Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, People's Republic of China.
Biogerontology. 2011 Dec;12(6):517-25. doi: 10.1007/s10522-011-9339-2. Epub 2011 May 4.
Alpha-2-macroglobulin (α2M), a protease inhibitor, is implicated in Alzheimer's disease, atherosclerosis, and other age-related diseases. The elevated level of α2M 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 α2M transcription enhancement element (ATEE), within the α2M promoter. This element differentially activates α2M 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 α2M 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 α2M during replicative senescence.
α2-巨球蛋白（α2M）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相关的疾病有关。在复制性衰老中，α2M mRNA 的水平升高，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。本研究在 α2M 启动子内鉴定到一个新的转录调控元件，即α2M 转录增强元件（ATEE）。该元件在衰老和成纤维细胞中的差异激活 α2M 表达。电泳迁移率变动分析显示，衰老细胞核提取物中存在大量复合物，而年轻细胞核提取物中则没有。DNase I 足迹分析揭示了该蛋白结合 ATEE 的核心序列。ATEE 内的突变选择性地消除了衰老（而非年轻）细胞中 α2M 启动子的活性。这些结果表明，ATEE 作为一个正转录调控元件，有助于复制性衰老过程中 α2M 的上调。
