Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
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DOI：
10.1016/s0092-8674(03)00401-x
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发表时间：
2003-06-13
期刊：
影响因子：
64.5
通讯作者：
Lowe, SW
中科院分区：
文献类型：
--
作者：
Narita, M;Nunez, S;Lowe, SW
细胞衰老是细胞周期停滞的一种非常稳定的形式，它限制了受损细胞的增殖，并可能成为癌症进展的天然屏障。在这项研究中，我们描述了一个独特的异染色质结构，积累在衰老的人成纤维细胞，我们指定的衰老相关异染色质病灶（SAHF）。SAHF的形成与异染色质蛋白和视网膜母细胞瘤（Rb）肿瘤抑制因子向E2F反应启动子的募集相一致，并与E2F靶基因的稳定抑制相关。值得注意的是，SAHF的形成和E2F靶基因的沉默都依赖于Rb途径的完整性，并且不会发生在可逆性停滞的细胞中。这些结果为衰老状态的稳定性提供了分子解释，也为Rb作为肿瘤抑制因子的作用提供了新的见解。
Cellular senescence is an extremely stable form of cell cycle arrest that limits the proliferation of damaged cells and may act as a natural barrier to cancer progression. In this study, we describe a distinct heterochromatic structure that accumulates in senescent human fibroblasts, which we designated senescence-associated heterochromatic foci (SAHF). SAHF formation coincides with the recruitment of heterochromatin proteins and the retinoblastoma (Rb) tumor suppressor to E2F-responsive promoters and is associated with the stable repression of E2F target genes. Notably, both SAHF formation and the silencing of E2F target genes depend on the integrity of the Rb pathway and do not occur in reversibly arrested cells. These results provide a molecular explanation for the stability of the senescent state, as well as new insights into the action of Rb as a tumor suppressor.