Control of Cellular Aging, Tissue Function, and Cancer by p53 Downstream of Telomeres.
Control of Cellular Aging, Tissue Function, and Cancer by p53 Downstream of Telomeres.
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DOI：
10.1101/cshperspect.a026088
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发表时间：
2017-05-01
影响因子：
5.4
通讯作者：
Artandi SE
中科院分区：
文献类型：
--
作者：
Roake CM;Artandi SE
端粒是真核生物染色体末端的核蛋白复合体，它在细胞中发挥着重要作用，部分原因是防止染色体末端启动dna损伤反应。端粒的这种功能可能会受到损害，因为端粒要么是培养细胞分裂的结果，要么是增殖组织中细胞衰老的正常部分。在这种情况下，端粒功能障碍导致dna损伤信号传导和肿瘤抑制蛋白p53的激活，从而导致细胞衰老或凋亡。通过剔除端粒功能失调的细胞，p53在保护组织免受端粒极短的影响方面起着关键作用。然而，随着端粒功能障碍的恶化，p53可能会加剧短端粒驱动的组织衰竭疾病，包括肺纤维化、再生障碍性贫血和肝硬化。在缺乏p53的细胞中，不受控制的端粒缩短驱动染色体端到端融合和染色体融合桥断裂的循环。面对这些端粒屏障的早期癌细胞必须禁用p53信号以避免衰老并最终上调端粒酶以实现细胞不朽。最近的研究发现，在不同的人类癌症中，端粒酶逆转录酶（TERT）基因的启动子高度复发性的激活突变，以及癌症中p53的广泛突变，为规避端粒-p53检查点对人类癌症恶性进展至关重要的观点提供了支持。
Telomeres, the nucleoprotein complex at the ends of eukaryotic chromosomes, perform an essential cellular role in part by preventing the chromosomal end from initiating a DNA-damage response. This function of telomeres can be compromised as telomeres erode either as a consequence of cell division in culture or as a normal part of cellular ageing in proliferative tissues. Telomere dysfunction in this context leads to DNA-damage signaling and activation of the tumor-suppressor protein p53, which then can prompt either cellular senescence or apoptosis. By culling cells with dysfunctional telomeres, p53 plays a critical role in protecting tissues against the effects of critically short telomeres. However, as telomere dysfunction worsens, p53 likely exacerbates short telomere-driven tissue failure diseases, including pulmonary fibrosis, aplastic anemia, and liver cirrhosis. In cells lacking p53, unchecked telomere shortening drives chromosomal end-to-end fusions and cycles of chromosome fusion-bridge-breakage. Incipient cancer cells confronting these telomere barriers must disable p53 signaling to avoid senescence and eventually up-regulate telomerase to achieve cellular immortality. The recent findings of highly recurrent activating mutations in the promoter for the telomerase reverse transcriptase (TERT) gene in diverse human cancers, together with the widespread mutations in p53 in cancer, provide support for the idea that circumvention of a telomere-p53 checkpoint is essential for malignant progression in human cancer.