γ-分泌酶组分基因APH-1A和PEN-2的转录调控
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摘要
PS/γ分泌酶负责老年痴呆症相关蛋白β淀粉样蛋白前体蛋白(APP)、信号转导受体Notch和其他Ⅰ型跨膜蛋白的剪切,其组成单位至少有四种:presenilins(PS,包括PS1和PS2)、nicastrin(NCT)、APH-1和PEN-2。尽管人们对这四种组分在蛋白质水平上的有机的相互调解作用已经有所了解,但是,关于它们的转录调控却只知之甚少。在这项研究中,我们克隆了PEN-2和APH-1A两种基因启动子区,并通过荧光素酶活性分析鉴定了这两种基因启动活性必需的最小启动子区。序列分析表明,在这些区域存在许多潜在的转录因子的结合位点。点突变和胶迁移实验揭示AP4和HIF-1结合到APH-1A启动子上,而CREB结合到PEN-2启动子上。进一步的研究表明,由forskolin激活的CREB显著地促进PEN-2 mRNA和蛋白质的表达,而对γ-分泌酶的其他组分没有影响。通过NiCl_2处理(一种模拟缺氧的化学条件)激活HIF-1,APH-1AmRNA和蛋白质的水平显著增加,而PEN-2和PS1的蛋白水平只是在长时间的NiCl_2处理条件下才会增加。更为重要的是,APP蛋白酶解的各种代谢产物的水平在forskolin或者NiCl_2处理的条件下也发生了改变。总之,我们的结果表明,APH-1A和PEN-2的转录分别受HIF-1和CREB的特异性调控,并且这种调控的特异性可能赋予APH-1和PEN-2其他特有的生理功能。
The intramembrane proteolytic cleavages of Alzheimer'sβ-amyloid precursor protein (APP) and signaling receptor Notch are mediated by the PS/γ-secretase complex, which comprises of presenilins (PS, including PS1 and PS2), nicastrin (NCT), APH-1 and PEN-2. Although the four components have been shown to coordinately regulate each other at the protein level, information regarding their transcriptional regulation is scarce. In the present study, we characterized upstream regions of the human PEN-2 and APH-1A genes and identified sequences critical for their promoter activity. Sequence analysis of these regions revealed several potential transcription factor binding sites. Site mutations and gel shift assays showed that CREB binds to PEN-2 promoter, whereas AP4 and HIF-1 bind to APH-1A promoter. Furthermore, activation of CREB by forskolin treatment dramatically promoted the expression of PEN-2 mRNA and protein, but not the expression of the other threeγ-secretase components. Activation of HIF-1 by nickel (chemical hypoxia) significantly promoted the expression of APH-1A mRNA and protein; whereas increased protein levels of PEN-2 and PS1 were only observed after chronic nickel treatment. Importantly, the levels of various proteolytic metabolites of APP were also altered by forskolin or nickel treatment. Together, our results demonstrate the differential transcriptional regulation of PEN-2 and APH-1A expression, and suggest additional physiological functions uniquely assigned to PEN-2 and APH-1A.
The intramembrane proteolytic cleavages of Alzheimer'sβ-amyloid precursor protein (APP) and signaling receptor Notch are mediated by the PS/γ-secretase complex, which comprises of presenilins (PS, including PS1 and PS2), nicastrin (NCT), APH-1 and PEN-2. Although the four components have been shown to coordinately regulate each other at the protein level, information regarding their transcriptional regulation is scarce. In the present study, we characterized upstream regions of the human PEN-2 and APH-1A genes and identified sequences critical for their promoter activity. Sequence analysis of these regions revealed several potential transcription factor binding sites. Site mutations and gel shift assays showed that CREB binds to PEN-2 promoter, whereas AP4 and HIF-1 bind to APH-1A promoter. Furthermore, activation of CREB by forskolin treatment dramatically promoted the expression of PEN-2 mRNA and protein, but not the expression of the other threeγ-secretase components. Activation of HIF-1 by nickel (chemical hypoxia) significantly promoted the expression of APH-1A mRNA and protein; whereas increased protein levels of PEN-2 and PS1 were only observed after chronic nickel treatment. Importantly, the levels of various proteolytic metabolites of APP were also altered by forskolin or nickel treatment. Together, our results demonstrate the differential transcriptional regulation of PEN-2 and APH-1A expression, and suggest additional physiological functions uniquely assigned to PEN-2 and APH-1A.
引文
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