p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma
p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma
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DOI：
10.1002/path.2748
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发表时间：
2010-10-01
影响因子：
7.3
通讯作者：
Sansom, Owen J.
中科院分区：
文献类型：
--
作者：
Doyle, Brendan;Morton, Jennifer P.;Sansom, Owen J.
多形性横纹肌肉瘤是这种肿瘤在成人中最常见的变体，并且具有非常差的结果。已知在横纹肌肉瘤发展中起作用的两个基因是KRas和p53。在大多数人类肿瘤中，p53异常是导致蛋白质突变形式表达的点突变。现在假设，这些突变形式的p53可能发挥致癌作用，而不仅仅是野生型功能的简单丧失。在这项研究中，我们使用Cre-LoxP技术开发了一种新的横纹肌肉瘤小鼠模型，将表达常见KRas突变（G12 V）的小鼠与失去p53表达或表达突变形式的p53的小鼠杂交。我们使用这个模型来探索在激活KRas突变的情况下p53缺失和突变的不同影响。我们发现无论是p53基因完全缺失（p53（fl/fl））还是一个突变型p53等位基因的表达伴随着第二个等位基因的缺失（p53（R172 H/fl））分别导致15/16和19/19小鼠横纹肌肉瘤的快速发展。相比之下，在丢失单拷贝p53（p53（fl/+））的小鼠和表达单拷贝突变型p53（p53（172 H/+））的小鼠之间存在显著差异。16只p53（R172 H/+）小鼠中有14只发生横纹肌肉瘤，而31只p53 fl/+小鼠中有2只发生横纹肌肉瘤。因此，p53 fl/+小鼠的中位寿命几乎是p53 R172 H/+小鼠的两倍。为了强调p53突变在肿瘤进展中的增强作用，仅在表达突变形式的那些小鼠中观察到转移。这些数据表明，突变型p53可以与激活的突变型KRas合作，影响肿瘤发生和转移潜力，而不仅仅是正常蛋白质功能的简单丧失。版权所有（C）2010大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Pleomorphic rhabdomyosarcoma is the most common variant of this tumour in adults and has a very poor outcome. Two genes which are known to play a role in rhabdomyosarcoma development are KRas and p53. In the majority of human tumours, p53 abnormalities are point mutations that result in the expression of a mutant form of the protein. It is now hypothesized that these mutant forms of p53 may be playing an oncogenic role, over and above simple loss of the wild-type function. In this study, we use Cre-LoxP technology to develop a novel mouse model of rhabdomyosarcoma, crossing mice expressing a common KRas mutation ( G12V) with mice that either lose p53 expression or express a mutant form of p53. We use this model to explore the different effects of p53 loss and mutation in the setting of an activating KRas mutation. We found that either complete loss of p53 ( p53(fl/fl)) or the expression of one mutant p53 allele with concomitant loss of the second allele ( p53(R172H/fl)) resulted in the rapid development of rhabdomyosarcoma in 15/16 and 19/19 mice, respectively. In contrast, there was a marked difference between mice which lose a single copy of p53 ( p53(fl/+)) and mice expressing a single copy of mutant p53 ( p53(172H/+)). Fourteen out of 16 p53(R172H/+) mice developed rhabdomyosarcoma, compared with two out of 31 p53fl/+ mice. As a consequence of this, p53fl/+ mice had a median lifespan nearly double that of the p53R172H/+ mice. To underline the enhanced effect of p53 mutation in tumour progression, metastases were seen only in those mice which expressed the mutant form. These data demonstrate that mutant p53 can co-operate with activated, mutant KRas to influence tumourigenesis and metastatic potential, over and above simple loss of normal protein function. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.