Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome
Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome
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DOI：
10.1016/j.cell.2004.11.006
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发表时间：
2004-12-17
期刊：
影响因子：
64.5
通讯作者：
Lozano, G
中科院分区：
文献类型：
--
作者：
Lang, GA;Iwakuma, T;Lozano, G
患有Li-Fraumeni综合征的个体携带p53肿瘤抑制基因的遗传突变，易患肿瘤。为了研究这些p53错义突变的机制性质，我们产生了在p53核苷酸515处具有G-to-A替换的小鼠（p53(+/515A)），与人类癌症中的p53R175H热点突变相对应。尽管p53（+/515A）小鼠的肿瘤谱和生存曲线与p53（+/-）小鼠相似，但p53（+/515A）小鼠的肿瘤转移频率较高。相应地，p53（515A/515A）突变小鼠的胚胎成纤维细胞表现出增强的细胞增殖、DNA合成和转化潜力。p53（-/-）细胞中p63和p73的破坏增加了转化能力，并重新启动了p53（515A/515A）细胞中观察到的DNA合成水平。此外，p63和p73在p53（515A）细胞中功能失活。这些结果为某些p53错义突变的功能获得特性提供了体内验证，并提出了这些表型的机制基础。
Individuals with Li-Fraumeni syndrome carry inherited mutations in the p53 tumor suppressor gene and are predisposed to tumor development. To examine the mechanistic nature of these p53 missense mutations, we generated mice harboring a G-to-A substitution at nucleotide 515 of p53 (p53(+/515A)) corresponding to the p53R175H hot spot mutation in human cancers. Although p53(+/515A) mice display a similar tumor spectrum and survival curve as p53(+/-) mice, tumors from p53(+/515A) mice metastasized with high frequency. Correspondingly, the embryonic fibroblasts from the p53(515A/515A) mutant mice displayed enhanced cell proliferation, DNA synthesis, and transformation potential. The disruption of p63 and p73 in p53(-/-) cells increased transformation capacity and reinitiated DNA synthesis to levels observed in p53(515A/515A) cells. Additionally, p63 and p73 were functionally inactivated in p53(515A) cells. These results provide in vivo validation for the gain-of-function properties of certain p53 missense mutations and suggest a mechanistic basis for these phenotypes.