An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations
An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations
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DOI：
10.1172/jci31721
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发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Roop, Dennis R.
中科院分区：
文献类型：
--
作者：
Caulin, Carlos;Nguyen, Thao;Roop, Dennis R.
Ras和p53突变是在人类非黑色素瘤皮肤癌中发现的最常见的突变。虽然一些P53突变会导致功能丧失，但大多数会导致P53表达形式的改变，这可能会表现出功能获得的特性。因此，了解获得P53功能增强与功能丧失突变的后果对于产生对携带P53突变的肿瘤的有效治疗至关重要。在这里，我们描述了一个可诱导的小鼠模型，在该模型中，皮肤肿瘤的形成是通过激活内源性K-ras(G12D)等位基因来启动的。利用这个模型，我们比较了激活P53功能获得突变P53(R172H)和删除P53基因的后果。与p53缺失相比，P53(R172H)等位基因的激活导致皮肤肿瘤的形成增加，肿瘤进展加快，并诱导转移。与这些观察结果一致的是，P53(R172H)肿瘤表现出与中心体扩增相关的非整倍体，这可能是P53(R172H)发挥其致癌特性的机制。这些结果清楚地表明，在裙部癌发生过程中，P53功能获得突变比P53丢失的预后更差，并对未来对表现出P53功能获得突变的肿瘤的治疗方案的设计具有重要意义。
Mutations in ras and p53 are the most prevalent mutations found in human nonmelanoma skin cancers. Although some p53 mutations cause a loss of function, most result in expression of altered forms of p53, which may exhibit gain-of-function properties. Therefore, understanding the consequences of acquiring p53 gain-of-fiinction versus loss-of-function mutations is critical for the generation of effective therapies for tumors harboring p53 mutations. Here we describe an inducible mouse model in which skin tumor formation is initiated by activation of an endogenous K-ras(G12D) allele. Using this model we compared the consequences of activating the p53 gain-of-function mutation p53(R172H) and of deleting the p53 gene. Activation of the p53(R172H) allele resulted in increased skin tumor formation, accelerated tumor progression, and induction of metastasis compared with deletion of p53. Consistent with these observations, the p53(R172H) tumors exhibited aneuploidy associated with centrosome amplification, which may underlie the mechanism by which p53(R172H) exerts its oncogenic properties. These results clearly demonstrate that p53 gain-of-function mutations confer poorer prognosis than loss of p53 during skirt carcinogenesis and have important implications for the future design of therapies for tumors that exhibit p53 gain-of-function mutations.