Abstract SY29-01: Functions of wild type and mutant p53

Abstract

The p53 protein is an important tumor suppressor that can function to inhibit cell growth through the activation of a number of different responses, including cell cycle arrest, senescence and apoptosis. Recent evidence has suggested that under conditions of low or transient stress, p53 can also contribute to the survival of stressed cells - allowing for the prevention or repair of damage. Each of these activities can restrain malignant progression, and most cancers show loss of the normal functions of p53. In many cancers this is due to a mutation in the p53 gene that leads to the expression of a mutant p53 protein. Interestingly, these tumor associated mutant p53s not only lose wild type p53 activity but can also acquire the ability to promote cell motility and migration, and so contribute to the development of metastases.

We have found that tumor associated mutant p53s can promote invasion and loss of directionality when cells migrate in vitro. These activities are independent of the loss of wild type p53 function, and reflect activation of integrin and EGFR trafficking that depends on Rab-coupling protein and which results in constitutive activation of EGFR/integrin signalling. These findings open the possibility that blocking alpha5/beta1 integrin and/or the EGF receptor will have therapeutic benefit in mutant p53 expressing cancers. We are now proposing to extend these observations by testing whether this activity of mutant p53 is restricted to the EGFR, or may also promote the activity of other cell surface receptors too. Simultaneous loss of p53 and p63 recapitulates the phenotype of mutant p53, suggesting that this function of mutant p53 reflects, at least in part, the inhibition of p63. However, mutant p53 is likely to have additional functions that contribute to the ability to induce an invasive phenotype, and we are presently investigating the activity of other mutant p53 binding proteins.

While mutant p53s are often expressed at very high levels in tumors, normal cells express mutant p53s at low level, like the wild type p53 protein. The turnover of mutant p53 in these cells is dependent on the function of the MDM2 ubiquitin ligase, which also regulates the stability of wild type p53, and deletion or inhibition of MDM2 leads to the stabilization of both mutant and wild type p53 proteins. A number of small molecule drugs that can inhibit MDM2's ability to target p53 for degradation have been described, with the hope that these will be useful in treating those tumors that retain wild type p53. However, studies have suggested that many apparently normal tissues harbour p53 mutations, leading to the possibility that systemic treatment with MDM2 inhibitors would result in the stabilization of these mutant p53s, with unanticipated, deleterious consequences. We are therefore investigating how mutant p53 turnover is regulated, with the view to testing whether the stabilization of mutant p53 would affect the behaviour of otherwise normal cells.

Citation Format: Patricia Muller, Patricia Roxburgh, Patrick Caswell, Jim Norman, Karen H. Vousden. Functions of wild type and mutant p53 [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY29-01