Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation
Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation
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DOI：
10.1038/ng1937
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发表时间：
2007-01-01
期刊：
影响因子：
30.8
通讯作者：
Rudolph, K. Lenhard
中科院分区：
文献类型：
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作者：
Choudhury, Aaheli Roy;Ju, Zhenyu;Rudolph, K. Lenhard
端粒缩短通过激活DNA损伤途径限制人类细胞的增殖寿命，包括上调细胞周期抑制物p21(由CDKN1A编码，也称为Cip1和Waf1)(参考文献。1-5)。在人类(6)和小鼠(7-9)中，端粒因编码端粒酶基因突变而缩短与器官维护受损和寿命缩短有关。在端粒功能障碍的背景下，p21的体内功能尚不清楚。在这里，我们表明，p21的缺失延长了端粒酶缺陷小鼠的寿命。P21缺失改善了造血和肠上皮细胞的维持，但并未挽救端粒功能。此外，p21的缺失挽救了肠道祖细胞的增殖，并改善了端粒功能障碍小鼠的造血干细胞的再繁殖能力和自我更新能力。在这些小鼠中，凋亡反应保持不变，p21缺失不会加速染色体不稳定或癌症形成。这项研究提供了实验证据，证明端粒功能障碍会在体内诱导依赖p21的检查点，从而在生物水平上限制寿命。
Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1-5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans(6) and in mice(7-9). The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.