Karen Vousden

p53 and Metabolism Laboratory

The p53 tumour suppressor protein plays an important role in determining cell fate in response to stress. While the activation of p53 in response to sustained or irreparable damage can promote the permanent elimination of cells through the induction of apoptosis or senescence, p53 can also help cells to adapt to more moderate, transient stress by limiting oxidative stress and promoting cell survival.

We are investigating how wild type p53 activities contribute to various aspects of health and disease, focusing on the ability of p53 to control metabolism. Our studies show that p53 plays a role in supporting the adaptation to nutrient starvation, both by providing antioxidant support and by promoting metabolic reprogramming. This work has led to a more general interest in how changes in metabolism contribute to cancer development, and whether these changes lead to vulnerabilities that might be targeted for cancer therapy. We have found, for example, that dietary limitation of key amino acids can retard tumour progression.

Perturbations in the p53 pathway are found in almost all cancers, regardless of tissue of origin. Many tumours carry mutations in p53 that lead to the expression of a mutant p53 protein. In addition to losing the canonical activities of wild type p53 that drive cell elimination, these mutant proteins acquire functions that support cancer cells survive and metastasise. We are working to understand these functions of mutant p53 and testing the efficacy of targeting these proteins as a therapeutic strategy.

Selected Publications

Maddocks ODK, Labuschagne CF, Adams PS and Vousden KH. Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol Cell, 61:210-221, 2016

Cheung EC, Lee P, Ceteci F, Nixon C, Blyth K, Sansom OJ and Vousden KH. Opposing effects of TIGAR and RAC1 derived ROS on Wnt driven proliferation in the mouse intestine. Genes Dev 30:52-63, 2016

Yang M and Vousden KH. Serine and one carbon metabolism in cancer. Nature Rev Cancer, doi: 10.1038, 2016.

Kruiswijk F, Labuschagne CF, Vousden KH. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol 16:393-405, 2015

Labuschagne CF, van den Broek NJ, Macjay GM, Vousden KH* and Maddocks OD*. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 7:1248-1258, 2014

Trinidad AG, Muller PA, Cuellar J, Klejnot M, Nobis M, Valpuesta JM, Vousden KH. Interaction of p53 with the CCT complex promotes protein folding and wild-type p53 activity. Mol Cell 50: 805-817, 2013

Cheung EC, Athineos D, Lee P, Ridgway RA, Lambie W, Nixon C, Strathdee D, Blyth K, Sansom OJ and Vousden KH TIGAR is required for efficient intestinal regeneration and tumorigenesis. Dev Cell 25: 463-477, 2013

Maddocks ODK, Berkers CR, Mason SM,Zheng L, Blyth K, Gottlieb E, Vousden KH. Serine starvation induces stress and p53 dependent metabolic remodeling in cancer cells. Nature, 493: 542-546, 2013

Cheung EC, Ludwig RL, Vousden KH. Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. PNAS, 109: 20491-20496, 2012

Muller PAJ, Caswell PT, Doyle B, Iwanicki MP, Tan EH, Karim S, Lukashchuk N, Gillespie DA, Ludwig RL, Gosselin P, Cromer A, Brugge JS, Sansom OJ, Norman JC, Vousden KH. Mutant p53 drives invasion by promoting integrin recycling. Cell 139: 1327-1341, 2009

Karen Vousden, Crick Group Leader and Cancer Research UK's chief scientist

KarenĀ Vousden

karen.vousden@crick.ac.uk
+44 (0)20 379 63444