Mouse Models for the p53 R72P Polymorphism Mimic Human Phenotypes
Mouse Models for the p53 R72P Polymorphism Mimic Human Phenotypes
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DOI：
10.1158/0008-5472.can-09-4646
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发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Johnson, David G.
中科院分区：
文献类型：
--
作者：
Zhu, Feng;Dolle, Martijn E. T.;Johnson, David G.
p53肿瘤抑制基因包含一个常见的单核苷酸多态性（SNP），导致p53蛋白的第72位为精氨酸或脯氨酸。这种多态性影响p53的凋亡活性，但这种表型差异的机制基础和生理相关性仍不清楚。在这里，我们描述了小鼠模型的p53 R72 P SNP使用两种不同的方法的发展。在这两组模型中，人或人源化p53蛋白是功能性的，如通过响应于DNA损伤的p53靶基因的转录诱导和早期淋巴瘤发生的抑制所证明的。与体外研究一致，与表达p53 P变体的小鼠相比，表达72 R变体蛋白（p53 R）的小鼠对几种刺激具有更大的凋亡反应。分子研究表明，转录和非转录机制可能有助于差异能力的p53变异体诱导细胞凋亡。尽管对紫外线辐射的急性反应存在差异，但在多态小鼠模型之间观察到对慢性紫外线暴露的致瘤反应无差异。这些发现表明，在至少某些条件下，R72 P多态性对细胞凋亡的调节并不影响癌变过程。Cancer Res; 70（14）; 5851-9.（C）2010年AACR。
The p53 tumor suppressor gene contains a common single nucleotide polymorphism (SNP) that results in either an arginine or proline at position 72 of the p53 protein. This polymorphism affects the apoptotic activity of p53 but the mechanistic basis and physiologic relevance of this phenotypic difference remain unclear. Here, we describe the development of mouse models for the p53 R72P SNP using two different approaches. In both sets of models, the human or humanized p53 proteins are functional as evidenced by the transcriptional induction of p53 target genes in response to DNA damage and the suppression of early lymphomagenesis. Consistent with in vitro studies, mice expressing the 72R variant protein (p53R) have a greater apoptotic response to several stimuli compared with mice expressing the p53P variant. Molecular studies suggest that both transcriptional and nontranscriptional mechanisms may contribute to the differential abilities of the p53 variants to induce apoptosis. Despite a difference in the acute response to UV radiation, no difference in the tumorigenic response to chronic UV exposure was observed between the polymorphic mouse models. These findings suggest that under at least some conditions, the modulation of apoptosis by the R72P polymorphism does not affect the process of carcinogenesis. Cancer Res; 70(14); 5851-9. (C)2010 AACR.