Preferential extension of short telomeres induced by low extracellular pH.
Preferential extension of short telomeres induced by low extracellular pH.
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低细胞外 pH 值诱导短端粒优先延伸
DOI：
10.1093/nar/gkw464
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发表时间：
2016-09-30
影响因子：
14.9
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Ge Y;Wu S;Xue Y;Tao J;Li F;Chen Y;Liu H;Ma W;Huang J;Zhao Y
大多数肿瘤细胞通过表达端粒酶克服增殖极限。端粒酶是否优先延伸最短的端粒仍在争论中。当人癌细胞在中性pH下培养时，端粒酶以端粒长度不依赖的方式延伸端粒。然而，肿瘤的微环境是微酸性的，目前还不知道这如何影响端粒酶的作用。在这里，我们研究端粒长度的稳态在pHe 6.8培养的肿瘤细胞。结果表明，端粒酶优先延长短端粒，使端粒长度分布变窄，端粒的大小变得几乎均匀。在pHe 6.8条件下生长后，端粒酶、TRF 1、TRF 2和TIN 2的表达减少，Cajal小体的丰度降低。因此，端粒酶不足以延伸每个端粒，携带较少shelterin蛋白的较短端粒更容易被端粒酶募集。这些发现支持了“蛋白质计数机制”，即端粒的延伸和未延伸状态由相关的shelterin蛋白的数量和端粒酶的丰度决定。端粒酶表达的降低和短端粒的优先延伸对肿瘤细胞的生存能力具有重要意义，并为端粒酶靶向抗癌治疗的研究提供了强有力的理论基础。
The majority of tumor cells overcome proliferative limit by expressing telomerase. Whether or not telomerase preferentially extends the shortest telomeres is still under debate. When human cancer cells are cultured at neutral pH, telomerase extends telomeres in telomere length-independent manner. However, the microenvironment of tumor is slightly acidic, and it is not yet known how this influences telomerase action. Here, we examine telomere length homeostasis in tumor cells cultured at pHe 6.8. The results indicate that telomerase preferentially extends short telomeres, such that telomere length distribution narrows and telomeres become nearly uniform in size. After growth at pHe 6.8, the expression of telomerase, TRF1, TRF2 and TIN2 decreases, and the abundance of Cajal bodies decreases. Therefore, telomerase are insufficient for extending every telomere and shorter telomeres bearing less shelterin proteins are more accessible for telomerase recruitment. The findings support the ‘protein-counting mechanism’ in which extended and unextended state of telomere is determined by the number of associated shelterin proteins and the abundance of telomerase. Decreased expression of telomerase and preferential extension of short telomeres have important implications for tumor cell viability, and generate a strong rationale for research on telomerase-targeted anti-cancer therapeutics.
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影响因子：
3.3
作者：
Tomlinson, RL;Ziegler, TD;Terns, MP
通讯作者：
Terns, MP
影响因子：
2.8
作者：
Ngo, Darleen C.;Ververis, Katherine;Karagiannis, Tom C.
通讯作者：
Karagiannis, Tom C.
端粒长度与 ES/iPS 细胞真实多能性的关联
影响因子：
44.1
作者：
Huang, Junjiu;Wang, Fang;Liu, Lin
通讯作者：
Liu, Lin
影响因子：
4.8
作者：
Ouellette, MM;Liao, M;Wright, WE
通讯作者：
Wright, WE
影响因子：
64.5
作者：
Hemann, MT;Strong, MA;Greider, CW
通讯作者：
Greider, CW