P53 in blind subterranean mole rats -: loss-of-function versus gain-offunction activities on newly cloned Spalax target genes
P53 in blind subterranean mole rats -: loss-of-function versus gain-offunction activities on newly cloned Spalax target genes
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DOI：
10.1038/sj.onc.1210045
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发表时间：
2007-04-12
期刊：
影响因子：
8
通讯作者：
Nevo, E.
中科院分区：
文献类型：
--
作者：
Avivi, A.;Ashur-Fabian, O.;Nevo, E.
肿瘤抑制基因p53控制细胞对各种应激条件的反应，包括DNA损伤和缺氧，导致生长停滞和/或凋亡。最近，我们证明，在盲地下鼹鼠，Spalax，缺氧耐受的模式生物，p53 DNA结合域包含一个特定的Arg 174 Lys氨基酸取代。这种取代降低了p53对凋亡基因（apaf 1，puma，pten和noxa）转录的影响，并增强了对人类细胞周期停滞和p53稳定/稳态基因（mdm 2，pten，p21和cycG）的影响。在本研究中，我们克隆了Spalax apaf 1启动子和mdm 2内含子区含有共识p53反应元件。我们比较了Spalax响应元件的人，小鼠和大鼠，并研究了Spalax和人类Arg 174 Lys突变的p53对这两个物种的靶基因的转录活性。Spalax和人类突变的p53失去了apaf 1转录的诱导，并增加了mdm 2转录的诱导。我们得出结论，Spalax进化的低氧适应机制，类似于肿瘤发展过程中癌细胞获得的改变，对细胞凋亡有偏见，同时有利于细胞停滞和DNA修复。
A tumor suppressor gene, p53, controls cellular responses to a variety of stress conditions, including DNA damage and hypoxia, leading to growth arrest and/or apoptosis. Recently, we demonstrated that in blind subterranean mole rats, Spalax, a model organism for hypoxia tolerance, the p53 DNA-binding domain contains a specific Arg174Lys amino acid substitution. This substitution reduces the p53 effect on the transcription of apoptosis genes ( apaf1, puma, pten and noxa) and enhances it on human cell cycle arrest and p53 stabilization/homeostasis genes (mdm2, pten, p21 and cycG). In the current study, we cloned Spalax apaf1 promoter and mdm2 intronic regions containing consensus p53-responsive elements. We compared the Spalax-responsive elements to those of human, mouse and rat and investigated the transcriptional activity of Spalax and human Arg174Lys-mutated p53 on target genes of both species. Spalax and human-mutated p53 lost induction of apaf1 transcription, and increased induction of mdm2 transcription. We conclude that Spalax evolved hypoxia-adaptive mechanisms, analogous to the alterations acquired by cancer cells during tumor development, with a bias against apoptosis while favoring cell arrest and DNA repair.