老年痴呆症相关基因Nicastrin的转录调控(英文)

Transcriptional Regulation of The Alzheimer's Disease-related Gene,Nicastrin

APP蛋白经过降解,形成老年痴呆症患者脑内老年斑的主要成分.由PS(早老素),NCT,PEN-2和APH-14种膜蛋白组成的γ分泌酶催化该降解过程.为了了解人类nicastrin(NCT)基因的转录调控机制,确定了其在人脑中的转录起始位点以及其编码区上游大小不等片段的转录起始活性.EMSA分析证实NCT启动子区的4个AP-1结合位点和2个NFAT结合位点能够与相应的转录因子结合,能够改变转录因子调控能力的定点突变和PDTC诱导使得NCT启动子在HeLa细胞和大鼠皮质神经元中的启动活性都有所改变.以上结果说明:AP-1和NFAT确实参与了人类NCT基因的转录调控.

The gamrna-secretase complex mediates the final cleavage of APP to generate the principal component of amyloid plaques in the brains of Alzheimer＇s disease patients. Four integral membrane proteins （PS, NCT, PEN-2 and APH-1） are essential and sufficient for gamma-secretase activity. To identify the promoter of human nicastrin gene （NCT）, its 5＇-flanking region has been characterized and a 270 bp fragment containing the TSS（transcription start site） for the promoter activity has been identified. EMSA assays confirmed that all four AP-1 binding sites and two NFAT sites in the NCT promoter region were able to bind relative transcription factors in vitro. Mutations, as well as treatment with PDTC, which adjust the regulatory effect of AP-1 and NFAT, altered NCT promoter activity in both HeLa cells and rat cortical neurons. The results demonstrated that AP-1 and NFAT are involved in the regulation of hNCT transcription and suggest that balanced activation of AP-1 and NFAT ensures a strict temporal and tissue-specific control of NCT transcription.