Transient induction of telomerase expression mediates senescence and reduces tumorigenesis in primary fibroblasts.
Transient induction of telomerase expression mediates senescence and reduces tumorigenesis in primary fibroblasts.
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端粒酶表达的瞬时诱导介导衰老并减少原代成纤维细胞的肿瘤发生。
DOI：
10.1073/pnas.1907199116
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发表时间：
2019
影响因子：
11.1
通讯作者：
Cao,Kan
中科院分区：
文献类型：
--
作者：
Sun,Linlin;Chiang,JeffreyY;Choi,JiYoung;Xiong,Zheng-Mei;Mao,Xiaojing;Collins,FrancisS;Hodes,RichardJ;Cao,Kan
端粒酶是一种核糖核蛋白复合物，在端粒的延长中作为逆转录酶。端粒酶活性在胚胎干细胞和绝大多数肿瘤细胞中有很好的记录，但其在体细胞中的作用仍有待了解。在这里，我们报告了一个意想不到的功能端粒酶在细胞衰老和肿瘤发生。我们将三杂合基因敲除小鼠（mTert+/−）杂交26代，在此期间端粒进行性缩短，并从第26代杂交的mTert +/+和mTert −/−后代中获得了原代皮肤成纤维细胞。由于前几代端粒酶活性不足，mTert +/+和mTert −/−成纤维细胞的端粒长度相当且极短。然而，mTert−/−细胞比mTert +/+细胞更快地接近细胞衰老，并且表现出显著更高的恶性转化率。此外，在衰老阶段，端粒酶逆转录酶（telomerase reverse-transcriptase，TERT）的表达在mTert +/+细胞中明显上调。此外，通过CRISPR/Cas9或shRNA去除或下调mTert +/+和人原代成纤维细胞中的TERT表达重现了加速衰老和转化的mTert −/−表型，以及mTert −/−细胞中的TERT过表达挽救了这些表型。综合这些数据，这项研究表明，由于端粒短，功能失调，并防止恶性转化，TERT在缓冲衰老压力方面具有以前未被充分认识的保护作用。
Telomerase is an enzymatic ribonucleoprotein complex that acts as a reverse transcriptase in the elongation of telomeres. Telomerase activity is well documented in embryonic stem cells and the vast majority of tumor cells, but its role in somatic cells remains to be understood. Here, we report an unexpected function of telomerase during cellular senescence and tumorigenesis. We crossedTertheterozygous knockout mice (mTert+/−) for 26 generations, during which time there was progressive shortening of telomeres, and obtained primary skin fibroblasts frommTert+/+andmTert−/−progeny of the 26th cross. As a consequence of insufficient telomerase activities in prior generations, bothmTert+/+andmTert−/−fibroblasts showed comparable and extremely short telomere length. However,mTert−/−cells approached cellular senescence faster and exhibited a significantly higher rate of malignant transformation thanmTert+/+cells. Furthermore, an evident up-regulation of telomerase reverse-transcriptase (TERT) expression was detected inmTert+/+cells at the presenescence stage. Moreover, removal or down-regulation of TERT expression inmTert+/+and human primary fibroblast cells via CRISPR/Cas9 or shRNA recapitulatedmTert−/−phenotypes of accelerated senescence and transformation, and overexpression of TERT inmTert−/−cells rescued these phenotypes. Taking these data together, this study suggests that TERT has a previously underappreciated, protective role in buffering senescence stresses due to short, dysfunctional telomeres, and preventing malignant transformation.