Characterization of a novel positive transcription regulatory element that differentially regulates the alpha-2-macroglobulin gene in replicative senescence
Characterization of a novel positive transcription regulatory element that differentially regulates the alpha-2-macroglobulin gene in replicative senescence
复制标题
一种新型正转录调控元件的表征，该元件在复制衰老过程中差异调节α-2-巨球蛋白基因
DOI：
10.1007/s10522-011-9339-2
复制
发表时间：
2011-12-01
期刊：
影响因子：
4.5
通讯作者：
Tong, Tanjun
中科院分区：
文献类型：
--
作者：
Li, Renzhong;Ma, Liwei;Tong, Tanjun
α-2-巨球蛋白（α 2 M）是一种蛋白酶抑制剂，与阿尔茨海默病、动脉粥样硬化和其他与年龄有关的疾病有关。在复制性衰老过程中，α 2 M mRNA水平升高，可作为衰老细胞的生物标志物。然而，其表达上调的机制尚不清楚。本报告确定了一个新的转录调控元件，α 2 M转录增强元件（ATEE），在α 2 M启动子。该元件差异激活衰老成纤维细胞与年轻成纤维细胞中的α 2 M表达。电泳迁移率变动分析显示，丰富的复合物在衰老细胞核提取物相比，年轻细胞核提取物。DNA酶I足迹揭示了蛋白结合核心序列，蛋白通过该序列结合ATEE。ATEE内的突变选择性地消除了衰老（但不是年轻）细胞中的α 2 M启动子活性。这些结果表明，ATEE作为一个正性转录调控元件，在复制衰老过程中参与了α 2 M的上调。
Alpha-2-macroglobulin (alpha 2M), a protease inhibitor, is implicated in Alzheimer's disease, atherosclerosis, and other age-related diseases. The elevated level of alpha 2M mRNA has been described in replicative senescence and it could be used as a biomarker of the aging cells. However, the mechanism responsible for the up-regulation of its expression is still unclear. This report identified a novel transcriptional regulatory element, the alpha 2M transcription enhancement element (ATEE), within the alpha 2M promoter. This element differentially activates alpha 2M expression in senescent versus young fibroblasts. Electrophoretic mobility shift assays revealed abundant complexes in senescent cell nuclear extracts compared with young cell nuclear extracts. The DNase I footprint revealed the protein-binding core sequence through which the protein binds the ATEE. Mutation within ATEE selectively abolished alpha 2M promoter activity in senescent (but not young) cells. These results indicated the ATEE, as a positive transcription regulatory element, contributes to the up-regulation of alpha 2M during replicative senescence.