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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
Author(s) -
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
Publication year - 2018
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22737
Subject(s) - biology , carcinogenesis , loss of heterozygosity , cancer research , mutant , mutation , tumor progression , cdkn2a , tumor initiation , microbiology and biotechnology , cancer , genetics , allele , gene
The mutation p53 N236S (p53S) has been identified as one of the recurrent mutations in human cancers by TCGA database. Our in vitro data revealed the oncogenic gain of function of p53S. To understand the function of p53S in vivo , we generated the p53S knock‐in mouse. The p53 S/S mice manifested highly invasive lymphomas and metastatic sarcomas with dramatically increased double minute chromosomes. The survival curve, the incidence of tumors and the tumor spectrum of p53 S/S mice is very similar to the p53 R172H mouse model. The p53 S/+ 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 in p53 S/S MEF and tumors, and the accumulation of p19 ARF protein in tumor tissues suggested p19 ARF might contribute to the accumulation of mutant p53S protein in the tumor and promote tumorigenesis. The high expression of p19 ARF correlated with mutant p53 accumulation and tumor progression, suggesting a dual role of p19 ARF in 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.