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Tumour Suppressors - Patricia Muller

After a PhD in copper metabolism at the University of Utrecht (the Netherlands), Patricia started her postdoctoral career in 2008 at the CRUK Beatson Institute in Glasgow in Karen Vousden’s lab. She obtained a personal Rubicon fellowship from the NWO (a Dutch scientific organisation) to work on mutant p53 function in metastasis for three years. This project resulted in a publication in Cell in 2009 and allowed for an extension of her postdoctoral position on an AICR grant with Karen Vousden for two years. Patricia continued her career with a Sir Henry Dale fellowship from the Wellcome Trust/Royal Society in 2013 at the MRC Toxicology Unit on the function of mutant p53 in chemoresistance. She received an early career award from the Biochemical Society in 2015.

Introduction

TP53 is the most frequently mutated gene in human cancers. The p53 protein is a transcription factor that acts as a major switch in decisions as to whether a cell lives or dies in response to various stresses. In many cancers, p53 function is inactivated due to mutations that either lead to a loss of expression or expression of mutant forms of the protein. Nearly all amino acids within p53 can be found mutated, giving rise to thousands of different mutant p53 proteins. Some of these occur more frequently than others and have been investigated in more detail. From this work it is clear that these mutants not only display a loss of p53 function, but can also gain novel functions in promoting tumourigenesis, inducing invasion or acquiring chemoresistance. Some of these novel functions seem to rely on an ability of mutant p53 cells to engulf other cells (Figure 1). In our lab we are using cellular and animal models to explore the molecular mechanisms underlying the novel gain-of-functions and to understand the role of cell engulfment in these.

Figure 1: 3D projection of a mutant p53 cell (green) engulfing a p53 null cell (red) made from a Z-stack of confocal images (one height is shown in insert). Blue is DAPI staining.

When looking at the different mutations that can occur within p53, it became apparent that different organs show different p53 mutational profiles. It is therefore likely that certain mutants are selected for and might even have slightly different gain-of-functions. In addition, we noticed that even the wildtype p53 protein can sometimes display a gain-of-function phenotype, dependent on the environment surrounding the tumour cell. In our lab we are investigating the extracellular conditions that determine if the wildtype p53 molecule displays a gain-of-function phenotype, which might help to explain why certain mutations are selected for.

 

Selected Publications

 

O’Regan L, Barone G, Adib R, Woo CG, Jeong J, Richardson W, Richards M, Muller PAJ, Collis S, Fennel D, Chor J, Bayliss R, Fry A. (2020)
EML4-ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7. 
Journal of Cell Science 133(9) PubMed abstract

Hall C, Muller PAJ. (2019)
The diverse functions of mutant p53 and its family members. 
International Journal of Molecular Sciences 20(24), 6188. [review] PubMed abstract

Mackay HI, Muller PAJ. (2019)
Biological relevance of cell-in-cell in cancers. 
Biochemical Society Transactions 47(2), 725–732. [review] PubMed abstract

Mackay HL, Moore D, Hall C, Birkbak NJ, Jamal-Hanjani M, Karim SA, Phatak VM, Piñon L, Morton JP, Swanton C, Le Quesne J, Muller PAJ. (2018)
Genomic instability in mutant p53 cancer cells upon entotic engulfment.
Nature Communications 9(1):3070. PubMed abstract

Eriksson M, Amboise G, Ouchida AT, Queiroz AL, Smoth D, Gimenez-Cassina A, Iwanicki MP, Muller PA, Norberg E, Vakifahmetoglu-Norberg H. (2017)
Effect of mutant p53 proteins on glycolysis and mitochondrial metabolism.
Molecular and Cellular Biology 37(24), e00328-17. PubMed abstract

Aschauer L, Muller PA. (2016)
Novel targets and interaction partners of mutant p53 gain-of-function.
Biochemical Society Transactions 44(2):460-6. PubMed abstract

Muller PA*, K. Vousden.* (2014)
Mutant p53 in cancer : New functions and therapeutic opportunites.
Cancer Cell 25(3):304-17.  PubMed abstract *Corresponding author

Muller PA*, Trinidad AG, Caswell PT, Norman JC, Vousden KH. (2014)
Mutant p53 regulates Dicer through p63 dependent and independent mechanisms to promote an invasive phenotype.
Journal of Biological Chemistry 289(1):122-32. PubMed abstract *Corresponding author

Tan EH, Morton JP, Timpson P, Tucci P, Melino G, Flores ER, Sansom OJ, Vousden KH, Muller PA. (2014)
Functions of TAp63 and p53 in restraining the development of metastatic cancer.
Oncogene 33(25):3325-33. PubMed abstract

Muller PA, Trinidad AG, Caswell P, Noll JE, Coffill CR, Lane DP, Neilsen PM, Norman JC, Vousden KH. (2013)
Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion.
Oncogene 32(10):1252-65. PubMed abstract


 

 

Team

Postdoctoral Fellow
Yannick von Grabowiecki

Graduate Student
Callum Hall

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