Gain of function in the mouse model of a recurrent mutation p53N236S promotes the formation of double minute chromosomes and the oncogenic potential of p19ARF

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.