Karen Vousden - Tumour Suppression

Introduction

vousden k

The p53 protein plays an important role in protecting from cancer. In part, this reflects its ability to inhibit proliferation or eliminate cells that have the potential for malignant progression but more recently, we have found that p53 can also contribute to protecting cells from DNA damage.

We are interested in understanding the signals that induce p53 and the functions of p53 that contribute to its ability to prevent cancer progression.

Ultimately, we hope to be able find ways to reactivate p53 for cancer therapy.

Lab Report

Key Publications

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: 542-6, 2013

Cheung EC, Ludwig RL, Vousden KH. Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. PNAS 109: 20491-6, 2012

Hock AK, Vigneron AM, Carter S, Ludwig RL and Vousden KH. Regulation of p53 stability and function by the deubiquitinating enzyme USP42. EMBO J 30: 4921-30, 2011

Vigneron AM, Ludwig RL and Vousden KH. Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP. Genes & Dev, 24: 2430-9, 2010

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, 1327-41, 2009

Bensaad K, Tsuruta A, Selak MA, Vidal MNC, Nakano K, Bartrons R, Gottlieb E and Vousden KH. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126: 107-12, 2006

Nakano K and Vousden KH. PUMA, a novel pro-apopototis gene, is induced by p53. Molecular Cell 7: 683-94, 2000

Kubbutat MHG, Jones SN.and Vousden KH (1997) Regulation of p53 stability by mdm2. Nature 387: 299-303, 1997

Biography

Education and qualifications

1982: PhD, University of London, Supervisor Lorna Casselton
1978: BSc, Genetics and Microbiology (First Class Honours), University of London

Appointments

2002-present: Director, CRUK Beatson Institute, Glasgow
1999-2002: Laboratory Chief, NCI-FCRDC, USA
1998-1999: Interim Director, ABL Basic Research Programme, USA
1995-1998: Laboratory Director, ABL Basic Research Programme, USA
1987-1995: Group Head, Ludwig Institute for Cancer Research, London
1985-1987: Visiting Fellow with Doug Lowy, NCI, USA
1981-1985: Postdoctoral Fellow with Chris Marshall, ICR, London

Honours and awards

Elected to EMBO Council, 2014
Fellow of the AAAS, 2014
Norman Heatley Lecture, Oxford, 2014
ECDO Lifetime Achievement Award, 2012
Elected to Board of Directors, AACR, 2012
Commander of the British Empire (Services to Clinical Science), 2010
Fellow of the European Academy of Cancer Sciences, 2009
Royal Society of Edinburgh Gold Medal, 2009
The Sir Frederick Gowland Hopkins Memorial Medal Lecture, 2008
The Mike Price Lecture, 2008
Honorary DSc, University of Strathclyde, 2008
Fellow of the Academy of Medical Sciences, 2006
Honorary DSc, University of London, 2006
Fellow of the Royal Society of Edinburgh, 2004
Member of EMBO, 2004
Tom Connors Award Lecture, BACR, 2003
Wellcome Trust Lecture, BSCB, 2003
Fellow of the Royal Society, 2003
NIH Merit Award for Major Contributions to Research, 2001
Tenovus Gold Medal for Contributions to the Field of Gene Expression, 1998

Recent Publications

2016

Walton J, Blagih J, Ennis D, Leung E, Dowson S, Farquharson M, Tookman LA, Orange C, Athineos D, Mason S, Stevenson D, Blyth K, Strathdee D, Balkwill FR, Vousden KH, Lockley M, McNeish IA.CRISPR/Cas9-mediated Trp53 and Brca2 knockout to generate improved murine models of ovarian high grade serous carcinoma. Cancer Res. 2016 Aug 16. pii: canres.1272.2016. [Epub ahead of print]

2015

Deschoemaeker S, Di Conza G, Lilla S, Martin-Perez R, Mennerich D, Boon L, Hendrikx S, Maddocks OD, Marx C, Radhakrishnan P, Prenen H, Schneider M, Myllyharju J, Kietzmann T, Vousden KH, Zanivan S, Mazzone M. PHD1 regulates p53-mediated colorectal cancer chemoresistance. EMBO Mol Med 7: 1350-65, 2015

Lee P, Hock AK, Vousden KH, Cheung EC. p53- and p73-independent activation of TIGAR expression in vivo. Cell Death Dis 6: e1842, 2015

Stindt MH, Muller PA, Ludwig RL, Kehrloesser S, Dotsch V, Vousden KH. Functional interplay between MDM2, p63/p73 and mutant p53. Oncogene 34: 4300-10, 2015

Buescher JM, Antoniewicz MR, Boros LG, Burgess SC, Brunengraber H, Clish CB, DeBerardinis RJ, Feron O, Frezza C, Ghesquiere B, Gottlieb E, Hiller K, Jones RG, Kamphorst JJ, Kibbey RG, Kimmelman AC, Locasale JW, Lunt SY, Maddocks ODK, Malloy C, Metallo CM, Meuillet EJ, Munger J, Noh K, Rabinowitz JD, Ralser M, Sauer U, Stephanopoulos G, St-Pierre J, Tennant DA, Wittmann C, Vander Heiden M, Vazquez A, Vousden K, Young JD, Zamboni N, Fendt SM. A roadmap for interpreting 13C metabolite labeling patterns from cells. Current Opinion in Biotechnology 34: 189-201, 2015

Gurpinar E, Vousden KH. Hitting cancers' weak spots: vulnerabilities imposed by p53 mutation. Trends Cell Biol 25: 486-95, 2015

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

2014

D'Alessandro A, Amelio I, Berkers CR, Antonov A, Vousden KH, Melino G, Zolla L. Metabolic effect of TAp63alpha: enhanced glycolysis and pentose phosphate pathway, resulting in increased antioxidant defense. Oncotarget 5: 7722-33, 2014

Haller M, Hock AK, Giampazolias E, Oberst A, Green DR, Debnath J, Ryan KM, Vousden KH, Tait SWG. Ubiquitination and proteasomal degradation of ATG12 regulates its pro-apoptotic activity, Autophagy 10: 2269-78, 2014

Hock AK, Vigneron A, Vousden KH. Ubiquitin specific peptidase 42 (USP42) functions to deubiquitylate histones and regulate transcriptional activity. J Biol Chem 289: 34862-70, 2014

Labuschagne CF, van den Broek NJ, Mackay GM, Vousden KH, Maddocks OD. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep 7: 1248-58, 2014

Lee P, Vousden KH, Cheung EC. TIGAR, TIGAR, burning bright. Cancer Metab 2: 1, 2014

Maddocks OD, Labuschagne CF, Vousden KH. Localization of NADPH production: a wheel within a wheel. Mol Cell 55: 158-60, 2014

Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25: 304-17, 2014

Paulus-Hock V, Cheung EC, Roxburgh P, Vousden KH, Hock AK. iRFP Is a Real Time Marker for Transformation Based Assays in High Content Screening. PLoS One 9: e98399, 2014

Phesse TJ, Myant KB, Cole AM, Ridgway RA, Pearson H, Muncan V, van den Brink GR, Vousden KH, Sears R, Vassilev LT, Clarke AR, Sansom OJ. Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo. Cell Death Differ 21: 956-66, 2014

2013

Cheung E, Athineos D, Lee P, Ridgway R, Lambie W, Nixon C, Strathdee D, Blyth K, Sansom O, Vousden KH. TIGAR is required for efficient intestinal regeneration and tumorigenesis. Dev Cell 25: 463-77, 2013

Hock AK, Lee P, Maddocks OD, Mason SM, Blyth K, Vousden KH. iRFP is a sensitive marker for cell number and tumor growth in high-throughput systems. Cell Cycle 2013; 13. Epub 2013/11/10

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: 542-6, 2013

Muller PA, Trinidad AG, Caswell PT, Norman JC, Vousden KH. Mutant p53 regulates Dicer through p63 dependent and independent mechanisms to promote an invasive phenotype. J Biol Chem 2013. Epub 2013/11/14

Muller PA, Trinidad AG, Timpson P, Morton JP, Zanivan S, van den Berghe PV, Nixon C, Karim SA, Caswell PT, Noll JE, Coffill CR, Lane DP, Sansom OJ, Neilsen PM, Norman JC, Vousden KH. Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion. Oncogene 32(10): 1252-65, 2013

Trinidad AG, Muller PA, Cuellar J, Klejnot M, Nobis M, Valpuesta JM, Vousden KH. Interaction of p53 with the CCT complex promoted protein folding and wild type p53 activity. Mol Cell 50: 805-17, 2013

Berkers C, Maddocks O, Cheung E, Mor I, Vousden KH. Metabolic regulation by p53 familty members. Cell Metabolism 2013. Epub 2013/08/21

Hock AK, Vousden KH. The role of ubiquitin modification in the regulation of p53. BBA Mol Cell Res 2013. Epub 2013/06/08

Muller PA, Vousden KH. p53 mutations in cancer. Nature Cell Biol 15: 2-8, 2013

Dickens MP, Roxburgh P, Hock A, Mezna M, Kellam B, Vousden KH, Fischer PM. 5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2. Bioorg Med Chem 21: 6868-77, 2013Tan EH, Morton JP, Timpson P, Tucci P, Melino G, Flores ER, Sansom OJ, Vousden KH, Muller PA. Functions of TAp63 and p53 in restraining the development of metastatic cancer. Oncogene 2013. Epub 2013/07

Kaelin W, Livingston D, Loda M, Vousden K, Mihich E. Twenty-fifth annual Pezcoller Symposium: Metabolism and tumorigenesis. Cancer Res 73: 6124-7, 2013

Muller PA. NCF2/p67phox: A novel player in the anti-apoptotic functions of p53. Cell Cycle 2013; 12: 14. Epub 2012/12/21

Tan EH, Morton JP, Timpson P, Tucci P, Melino G, Flores ER, Sansom OJ, Vousden KH, Muller PA. Functions of TAp63 and p53 in restraining the development of metastatic cancer. Oncogene, in press 2013

2012

Cheung EC, Ludwig RL, Vousden KH. Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. PNAS 109: 20491-6, 2012

Roxburgh P, Hock AK, Dickens MP, Mezna M, Fischer PM, Vousden KH. Small molecules that bind the Mdm2 RING stabilize and activate p53. Carcinogenesis 33: 791-8, 2012

Hock AK, Vousden KH. Tumor Suppression by p53: Fall of the Triumvirate? Cell 149: 1183-5, 2012

Chaneton B, Hillmann P, Zheng L, Martin ACL, Maddocks ODK, Chokkathukalam A, Coyle JE, Jankevics A, Holding FP, Vousden KH, Frezza C, O’Reilly M, Gottlieb E. Serine is a natural ligand and allosteric activator of pyruvate kinase M1. Nature 491: 458-462, 2012

Coffill CR, Muller PA, Oh HK, Neo SP, Hogue KA, Cheok CF, Vousden KH, Lane DP, Blackstock WP, Gunaratne J. Mutant p53 interactome identifies nardilysin as a p53R273H-specific binding partner that promotes invasion. EMBO Rep 13: 638-44, 2012

Dolezelova P, Cetkovska K, Vousden KH, Uldrijan S. Mutational analysis reveals a dual role of Mdm2 acidic domain in the regulation of p53 stability. FEBS Lett 586: 2225-31, 2012

Dolezelova P, Cetkovska K, Vousden KH, Uldrijan S. Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers. Cell Cycle 11(5): 953-62, 2012

Dou H, Buetow L, Hock A, Sibbet GJ, Vousden KH, Huang DT. Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl. Nat Struct Mol Biol 19: 184-92, 2012

Rainero E, Caswell PT, Muller PA, Grindlay J, McCaffrey MW, Zhang Q, Wakelam MJ, Vousden KH, Graziani A, Norman JC. Diacylglycerol kinase alpha controls RCP-dependent integrin trafficking to promote invasive migration. J Cell Biol 196: 277-95, 2012

Tucci P, Agostini M, Grespi F, Markert EK, Terrinoni A, Vousden KH, Muller PA, Dotsch V, Kehrloesser S, Sayan BS, Giaccone G, Lowe SW, Takahashi N, Vandenabeele P, Knight RA, Levine AJ, Melino G. Loss of p53 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer. PNAS 109: 15312-7, 2012

Vandenabeele P, Knight RA, Levine AJ, Melino G. Loss of p53 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer. PNAS 109: 15312-7, 2012

2011

Hock AK, Vigneron AM, Carter S, Ludwig RL, Vousden KH. Regulation of p53 stability and function by the deubiquitinating enzyme USP42. EMBO J 2011; 30: 4921-30

Stindt MH, Carter S, Vigneron AM, Ryan KM, Vousden KH. MDM2 promotes SUMO-2/3 modification of p53 to modulate transcriptional activity. Cell Cycle 2011;10: 3176-88

Vigneron AM, Vousden KH. An indirect role for ASPP1 in limiting p53- dependent p21 expression and cellular senescence. EMBO J doi: 10.1038/emboj.2011.402 * Nov 2011

Cao Y, DePinho RA, Ernst M, Vousden K. Cancer research: past, present and future. Nature Rev Cancer 2011; 11: 749-54

Maddocks OD, Vousden KH (2011). Metabolic regulation by p53. J Mol Med. 89, 237-45. Erratum in: J Mol Med. 89, 531.

Marshall C, Vousden K. Genetic and cellular mechanisms of oncogenesis. Curr Opin Genet Dev 2011; 21: 1-3

Mor I, Cheung EC, Vousden KH. Control of Glycolysis through Regulation of PFK1: Old Friends and Recent Additions. Cold Spring Harb Symp Quant Biol doi:10.1101/sqb.2011.76.010868, published online 17 Nov 2011

Muller PA, Vousden KH, Norman JC (2011). p53 and its mutants in tumor cell migration and invasion. J Cell Biol. 192, 209-18.

2010

Vigneron AM, Ludwig RL, Vousden KH (2010). Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP. Genes Dev. 24, 2430-9.

Croft DR, Crighton D, Samuel MS, Lourenco FC, Munro J, Wood J, Bensaad K, Vousden KH, Sansom OJ, Ryan KM, Olson MF (2010). p53-mediated transcription and activation of the actin cytoskeleton regulatory RhoC to LIMK2 signaling pathway promotes cell survival. Cell Res. 21, 666-82.

O'Prey J, Crighton D, Martin AG, Vousden KH, Fearnhead HO, Ryan KM (2010). p53-mediated induction of Noxa and p53AIP1 requires NFkappaB. Cell Cycle 9, 947-52.

Cheung EC, Vousden KH (2010). The role of p53 in glucose metabolism. Curr Opin Cell Biol. 22, 186-91.

Hock A, Vousden KH (2010). Regulation of the p53 pathway by ubiquitin and related proteins. Int J Biochem Cell Biol. 42, 1618-21.

Vigneron A, Vousden KH (2010). p53 and Mdm2: an auld alliance. Cell Cycle 9, 865-6.

Vigneron A, Vousden KH (2010). p53, ROS and senescence in the control of aging. Aging 2, 471-4.

Vousden KH (2010). Alternative fuel - another role for p53 in the regulation of metabolism. Proc Natl Acad Sci USA 107, 7117-8.

Lab Members

vousden lab 2013

Associate Scientist

Eric Cheung (ERC)

Post-docs

Julianna Blagih
Evrim Gurpinar
Andreas Hock
Timothy Humpton
Flore Kruiswijk
Christiaan Labuschagne (ERC)
Oliver Maddocks (ERC)
Mylene Tajan
Ming Yang

Scientific Officer

Bob Ludwig

Associate Clinical Scientist

Patricia Roxburgh (ERC)

PhD Students

Pearl Lee (MRC)
Koji Nomura

Research

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Seminars

Beatson Institute Seminars

Find out more about our seminars including our Distinguished Seminar Programme.

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