Researchers in Dr. Laura Attardi’s lab have created a knock-in mouse strain which generates a form of p53 that is not subject to degradation by the proteasome. p53 is a tumor suppressor protein that senses and responds to cellular stress and is crucial for genomic stability and thus is involved in preventing cancer. In this mouse the wild-type p53 locus is replaced with a p53-VP16 fusion; such that the p53 transactivation domain is replaced with that of the VP16 transactivator protein. The p53-VP16 is silenced through an upstream floxed transcriptional stop element until Cre recombinase is expressed and the transcriptional stop element is excised. Furthermore, the Mdm-2 ubiquitin ligase binding domain has been removed thereby increasing the stability of p53. This mouse will serve as a useful model for investigating and developing p53-based cancer therapeutics.Stage of Research
The inventors demonstrated, through analysis of mouse embryo fibroblasts derived from these mice, that upon activation of the p53-VP16 gene there is very potent growth suppression. In addition, they have shown that this fusion protein is like wild-type p53 in its ability to activate p53 target genes.