Narita Masashi, Nũnez Sabrina, Heard Edith, Narita Masako, Lin Athena W, Hearn Stephen A, Spector David L, Hannon Gregory J, Lowe Scott W
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Cell. 2003 Jun 13;113(6):703-16. doi: 10.1016/s0092-8674(03)00401-x.
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.
细胞衰老一种极其稳定的细胞周期停滞形式，它限制受损细胞的增殖，并可能作为癌症进展的天然屏障。在本研究中，我们描述了一种在衰老的人成纤维细胞中积累的独特异染色质结构，我们将其命名为衰老相关异染色质灶（SAHF）。SAHF的形成与异染色质蛋白和视网膜母细胞瘤（Rb）肿瘤抑制因子募集到E2F反应性启动子相吻合，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通路的完整性，并且在可逆性停滞的细胞中不会发生。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。
