The p53 tumor suppressor protein restrains malignant progression through a number of mechanisms, and most cancers show loss of the normal functions of p53. In many cancers this is due to mutations in the p53 gene, leading to the expression of mutant p53 proteins that have lost wild type activity and acquired an oncogenic function that can promote metastasis. We have found that mutant p53 can promote the activation of integrin and cell surface receptor trafficking that depends on Rab-coupling protein (RCP) and which results in constitutive activation of signaling though the EGFR, MET and integrin. Simultaneous loss of p53 and p63 recapitulates the phenotype of mutant p53 both in cells and in vivo, and this function of mutant p53 reflects, at least in part, the inhibition of the p53 family member p63 . Interestingly, the tumor-associated point mutations induce conformational instability of the p53 protein, and the misfolding of p53 correlates with loss of wild type and gain of mutant activity. We have found that folding of wild type p53 is promoted by an interaction with the chaperonin CCT. Intriguingly, p53 proteins mutated to prevent the interaction with CCT show conformational instability, and acquire an ability to promote invasion and random motility that is similar to the activity of tumor derived p53 mutants. Our data therefore suggest that both growth suppression and cell invasion may be differentially regulated functions of wild type p53.
Citation Format: Karen H. Vousden. Activities of wild-type and mutant p53. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA18.