P53 status and toxic response in tumour cells
Programme Leader: Patricia Muller
The tumour suppressor protein p53 is one of the most important and powerful proteins to protect against tumour formation. In response to a variety of stresses, the p53 protein is stabilized to induce a transcriptional programme that will determine the faith of a cell; induction of apoptosis or cell cycle arrest and DNA repair. In a large number of tumours, mutations in the p53 gene are found that either abolish p53 expression or lead to the expression of a mutant protein. Most of these mutations occur within the DNA binding domain of p53 and result in the formation of an unfolded protein or a protein that has lost the ability to bind to DNA. Many of these mutant p53 proteins therefore have no or impaired transcriptional function and can dominant negatively inhibit the wild type protein. Although loss of p53 is sufficient to induce tumour formation, expression of a mutant p53 protein gives rise to more malignant tumours and metastasis that are often resistant to chemotherapy. These results therefore suggest that mutant p53 proteins have gained new functions in promoting metastasis and chemoresistance.
Summary of research interests
The p53 status in cells is important in determining how cells react to toxic insults. A wild type p53 can easily promote cell cycle arrest or apoptosis, whereas a cell that doesn’t express p53 or expresses a mutant p53 often does not. Previously I have revealed gain-of-function mechanisms through which mutant p53 can promote invasion and metastasis by inhibiting its family member TAp63. This results in enhanced recycling of growth factor receptors and integrins from intracellular vesicles back to the plasma membrane. The process of recycling allows these receptors to more frequently engage with their ligands leading to increased signalling to downstream signalling molecules such as pERK1/2 and pAKT. The recycling process is dependent on RCP (Rab Coupling Protein or Rab11FIP1). However, the precise mechanisms underlying p63/RCP-dependent activation of growth factor receptors and integrins are currently unknown. Preliminary data suggests a role for receptor recycling in mutant p53 mediated resistance to a variety of toxic stresses that is not seen in cells that do not express p53 or express wild type p53. A better understanding of the molecular mechanisms through which mutant p53 activates receptor recycling might therefore help in the design of novel strategies to target mutant p53 mediated metastasis and potentially reduce chemoresistance.
Another interesting observation is that zinc therapy can restore mutant p53 folding to certain extents promoting wild type function, whereas copper can unfold p53. Unfolded p53 has been shown to act in a similar manner as mutant p53 to promote invasion. Recent data in our lab furthermore revealed an interaction between copper transporters (which can also transport the chemotoxic drug cisplatin) and RCP suggesting that (mutant) p53 can influence cellular copper homeostasis and cisplatin levels.
The key objectives are:
(1) To characterize the inhibitory role of mutant p53 on Dicer.
(2) To investigate the mechanisms through which mutant p53 (and loss of p63) causes chemo-resistance and to explore a role for multidrug receptor recycling in chemo-resistance.
(3) To assess the role of the tumour microenvironment and cell-cell interactions in the behaviour of mutant p53 cells to chemotherapy.
(4) Characterization of the link between mutant p53 and copper/ cisplatin homeostasis
1. Phatak VM, Muller PA. p53 and metal toxicity; An intimate relationship. Toxicology Research 2015, 4, 576-591
2. Muller PA, Vousden KH. Mutant p53 in Cancer: New Functions and Therapeutic Opportunities. Cancer Cell 2014 Mar 17;25(3):304-31
3. Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol. 2013 Jan;15(1):2-8
4. Muller PA, Vousden KH, Norman JC The emerging role of p53 and its mutants in tumour cell migration and invasion. J Cell Biol. 2011 Jan 24;192(2):209-18