP production suggests new approaches to discover disease modifiying agents for AD. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码：227 / 235
页数：9
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