Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism
Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism
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DOI：
10.1182/blood-2010-08-297390
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发表时间：
2011-04-21
期刊：
影响因子：
20.3
通讯作者：
Suda, Toshio
中科院分区：
文献类型：
--
作者：
Nitta, Eriko;Yamashita, Masayuki;Suda, Toshio
端粒酶逆转录酶（TERT）通过一种与端粒延长无关的机制来防止衰老。本研究使用共济失调-毛细血管扩张突变（ATM）和TERT双缺陷小鼠来评估2种衰老调节分子，TERT和ATM对衰老过程的贡献。ATM和TERT双缺陷小鼠表现出衰老进程加快，寿命比ATM缺失小鼠短，而单独的TERT不足以影响寿命。ATM-TERT双缺陷小鼠显示出体内衰老，特别是在造血组织中，这依赖于p16（INK 4a）和p19（ARF），但不依赖于p21。由于它们的HSC显示干细胞活性降低，在这些小鼠中观察到的加速衰老归因于干细胞功能受损。TERT缺陷的HSC的特征在于活性氧（ROS）脆性，其已被认为在衰老期间引起干细胞损伤，并且凋亡的HSC在这些小鼠中显著增加。p38 MAPK的激活部分参与了ROS诱导的TERT缺失的HSC的凋亡，BCL-2被认为是通过TERT提供HSC保护机制的一部分。目前的研究表明，在压力条件下，TERT通过端粒长度非依赖性机制保护HSC来减轻衰老。（血。2011; 117（16）：4169-4180）
Telomerase reverse transcriptase (TERT) contributes to the prevention of aging by a largely unknown mechanism that is unrelated to telomere lengthening. The current study used ataxia-telangiectasia mutated (ATM) and TERT doubly deficient mice to evaluate the contributions of 2 aging-regulating molecules, TERT and ATM, to the aging process. ATM and TERT doubly deficient mice demonstrated increased progression of aging and had shorter lifespans than ATM-null mice, while TERT alone was insufficient to affect lifespan. ATM-TERT doubly null mice show in vivo senescence, especially in hematopoietic tissues, that was dependent on p16(INK4a) and p19(ARF), but not on p21. As their HSCs show decreased stem cell activities, accelerated aging seen in these mice has been attributed to impaired stem cell function. TERT-deficient HSCs are characterized by reactive oxygen species (ROS) fragility, which has been suggested to cause stem cell impairment during aging, and apoptotic HSCs are markedly increased in these mice. p38MAPK activation was indicated to be partially involved in ROS-induced apoptosis in TERT-null HSCs, and BCL-2 is suggested to provide a part of the protective mechanisms of HSCs by TERT. The current study demonstrates that TERT mitigates aging by protecting HSCs under stressful conditions through telomere length-independent mechanisms. (Blood. 2011; 117(16):4169-4180)