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

ABSTRACT: Growing evidence suggests the ?133p53? 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 ?133p53? 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 ?133p53?-like isoform (?122p53) and a p53 mutant with weak tumor-suppressor function (m?pro). The ?122p53/m?pro mice showed a unique survival curve with a wide range of survival times (92-495 days) which was much greater than m?pro/- mice (range 120-250 days) and mice heterozygous for the ?122p53 and p53 null alleles (?122p53/-, range 78-150 days), suggesting ?122p53 increased the tumor-suppressor activity of m?pro. Moreover, some of the mice that survived longest only developed benign tumors. In vitro analyses to investigate why some ?122p53/m?pro mice were protected from aggressive tumors revealed that ?122p53 stabilized m?pro and prolonged the response to DNA damage. Similar effects of ?122p53 and ?133p53? were observed on wild-type of full-length p53, but these did not result in improved biological responses. The data suggest that ?122p53 (and ?133p53?) could offer some protection against tumors by enhancing the p53 response to stress.

SUBMITTER: Slatter TL 

PROVIDER: S-EPMC4669831 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other