Karen Vousden

Karen H. Vousden, FRS, FRSE, FMedSci is a British medical researcher. She is known for her work on the tumour suppressor protein, p53, and in particular her discovery of the important regulatory role of Mdm2, an attractive target for anti-cancer agents. She is currently the director of Cancer Research UK's Beatson Institute of Cancer Research in Glasgow, UK.

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Education and career

Vousden gained a first degree in genetics and microbiology (1978) and a PhD in genetics (1982) from the University of London.^[1][2][3] Her early post-doctoral positions were with Chris Marshall at the Institute of Cancer Research, London, UK (1981–5) and Douglas Lowy at the National Cancer Institute, Bethesda, USA (1985–7).^[1][4]

From 1987 to 1995, she led the Human Papillomavirus Group at the Ludwig Institute for Cancer Research, London, UK.^[1][4] In 1995, she joined the National Cancer Institute in Frederick, USA,^[4] serving successively as head of the Molecular Carcinogenesis section of the ABL-Basic Research Program (1995–7), director of the Molecular Virology and Carcinogenesis Laboratory (1997–8), interim director of the ABL-Basic Research Program (1998–9) and chief of the Regulation of Cell Growth Laboratory, Division of Basic Sciences (1999–2002).^[1][3]

Since 2002, she has been the director of the Cancer Research UK's Beatson Institute of Cancer Research in Glasgow, UK, where she has overseen a £15 million expansion.^[4][5][6] She also leads the institute's Tumour Suppression research group.^[7]

Research

Human papillomaviruses

Vousden's early work focused on the molecular biology of human papillomaviruses (HPVs), which are associated with cervical cancer. With Douglas Lowy and others, she pinpointed the specific viral oncoproteins required by HPV-16 to immortalise epithelial cells.^[8] She was also part of a group which showed that E6, one of the HPV-16 oncoproteins, binds to the human tumour suppressor protein p53 in vivo, resulting in its degradation.^[9]

p53

Vousden's recent research has centered on p53.^[10] Sometimes called "the guardian of the genome", p53 plays a critical role in preventing the development of tumours by inducing cells subject to stress, such as DNA damage, to commit suicide via the apoptosis mechanism. Vousden's work has been important in delineating the mechanism of this process. With Katsunori Nakano, she discovered a key component in the apoptosis pathway triggered by p53, the protein PUMA (P53 Upregulated Modulator of Apoptosis).^[11][12]

  To prevent it being activated inappropriately, p53 is strictly controlled in the normal cell. Vousden discovered that a key element in this regulation is the protein Mdm2. With Allan Weissman and others, she showed that Mdm2 is a ubiquitin ligase which targets p53 for degradation by the proteasome, thus ensuring levels of the protein remain low when the cell is not under stress.^[13][14][15]

Reactivating p53 can inhibit the growth of some tumours, making Mdm2 an attractive target for cancer therapeutics. As Mdm2 targets only a small number of proteins for destruction, an inhibitor might have few side effects.^[13] A major focus of Vousden's recent work has been investigating the structure of Mdm2 and seeking molecules that inhibit it; a group of low-molecular-weight compounds (discovered in collaboration with the Department of Chemistry at the University of Glasgow) have recently shown promise in cell-culture studies.^[13][16] Mdm2 inhibitors have also been discovered by researchers at Hoffmann–La Roche and the Karolinska Institute.^[13]

p53 can also help to prevent or repair minor damage to the genome under conditions of low stress. Vousden's group have recently discovered a novel p53-regulated protein, TIGAR (T-p53 Inducible Glycolysis and Apoptosis Regulator), which can reduce oxidative stress in cells and might mediate part of this effect of p53.^[17]

Awards and honours

Vousden is a fellow of the Royal Society (2003)^[10], Royal Society of Edinburgh (2004)^[18] and the Academy of Medical Sciences (2006);^[19] she was also elected a member of the European Molecular Biology Organization in 2004.^[20] The Institute of Cancer Research awarded her an Honorary Doctorate in Science (Medicine) in 2006.^[21] She will give the Sir Frederick Gowland Hopkins Memorial Lecture of the Biochemical Society in 2008.^[22]

In 2004, The Scotsman named Vousden among the 25 most powerful Scottish women.^[2]

Key publications

Reviews and books

• Yee KS, Vousden KH. (2005) Complicating the complexity of p53 Carcinogenesis 26: 1317–1322 (PMID 15888490) (full-text pdf)
• Evan GI, Vousden KH. (2001) Proliferation, cell cycle and apoptosis in cancer Nature 411: 342–348 (PMID 11357141) (full-text pdf)
• Peters G, Vousden KH, eds. Oncogenes and Tumour Suppressors (Oxford University Press; 1997) (ISBN 0199635951)

Primary

• Wilson JM, Henderson G, Black F, et al. (2007) Synthesis of 5-deazaflavin derivatives and their activation of p53 in cells Bioorg Med Chem 15: 77–86 (PMID 17064912)
• Bensaad K, Tsuruta A, Selak MA, et al. (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis Cell 126: 107–120 (PMID 16839880)
• Nakano K, Vousden KH. (2001) PUMA, a novel proapoptotic gene, is induced by p53 Mol Cell 7: 683–694 (PMID 11463392)
• Fang S, Jensen JP, Ludwig RL, et al. (2000) Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53 J Biol Chem 275: 8945–8951 (PMID 10722742) (full-text pdf)
• Kubbutat MHG, Jones SN, Vousden KH. (1997) Regulation of p53 stability by Mdm2 Nature 387: 299–303 (PMID 9153396)
• Hawley-Nelson P, Vousden KH, Hubbert NL et al. (1989) HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes EMBO J 8: 3905–3910 (PMID 2555178) (full-text pdf)

References