Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation
Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation
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DOI：
10.1073/pnas.0404998101
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发表时间：
2004-08-17
影响因子：
11.1
通讯作者：
Rechavi, G
中科院分区：
文献类型：
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作者：
Ashur-Fabian, C;Avivi, A;Rechavi, G
肿瘤抑制基因 p53 控制细胞对多种应激条件的反应，包括 DNA 损伤和缺氧，导致生长停滞和/或细胞凋亡。 p53 失活存在于 40-50% 的人类癌症中，在肿瘤进展过程中的缺氧微环境下赋予了选择性优势。鼹鼠，Spalax，其整个生命周期都在地下度过，其氧气浓度明显低于所研究的任何其他哺乳动物。由于 Spalax 进化出了对缺氧应激的广泛呼吸适应，因此我们推测它可能也发展出了类似于肿瘤进展过程中获得的遗传/表观遗传改变的缺氧适应机制。将 Spalax 与人和小鼠 p53 进行比较，发现 Spalax（人中为 Arg-174）的 DNA 结合域中存在精氨酸 (R) 替换为赖氨酸 (K)，这与已知的肿瘤相关突变相同。与另外 41 个物种的多个 p53 序列比对证实 Arg-174 高度保守。记者检测发现，Spalax p53 蛋白无法诱导凋亡调节靶基因，导致 apaf1 不表达，puma、pten 和 noxa 部分表达。然而，细胞周期停滞和 p53 稳定/稳态基因被 Spalax p53 过度激活。 Lys-174被发现对于apaf1表达失活至关重要。无 DNA 的 p53 结构模型预测 Arg-174 对于二聚化很重要，而 Spalax Lys-174 则阻止这种相互作用。在人类肿瘤中发现的类似邻近突变有利于生长停滞而不是细胞凋亡。我们假设，与人类肿瘤的进展类似，Spalax 在 4000 万年的地下缺氧生活中经历了显着的适应性 p53 进化。
The tumor suppressor gene p53 controls cellular response to a variety of stress conditions, including DNA damage and hypoxia, leading to growth arrest and/or apoptosis. Inactivation of p53, found in 40-50% of human cancers, confers selective advantage under hypoxic microenvironment during tumor progression. The mole rat, Spalax, spends its entire life cycle underground at decidedly lower oxygen tensions than any other mammal studied. Because a wide range of respiratory adaptations to hypoxic stress evolved in Spalax, we speculated that it might also have developed hypoxia adaptation mechanisms analogous to the genetic/epigenetic alterations acquired during tumor progression. Comparing Spalax with human and mouse p53 revealed an arginine (R) to lysine (K) substitution in Spalax (Arg-174 in human) in the DNA-binding domain, identical to known tumor associated mutations. Multiple p53 sequence alignments with 41 additional species confirmed that Arg-174 is highly conserved. Reporter assays uncovered that Spalax p53 protein is unable to induce apoptosisregulating target genes, resulting in no expression of apaf1 and partial expression of puma, pten, and noxa. However, cell cycle arrest and p53 stabilization/homeostasis genes were overactivated by Spalax p53. Lys-174 was found critical for apaf1 expression inactivation. A DNA-free p53 structure model predicts that Arg-174 is important for dimerization, whereas Spalax Lys-174 prevents such interactions. Similar neighboring mutations-found in human tumors favor growth arrest rather than apoptosis. We hypothesize that, in an analogy with human tumor progression, Spalax underwent remarkable adaptive p53 evolution during 40 million years of underground hypoxic life.