Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
Am J Pathol. 2011 Oct;179(4):1616-22. doi: 10.1016/j.ajpath.2011.06.036. Epub 2011 Aug 18.
The TP53 tumor suppressor gene is mutated in the majority of human cancers. Inactivation of p53 in a variety of animal models results in early-onset tumorigenesis, reflecting the importance of p53 as a gatekeeper tumor suppressor. We generated a mutant Tp53 allele in the rat using a target-selected mutagenesis approach. Here, we report that homozygosity for this allele results in complete loss of p53 function. Homozygous mutant rats predominantly develop sarcomas with an onset of 4 months of age with a high occurrence of pulmonary metastases. Heterozygous rats develop sarcomas starting at 8 months of age. Molecular analysis revealed that these tumors exhibit a loss-of-heterozygosity of the wild-type Tp53 allele. These unique features make this rat highly complementary to other rodent p53 knockout models and a versatile tool for investigating tumorigenesis processes as well as genotoxic studies.
TP53 肿瘤抑制基因在大多数人类癌症中发生突变。在多种动物模型中，p53 的失活会导致早期肿瘤发生，这反映了 p53 作为“守门员”肿瘤抑制因子的重要性。我们使用靶向选择诱变方法在大鼠中产生了一个突变的 Tp53 等位基因。在这里，我们报告说，这个等位基因的纯合子导致 p53 功能完全丧失。纯合子突变大鼠主要发生肉瘤，发病年龄为 4 个月，肺转移发生率很高。杂合子大鼠从 8 个月大开始发生肉瘤。分子分析表明，这些肿瘤表现出野生型 Tp53 等位基因的杂合性丢失。这些独特的特征使得这种大鼠与其他啮齿动物 p53 敲除模型高度互补，是研究肿瘤发生过程以及遗传毒性研究的多功能工具。
