Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice
Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice
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DOI：
10.1038/ng1282
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发表时间：
2004-01-01
期刊：
影响因子：
30.8
通讯作者：
Lozano, G
中科院分区：
文献类型：
--
作者：
Liu, G;Parant, JM;Lozano, G
P53蛋白整合了多个上游信号，并通过激活不同的下游基因发挥肿瘤抑制作用(1-3)。在细胞水平上，P53诱导细胞凋亡、细胞周期停滞和衰老。在人类肿瘤中发现了一种罕见的带有氨基酸替代R175P的p53突变形式，它在启动细胞凋亡方面完全缺陷，但仍然诱导细胞周期停滞(4，5)。为了破译这些途径在自发肿瘤发生中的功能重要性，我们使用同源重组产生了突变的P53-R172P(相当于人类的R175P)的小鼠。继承这种突变的两个副本(Trp53(515C/515C))的小鼠可以逃脱以Trp53缺失的小鼠为特征的胸腺淋巴瘤的早期发病。在7个月龄时，90%的TrP53基因缺失小鼠死亡，但85%的TrP53(515C/515C)小鼠存活且无瘤，这表明P53依赖的细胞凋亡不是抑制早期自发肿瘤发生所必需的。最终在Trp53(515C/515C)小鼠中发展起来的淋巴瘤和肉瘤保留了二倍体的染色体数量，这与在Trp53缺失小鼠的肿瘤和细胞中观察到的非整倍体形成了鲜明的对比。突变型P53-R172P诱导部分细胞周期停滞和保持染色体稳定性的能力对于抑制早期肿瘤的发生至关重要。
The p53 protein integrates multiple upstream signals and functions as a tumor suppressor by activating distinct downstream genes(1-3). At the cellular level, p53 induces apoptosis, cell cycle arrest and senescence. A rare mutant form of p53 with the amino acid substitution R175P, found in human tumors, is completely defective in initiating apoptosis but still induces cell cycle arrest(4,5). To decipher the functional importance of these pathways in spontaneous tumorigenesis, we used homologous recombination to generate mice with mutant p53-R172P ( the mouse equivalent of R175P in humans). Mice inheriting two copies of this mutation (Trp53(515C/515C)) escape the early onset of thymic lymphomas that characterize Trp53-null mice. At 7 months of age, 90% of Trp53-null mice had died, but 85% of Trp53(515C/515C) mice were alive and tumor-free, indicating that p53-dependent apoptosis was not required for suppression of early onset of spontaneous tumors. The lymphomas and sarcomas that eventually developed in Trp53(515C/515C) mice retained a diploid chromosome number, in sharp contrast to aneuploidy observed in tumors and cells from Trp53 null mice. The ability of mutant p53-R172P to induce a partial cell cycle arrest and retain chromosome stability are crucial for suppression of early onset tumorigenesis.