摘要
ATP结合盒转运子2(ABCA2)是一种多通道跨膜蛋白,它用ATP水解的能量通过膜双分子层运送基质。ABCA2也被从遗传学角度与老年痴呆关联,然其分子机制不明。本文假设鞘脂代谢的ABCA2调节激活了控制淀粉样前体蛋白转录的信号通路。我们从神经酰胺的分解代谢推断,N2a细胞中的ABCA2超表达与鞘脂类鞘氨醇质量的增加有关。ABCA2超表达增加了体外碱性和酸性神经酰胺酶的活性。鞘氨醇是一种蛋白激酶C(PKC)的活性的生理性抑制剂。用12-十四酸-13-乙酸(PMA)或二酰基甘油(DAG)造成的神经酰胺酶活性或PKC活性的药理性抑制降低了ABCA2超表达的细胞中内源APPmRNA的水平。PMA处理也降低了转染的人APP启动子报告基因构造的表达,而普通PKC抑制剂GF109203x处理增强了APP启动子的活性。N2a细胞中的染色质免疫沉淀实验显示,人APP启动子上AP-1点形成了一个抑制的复合体,包含c-jun,c-jun二聚蛋白2(JDP2)和HDAC3,且该复合体在ABCA2超表达的细胞中减少。A2细胞中,人APP启动子的激活被上游刺激因子USF-1和USF-2控制,这些因子受制于体内的E-box元件。这些发现表明ABCA2的超表达能调节鞘氨醇水平,且能控制内源性APP基因的转录。
关键词: ABCA2,APP,阿尔茨海默,转录,鞘氨醇,PKC。
Current Alzheimer Research
Title:The ATP-Binding Cassette Transporter-2 (ABCA2) Overexpression Modulates Sphingosine Levels and Transcription of the Amyloid Precursor Protein (APP) Gene
Volume: 12 Issue: 9
Author(s): Warren Davis Jr.
Affiliation:
关键词: ABCA2,APP,阿尔茨海默,转录,鞘氨醇,PKC。
摘要: The ATP-binding cassette transporter-2 (ABCA2) is a member of a family of multipass transmembrane proteins that use the energy of ATP hydrolysis to transport substrates across membrane bilayers. ABCA2 has also been genetically linked with Alzheimer’s disease but the molecular mechanisms are unknown. In this report, we hypothesized that ABCA2 modulation of sphingolipid metabolism activates a signaling pathway that regulates amyloid precursor protein transcription. We found that ABCA2 overexpression in N2a cells was associated with increased mass of the sphingolipid sphingosine, derived from the catabolism of ceramide. ABCA2 overexpression increased in vitro alkaline and acid ceramidase activity. Sphingosine is a physiological inhibitor of protein kinase C (PKC) activity. Pharmacological inhibition of ceramidase activity or activation PKC activity with 12-myristate 13-acetate (PMA) or diacylglycerol (DAG) decreased endogenous APP mRNA levels in ABCA2 overexpressing cells. Treatment with PMA also decreased the expression of a transfected human APP promoter reporter construct, while treatment with a general PKC inhibitor, GF109203x, increased APP promoter activity. In N2a cells, chromatin immunoprecipitation experiments revealed that a repressive complex forms at the AP-1 site in the human APP promoter, consisting of c-jun, c-jun dimerization protein 2 (JDP2) and HDAC3 and this complex was reduced in ABCA2 overexpressing cells. Activation of the human APP promoter in A2 cells was directed by the upstream stimulatory factors USF-1 and USF-2 that bound to an E-box element in vivo. These findings indicate that ABCA2 overexpression modulates sphingosine levels and regulates transcription of the endogenous APP gene.
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Warren Davis Jr. , The ATP-Binding Cassette Transporter-2 (ABCA2) Overexpression Modulates Sphingosine Levels and Transcription of the Amyloid Precursor Protein (APP) Gene, Current Alzheimer Research 2015; 12 (9) . https://dx.doi.org/10.2174/156720501209151019105834
DOI https://dx.doi.org/10.2174/156720501209151019105834 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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