Gain of function in the mouse model of a recurrent mutation p53(N236S) promotes the formation of double minute chromosomes and the oncogenic potential of p19(ARF).
Gain of function in the mouse model of a recurrent mutation p53(N236S) promotes the formation of double minute chromosomes and the oncogenic potential of p19(ARF).
复制标题
反复突变 p53(N236S) 的小鼠模型中的功能获得促进双微小染色体的形成和 p19(ARF) 的致癌潜力。
DOI：
10.1002/mc.22737
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发表时间：
2018
影响因子：
4.6
通讯作者：
Luo Ying
中科院分区：
文献类型：
--
作者：
Zhao Lanjun;Wang Boyuan;Zhao Xilong;Wu Xiaoming;Zhang Qiushi;Wei Chuanyu;Shi Minling;Li Yunlong;Tang Wenru;Zhang Jihong;Yang Julun;Singh Sanjay K;Jia Shuting;Luo Ying
p53 N236 S（p53 S）突变已被TCGA数据库鉴定为人类癌症中的复发性突变之一。我们的玻璃体数据显示p53 S的致癌性功能获得。为了了解p53在体内的功能，我们产生了p53 S敲入小鼠。p53 S/S小鼠表现为高度侵袭性淋巴瘤和转移性肉瘤，并伴有显著增加的双微染色体。p53 S/S小鼠的生存曲线、肿瘤发生率和肿瘤谱与p53 R172 H小鼠模型非常相似。p53 S/+小鼠的肿瘤发生延迟，转移率高（40%），杂合性丢失率低（2/16）。p53 S/SMEF和肿瘤中CDKN 2A通路的激活以及p19 ARF蛋白在肿瘤组织中的积聚提示p19 ARF可能参与了突变型p53 S蛋白在肿瘤中的积聚并促进肿瘤的发生。p19 ARF的高表达与突变型p53积聚和肿瘤进展相关，提示p19 ARF在肿瘤促进或抑制中的双重作用可能取决于肿瘤细胞中的p53突变状态。这种复发性突变p53 S的致癌性功能获得促使重新考虑以低频率发生的p53突变功能。
The mutation p53N236S(p53S) has been identified as one of the recurrent mutations in human cancers by TCGA database. Ourin vitrodata revealed the oncogenic gain of function of p53S. To understand the function of p53Sin vivo, we generated the p53S knock‐in mouse. Thep53S/Smice manifested highly invasive lymphomas and metastatic sarcomas with dramatically increased double minute chromosomes. The survival curve, the incidence of tumors and the tumor spectrum ofp53S/Smice is very similar to the p53R172Hmouse model. Thep53S/+mice showed delayed onset of tumorigenesis and a high metastasis rate (40%) and low loss of heterozygosity rate (2/16). The activation of CDKN2A pathway inp53S/SMEF and tumors, and the accumulation of p19ARFprotein in tumor tissues suggested p19ARFmight contribute to the accumulation of mutant p53S protein in the tumor and promote tumorigenesis. The high expression of p19ARFcorrelated with mutant p53 accumulation and tumor progression, suggesting a dual role of p19ARFin tumor promotion or suppression that might depend on the p53 mutation status in tumor cells. The oncogenic gain of function of this recurrent mutation p53S prompts the reconsideration of p53 mutations function that occurs at a low frequency.