TeI2 regulates the stability of PI3K-related protein kinases
TeI2 regulates the stability of PI3K-related protein kinases
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DOI：
10.1016/j.cell.2007.10.052
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发表时间：
2007-12-28
期刊：
影响因子：
64.5
通讯作者：
de lange, Titia
中科院分区：
文献类型：
--
作者：
Takai, Hiroyuki;Wang, Richard C.;de lange, Titia
我们报告了一个意想不到的Tel 2在所有哺乳动物磷脂酰肌醇3-激酶相关蛋白激酶（PIKKs）的表达中的作用。虽然Tel 2被鉴定为维持端粒长度所需的芽殖酵母基因，但我们发现哺乳动物Tel 2没有明显的端粒功能。靶向基因缺失表明，小鼠Tel 2在胚胎发育、胚胎干细胞（ES）和胚胎成纤维细胞中是必需的。从胚胎成纤维细胞中有条件地删除Tel 2损害了它们对IR和UV的反应，减少了检查点激酶及其下游效应物的激活。Tel 2缺失的影响与PI 3 K相关激酶共济失调毛细血管扩张突变（ATM）、ATM和Rad 3相关（ATR）、DNA依赖性蛋白激酶催化亚基共济失调（DNA-PKcs）的蛋白水平显著降低相关。Tel 2缺失还引起了哺乳动物雷帕霉素靶蛋白（mTOR）、对生殖器具有形态学影响的抑制因子1（SMG 1）和转化/转录结构域相关蛋白（TRRAP）的特异性耗竭，并抑制了mTOR信号传导，表明Tel 2影响所有六种哺乳动物PIKK。虽然Tel 2缺失没有改变PIKK mRNA水平，但体内脉冲标记实验表明，Tel 2控制ATM和mTOR的稳定性。与Tel 2相关的每个PIKK家族成员的体内和体外实验表明，Tel 2结合ATM和mTOR的部分HEAT重复片段。这些数据将Tel 2鉴定为PIKK稳定性的高度保守调节剂。
We report an unexpected role for Tel2 in the expression of all mammalian phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Although Tel2 was identified as a budding yeast gene required for the telomere length maintenance, we found no obvious telomeric function for mammalian Tel2. Targeted gene deletion showed that mouse Tel2 is essential in embryonic development, embryonic stem (ES) cells, and embryonic fibroblasts. Conditional deletion of Tel2 from embryonic fibroblasts compromised their response to IR and UV, diminishing the activation of checkpoint kinases and their downstream effectors. The effects of Tel2 deletion correlated with significantly reduced protein levels for the PI3K-related kinases ataxia telangiectasia mutated (ATM), ATM and Rad3 related (ATR), DNA-dependent protein kinase catalytic subunit ataxia (DNA-PKcs). Tel2 deletion also elicited specific depletion of the mammalian target of rapamycin (mTOR), suppressor with morphological effect on genitalia 1 (SMG1), and transformation/transcription domain-associated protein (TRRAP), and curbed mTOR signaling, indicating that Tel2 affects all six mammalian PIKKs. While Tel2 deletion did not alter PIKK mRNA levels, in vivo pulse labeling experiments showed that Tel2 controls the stability of ATM and mTOR. Each of the PIKK family members associated with Tel2 in vivo and in vitro experiments indicated that Tel2 binds to part of the HEAT repeat segments of ATM and mTOR. These data identify Tel2 as a highly conserved regulator of PIKK stability.