核因子-kappaB对唐氏综合征关键区域蛋白RCAN1异构体4的转录调节异常参与了阿尔茨海默病的发生

项目名称： 核因子-kappaB对唐氏综合征关键区域蛋白RCAN1异构体4的转录调节异常参与了阿尔茨海默病的发生

项目编号： No.30871387

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 孙秀莲

作者单位： 山东大学

项目金额： 33万元

中文摘要： RCAN1在神经退行性疾病和多种癌症的发病机制中具有重要作用。研究发现，在唐氏综合症和阿尔茨哈默氏症中RCAN1表达量显著升高，进而诱导神经元凋亡。因为RCAN1对细胞生存率影响显著，故其表达水平受到严格调控。我们先前的研究发现糖皮质激素对RCAN1的1型异构体（RCAN1.1）启动子有调节作用，为了进一步研究RCAN1表达的具体机制，我们克隆了人类RCAN1的4型异构体（RCAN1.4），结果发现两种异构体的启动子调控机制有显著区别。RCAN1.4的转录可以被NF-κ#20449;号激活。荧光素酶检测、EMSA和染色质免疫沉淀的结果发现，位于RCAN1.4启动子-576-554bp区域存在一个激活其表达的NF-κ#21453;应原件，同时RCAN1.4基因表达亦受其自身蛋白表达的调控。我们的研究结果进一步说明RCAN1在AD发病机制和细胞功能上具有重要作用。

中文关键词： 唐氏综合症;老年痴呆症;钙调磷酸酶调节因子1;核因子－kappaB;基因调控

英文摘要： Regulator of calcineurin 1 (RCAN1) has been implicated in pathogenesis of neurodegeneration as well as various cancers. Recently, we showed that RCAN1 expression was elevated in Down Syndrome and Alzheimer’ disease and its overexpression induced neuronal apoptosis. As RCAN1 played vital roles in cell viability, its gene expression must be strictly regulated. We previously showed that RCAN1 isoform 1 promoter was regulated by glucocorticoid. To further elucidate the regulatory mechanism of RCAN1 gene expression, we cloned the isoform 4 promoter of human RCAN1 gene and found that the isoform 1 and isoform 4 promoters of RCAN1 were distinctly regulated. Our results showed that the RCAN1 isoform 4 gene transcription can be activated by NF-κsignaling. Luciferase assay, EMSA and chromatin immunoprecipitation identified a NF-κresponsive element in the region of -576-554bp of the RCAN1 isoform 4 promoter, which was responsible for the activation of RCAN1 isoform 4 gene by NF-κ RCAN1 isoform 4 gene transcription was regulated by its own protein expression. Our findings about RCAN1 gene transcription regulated by NF-κfurther supported the vital roles of RCAN1 in cellular functions and its involvement in AD pathogenesis.

英文关键词： RCAN1; NF-κ gene transcription; Down syndrome; Alzheimer’ disease