IFN-γ-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes
IFN-γ-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes
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DOI：
10.1002/glia.20451
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发表时间：
2007-02-01
期刊：
影响因子：
6.2
通讯作者：
Mook-Jung, Inhee
中科院分区：
文献类型：
--
作者：
Cho, Hyun Jin;Kim, Su-Kyoung;Mook-Jung, Inhee
β -位点淀粉样前体蛋白裂解酶1（BACE1）是产生Aβ淀粉样蛋白的关键酶。由于我们发现向幼鼠大脑中注射干扰素 -γ（IFN -γ）会增加星形胶质细胞中BACE1的表达，我们通过克隆一个假定的BACE1启动子来研究这一过程的分子机制。BACE1启动子活性受IFN -γ以区域特异性方式差异调节，并被Janus激酶2（JAK2）抑制剂下调。信号转导和转录激活因子1（STAT1）的显性负突变体表达抑制BACE1启动子活性，而转染野生型STAT1可挽救这种抑制作用。电泳迁移率变动分析和启动子活性分析表明STAT1直接结合到BACE1启动子假定的STAT1结合序列上。因为IFN -γ处理诱导STAT1磷酸化，我们检测了细胞因子信号传导抑制因子（SOCS，JAK2的负调节因子）的表达是否抑制BACE1启动子活性。结果表明SOCS1或SOCS3的表达通过阻断STAT1中Tyr701残基的磷酸化来抑制BACE1启动子。此外，因为IFN -γ处理特异性地增强细胞外信号调节激酶（ERK）1/2的活化，有丝分裂原活化蛋白激酶或细胞外信号调节蛋白激酶（MEK）抑制剂PD98059预处理通过阻断STAT1中Ser727残基的磷酸化显著减弱IFN -γ诱导的BACE1启动子活性和蛋白表达，这表明ERK1/2与IFN -γ诱导的STAT1信号级联相关。综上所述，我们的结果表明IFN -γ激活JAK2和ERK1/2，然后磷酸化的STAT1结合到BACE1启动子区域假定的STAT1结合序列上，以调节星形胶质细胞中BACE1蛋白的表达。（c）2006威利 - 利斯公司
beta-Site APP cleaving enzyme 1 (BACE1) is an essential enzyme for the production of P amyloid. Since we found that injection of interferon-gamma (IFN-gamma) into young mouse brains increased BACE1 expression in astrocytes, we investigated molecular mechanisms underlying this process by cloning a putative BACE1 promoter. BACE1 promoter activity was differentially regulated by IFN-gamma in a region specific manner and down-regulated by an inhibitor of Janus kinase 2 (JAK2). A dominant negative mutant of signal transducer and activator of transcription 1 (STAT1) expression suppressed BACE1 promoter activity, and this was rescued by transfecting wild type STAT1. Electrophoretic mobility shift assay and promoter activity assays indicated that STAT1 binds directly to the putative STAT1 binding sequence of BACE1 promoter. Because IFN-gamma treatment induced STAT1 phosphorylation, we examined whether the expression of a suppressor of cytokine signaling (SOCS), negative regulator of JAK2, suppresses BACE1 promoter activity. The results show that SOCS1 or SOCS3 expression suppressed BACE1 promoter by blocking phosphorylation of Tyr701 residue in STAT1. Also, because IFN-gamma treatment specifically potentiated extracellular signal regulated MA-P kinase (ERK) 1/2 activation, pretreatment of mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, PD98059, significantly attenuated IFN-gamma-induced BACE1 promoter activity and protein expression through blocking phosphorylation of Ser727 residue in STAT1, suggesting that ERK1/2 is associated with IFN-gamma-induced STAT1 signaling cascade. Taken together, our results suggest that IFN-gamma activates JAK2 and ERK1/2 and then phosphorylated STAT1 binds to the putative STAT1 binding sequences in BACE1 promoter region to modulate BACE1 protein expression in astrocytes. (c) 2006 Wiley-Liss, Inc.