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Overview

Dr Patricia Muller

Associate Professor


Affiliations
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Associate Professor in the Department of Biosciences145 

Biography

I started my academic career as a PhD student working on copper homeostasis and the COMMD1 protein in the UMC Utrecht, the Netherlands. I got inspired by p53 nuclear export regulation to understand the function and regulation of COMMD1. My fascination for p53 lead me to do a postdoc in the lab of Prof Karen Vousden, CRUK: the Beatson Institute, Glasgow, UK. I managed to get this position funded through the Dutch organisation NWO (A Rubicon fellowship). We set out to understand why expression of a mutant p53 protein is different than loss of p53 expression in cancers. We discovered a new signalling pathway adopted by mutant p53 to promote invasion and metastasis via RCP (Rab11FIP1). Mutant p53 facilitated the recycling of integrins and growth factor receptors to the plasma membrane, leading to enhanced Erk1/2 and Akt signalling. In a screen to detect novel interaction partners of RCP, I found several membrane transporters. This screen formed the basis of my application for a Henry Dale Fellowship (Welcome Trust) with which I started my independent research group in 2014 in the MRC Toxicology Unit in Leicester, UK.

In 2016 I was awarded an early career award from the Biochemistry Society. I uncovered a role for RCP in regulating drug transporter membrane expression in mutant p53 cells. Additionally, while doing this work, we made an observation that mutant p53 cancer cells are more likely to engulf neighbouring cells. We could correlate this behaviour to cell-in-cell structures in cancers, which we believe are pro-tumourigenic. Due to relocation of the MRC institute, I decided to continue my fellowship in the CRUK Manchester Institute in 2017 and broadened my interest into discovering therapeutic opportunities in tumours with (mutant) p53. Based on my previous work in copper homeostasis during my PhD, I also started a research line into the toxic properties of the metal copper on p53 signalling.

In 2021, I moved to Durham to further the research into the relationship between metals and p53. Metals can unfold the p53 molecule and change its function. In cancer cells, p53 unfolding upon metal load impairs p53 tumour suppressor function and make it act like a mutant p53 protein. This happens at very low levels of metal and suggest a physiological role for metals in regulating p53 function. 

Research Interests

In our lab we are interested in answering the following questions:

  1. How does mutant p53 promote gain-of-function in invasion, metastasis and chemoresistance? What are the underlying mechanisms?
  2. Why are certain p53 mutants selected for in certain cancers? Is this related to the environment of the cancer?
  3. To what extent do mutant p53 induced cell-in-cell structures contribute to mutant p53 Gain-of-function and how are these structures formed?
  4. How do metals impact on p53 function in cancer, other diseases and physiological processes?

Research groups

  • Animal Cells and Systems

Publications

Journal Article

  • Hall, C., von Grabowiecki, Y., Pearce, S.P., Dive, C., Bagley, S. & Muller, P.A.J. (2021). iRFP (near-infrared fluorescent protein) imaging of subcutaneous and deep tissue tumours in mice highlights differences between imaging platforms. Cancer Cell International 21(1).
  • Phatak, V., von Grabowiecki, Y., Janus, J., Officer, L., Behan, C., Aschauer, L., Pinon, L., Mackay, H., Zanivan, S., Norman, J.C., Kelly, M., Le Quesne, J. & Muller, P.A.J. (2021). Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane. Cell Death and Disease 12(2).
  • Budden, T., Gaudy-Marqueste, C., Porter, A., Kay, E., Gurung, S., Earnshaw, C.H., Roeck, K., Craig, S., Traves, V., Krutmann, J., Muller, P., Motta, L., Zanivan, S., Malliri, A., Furney, S.J., Nagore, E. & Virós, A. (2021). Ultraviolet light-induced collagen degradation inhibits melanoma invasion. Nature Communications 12(1).
  • O'Regan, L., Barone, G., Adib, R., Woo, C.G., Jeong, H.J., Richardson, E.L., Richards, M.W., Muller, P.A.J., Collis, S.J., Fennell, D.A., Choi, J., Bayliss, R. & Fry, A.M. (2020). EML4-ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7. Journal of Cell Science 133(9).
  • Mackay, H.L. & Muller, P.A.J. (2019). Biological relevance of cell-in-cell in cancers. Biochemical Society Transactions 47(2): 725-732.
  • Hall, C. & Muller, P.A.J. (2019). The diverse functions of mutant 53, its family members and isoforms in cancer. International Journal of Molecular Sciences 20(24).
  • Mackay, H.L., Moore, D., Hall, C., Birkbak, N.J., Jamal-Hanjani, M., Karim, S.A., Phatak, V.M., Piñon, L., Morton, J.P., Swanton, C., Le Quesne, J. & Muller, P.A.J. (2018). Genomic instability in mutant p53 cancer cells upon entotic engulfment. Nature Communications 9(1).
  • Mackay, H.L., Moore, D., Hall, C., Birkbak, N.J., Jamal-Hanjani, M., Karim, S.A., Phatak, V.M., Piñon, L., Morton, J.P., Swanton, C., Le Quesne, J. & Muller, P.A.J. (2018). Erratum to: Genomic instability in mutant p53 cancer cells upon entotic engulfment (Nature Communications, (2018), 9, 1, (3070), 10.1038/s41467-018-05368-1). Nature Communications 9(1).
  • Eriksson, M., Ambroise, G., Ouchida, A.T., Queiroz, A.L., Smith, D., Gimenez-Cassina, A., Iwanicki, M.P., Muller, P.A., Norberg, E. & Vakifahmetoglu-Norberg, H. (2017). Effect of mutant p53 proteins on glycolysis and mitochondrial metabolism. Molecular and Cellular Biology 37(24).
  • Hall, A.E., Lu, W.-T., Godfrey, J.D., Antonov, A.V., Paicu, C., Moxon, S., Dalmay, T., Wilczynska, A., Muller, P.A.J. & Bushell, M. (2016). The cytoskeleton adaptor protein ankyrin-1 is upregulated by p53 following DNA damage and alters cell migration. Cell Death and Disease 7.
  • Aschauer, L. & Muller, P.A.J. (2016). Novel targets and interaction partners of mutant p53 Gain-Of-Function. Biochemical Society Transactions 44(2): 460-466.
  • Viticchiè, G. & Muller, P.A.J. (2015). c-Met and other cell surface molecules: Interaction, activation and functional consequences. Biomedicines 3(1): 46-70.
  • Stindt, M.H., Muller, P.A.J., Ludwig, R.L., Kehrloesser, S., Dötsch, V. & Vousden, K.H. (2015). Functional interplay between MDM2, p63/p73 and mutant p53. Oncogene 34(33): 4300-4310.
  • Phatak, V.M. & Muller, P.A.J. (2015). Metal toxicity and the p53 protein: An intimate relationship. Toxicology Research 4(3): 576-591.
  • Muller, P.A.J. & Vousden, K.H. (2014). Mutant p53 in cancer: New functions and therapeutic opportunities. Cancer Cell 25(3): 304-317.
  • Tan, E.H., Morton, J.P., Timpson, P., Tucci, P., Melino, G., Flores, E.R., Sansom, O.J., Vousden, K.H. & Muller, P.A.J. (2014). Functions of TAp63 and p53 in restraining the development of metastatic cancer. Oncogene 33(25): 3325-3333.
  • Muller, P.A.J., Trinidad, A.G., Caswell, P.T., Norman, J.C. & Vousden, K.H. (2014). Mutant p53 regulates dicer through p63-dependent and -independent mechanisms to promote an invasive phenotype. Journal of Biological Chemistry 289(1): 122-132.
  • Muller, P.A.J., Trinidad, A.G., Timpson, P., Morton, J.P., Zanivan, S., Van Den Berghe, P.V.E., Nixon, C., Karim, S.A., Caswell, P.T., Noll, J.E., Coffill, C.R., Lane, D.P., Sansom, O.J., Neilsen, P.M., Norman, J.C. & Vousden, K.H. (2013). Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion. Oncogene 32(10): 1252-1265.
  • Muller, P.A.J. & Vousden, K.H. (2013). P53 mutations in cancer. Nature Cell Biology 15(1): 2-8.
  • Trinidad, A.G., Muller, P.A.J., Cuellar, J., Klejnot, M., Nobis, M., Valpuesta, J.M. & Vousden, K.H. (2013). Interaction of p53 with the CCT Complex Promotes Protein Folding and Wild-Type p53 Activity. Molecular Cell 50(6): 805-817.
  • Muller, P.A.J. (2013). NCF2/p67phox: A novel player in the anti-apoptotic functions of p53. Cell Cycle 12(1): 14.
  • Rainero, E., Caswell, P.T., Muller, P.A., Grindlay, J., Mccaffrey, M.W., Zhang, Q., Wakelam, M.J., Vousden, K.H., Graziani, A. & Norman, J.C. (2012). Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration. Journal of Cell Biology 196(2): 277-295.
  • Coffill, C.R., Muller, P.A.J., Oh, H.K., Neo, S.P., Hogue, K.A., Cheok, C.F., Vousden, K.H., Lane, D.P., Blackstock, W.P. & Gunaratne, J. (2012). Mutant p53 interactome identifies nardilysin as a p53R273H-specific binding partner that promotes invasion. EMBO Reports 13(7): 638-644.
  • Tucci, P., Agostini, M., Grespi, F., Markert, E.K., Terrinoni, A., Vousden, K.H., Muller, P.A.J., Dötsch, V., Kehrloesser, S., Sayan, B.S., Giaccone, G., Lowe, S.W., Takahashi, N., Vandenabeele, P., Knight, R.A., Levine, A.J. & Melino, G. (2012). Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 109(38): 15312-15317.
  • Muller, P.A.J., Vousden, K.H. & Norman, J.C. (2011). p53 and its mutants in tumor cell migration and invasion. Journal of Cell Biology 192(2): 209-218.
  • Muller, P.A.J., De Sluis, B.V., Groot, A.J., Verbeek, D., Vonk, W.I.M., Maine, G.N., Burstein, E., Wijmenga, C., Vooijs, M., Reits, E. & Klomp, L.W.J. (2009). Nuclear-cytosolic transport of COMMD1 regulates NF-κB and HIF-1 activity. Traffic 10(5): 514-527.
  • Maine, G.N., Mao, X., Muller, P.A., Komarck, C.M., Klomp, L.W.J. & Burstein, E. (2009). COMMD1 expression is controlled by critical residues that determine XIAP binding. Biochemical Journal 417(2): 601-609.
  • Muller, P.A.J., Caswell, P.T., Doyle, B., Iwanicki, M.P., Tan, E.H., Karim, S., Lukashchuk, N., Gillespie, D.A., Ludwig, R.L., Gosselin, P., Cromer, A., Brugge, J.S., Sansom, O.J., Norman, J.C. & Vousden, K.H. (2009). Mutant p53 Drives Invasion by Promoting Integrin Recycling. Cell 139(7): 1327-1341.
  • Muller, P.A.J. & Klomp, L.W.J. (2009). ATOX1: A novel copper-responsive transcription factor in mammals? International Journal of Biochemistry and Cell Biology 41(6): 1233-1236.
  • Muller, P.A.J. & Klomp, L.W. (2008). Novel perspectives in mammalian copper metabolism through the use of genome-wide approaches. American Journal of Clinical Nutrition 88(3): 821S-825S.
  • de Bie, P., van de Sluis, B., Burstein, E., van de Berghe, P.V.E., Muller, P., Berger, R., Gitlin, J.D., Wijmenga, C. & Klomp, L.W.J. (2007). Distinct Wilson's Disease Mutations in ATP7B Are Associated With Enhanced Binding to COMMD1 and Reduced Stability of ATP7B. Gastroenterology 133(4): 1316-1326.
  • De Bie, P., Muller, P., Wijmenga, C. & Klomp, L.W.J. (2007). Molecular pathogenesis of Wilson and Menkes disease: Correlation of mutations with molecular defects and disease phenotypes. Journal of Medical Genetics 44(11): 673-688.
  • Muller, P., Van Bakel, H., Van De Sluis, B., Holstege, F., Wijmenga, C. & Klomp, L.W.J. (2007). Gene expression profiling of liver cells after copper overload in vivo and in vitro reveals new copper-regulated genes. Journal of Biological Inorganic Chemistry 12(4): 495-507.
  • Van De Sluis, B., Muller, P., Duran, K., Chen, A., Groot, A.J., Klomp, L.W., Liu, P.P. & Wijmenga, C. (2007). Increased activity of hypoxia-inducible factor 1 is associated with early embryonic lethality in Commd1 null mice. Molecular and Cellular Biology 27(11): 4142-4156.