Delta 122p53, a mouse model of Delta 133p53 alpha, enhances the tumor-suppressor activities of an attenuated p53 mutant

作者：Slatter T L; Hung N; Bowie S; Campbell H; Rubio C; Speidel D; Wilson M; Baird M; Royds J A; Braithwaite A W^*

来源：Cell Death & Disease, 2015, 6(6): e1783.

DOI：10.1038/cddis.2015.149

Growing evidence suggests the Delta 133p53 alpha isoform may function as an oncogene. It is overexpressed in many tumors, stimulates pathways involved in tumor progression, and inhibits some activities of wild-type p53, including transactivation and apoptosis. We hypothesized that Delta 133p53 alpha would have an even more profound effect on p53 variants with weaker tumor-suppressor capability. We tested this using a mouse model heterozygous for a Delta 133p53 alpha-like isoform (Delta 122p53) and a p53 mutant with weak tumor-suppressor m Delta pro). The Delta 122p53/m Delta pro mice showed a unique survival curve with a wide range of survival times (92-495 days) which was much greater than m Delta pro/-mice (range 120-250 days) and mice heterozygous for the Delta 122p53 and p53 null alleles (Delta 122p53/-, range 78-150 days), suggesting Delta 122p53 increased the tumor-suppressor activity of m Delta pro. Moreover, some of the mice that survived longest only developed benign tumors. In vitro analyses to investigate why some Delta 122p53/m Delta pro mice were protected from aggressive tumors revealed that Delta 122p53 stabilized m Delta pro and prolonged the response to DNA damage. Similar effects of Delta 122p53 and Delta 133p53 alpha were observed on wild-type of full-length p53, but these did not result in improved biological responses. The data suggest that Delta 122p53 (and Delta 133p53 alpha) could offer some protection against tumors by enhancing the p53 response to stress.

• 出版日期2015-6