Karen Vousden

Karen Vousden
Born (1957-07-19) 19 July 1957[1]
Fields Cancer[2][3]
Institutions University of Glasgow[1]
Cancer Research UK Beatson Institute
Cancer Research UK
Institute of Cancer Research
National Cancer Institute
Alma mater Queen Mary and Westfield College[1]
Thesis Use of suppressor gene mutations to study transfer RNA redundancy in Coprinus (1982)
Known for Work on p53 tumour suppressor protein[4][5] and Mdm2 protein[6]
Notable awards CBE (2010)
FRS (2003)
FRSE (2004)[7]
FMedSci
Spouse Robert Ludwig[1]

Professor Karen Heather Vousden, CBE, FRS, FRSE, FMedSci (born 19 July 1957)[1] 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. As of 2003, she is the director of the Cancer Research UK Beatson Institute in Glasgow, UK.

Education

After attending Gravesend Grammar School for Girls, Vousden gained a Bachelor of Science degree in genetics and microbiology (1978) and a PhD from Queen Mary College, University of London on the use of suppressor gene mutations to study transfer RNA redundancy in the fungus Coprinus.[8][9][10][11]

Career

Vousden's early postdoctoral research positions were with Chris Marshall[12] at the Institute of Cancer Research, London, UK (1981–5) and Douglas Lowy[13] at the National Cancer Institute, Bethesda, USA (1985–7).[8][14]

From 1987 to 1995, she led the Human Papillomavirus Group at the Ludwig Institute for Cancer Research, London, UK.[8][14] In 1995, she joined the National Cancer Institute in Frederick, USA,[14] 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).[8][10]

Since 2003, she has been the director of the Cancer Research UK Beatson Institute in Glasgow, UK, where she has overseen a £15 million expansion.[14][15][16] She also leads the institute's Tumour Suppression research group.[17]

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.[18] 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.[19]

p53 suppressor protein

Vousden's recent research has centered on p53.[20] 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).[21][22]

Structure of Mdm2

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.[6][23][24]

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.[23] 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.[23][25] Mdm2 inhibitors have also been discovered by researchers at Hoffmann–La Roche and the Karolinska Institute.[23]

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.[26]

Awards and honours

Vousden is a fellow of the Royal Society (2003),[20] Royal Society of Edinburgh (2004)[7] and the Academy of Medical Sciences (2006);[27] she was also elected a member of the European Molecular Biology Organization in 2004.[28] The Institute of Cancer Research awarded her an Honorary Doctorate in Science (Medicine) in 2006.[29] She gave the Sir Frederick Gowland Hopkins Memorial Lecture of the Biochemical Society in 2008.[30] Vousden was appointed Commander of the Order of the British Empire (CBE) in the 2010 New Year Honours.[31]

In 2004, The Scotsman named Vousden among the 25 most powerful Scottish women.[9]

Key publications

Reviews and books

Primary

References

  1. 1 2 3 4 5 "VOUSDEN, Prof. Karen Heather, (Mrs R. Ludwig)". Who's Who 2013, A & C Black, an imprint of Bloomsbury Publishing plc, 2013; online edn, Oxford University Press.(subscription required)
  2. ↑ Evan, Gerard I.; Vousden, Karen H. (2001). "Proliferation, cell cycle and apoptosis in cancer". Nature 411 (6835): 342–348. doi:10.1038/35077213. PMID 11357141.
  3. ↑ Peters G, Vousden KH, eds. Oncogenes and Tumour Suppressors (Oxford University Press; 1997) (ISBN 0199635951)
  4. ↑ Sedwick, C. (2012). "Karen Vousden: Getting the big picture on p53". The Journal of Cell Biology 198 (2): 148–149. doi:10.1083/jcb.1982pi. PMC 3410416. PMID 22826118.
  5. ↑ Yee, K. S.; Vousden, K. H. (2005). "Complicating the complexity of p53". Carcinogenesis 26 (8): 1317–1322. doi:10.1093/carcin/bgi122. PMID 15888490.
  6. 1 2 Fang, S.; Jensen, J. P.; Ludwig, R. L.; Vousden, K. H.; Weissman, A. M. (2000). "Mdm2 is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53". Journal of Biological Chemistry 275 (12): 8945–8951. doi:10.1074/jbc.275.12.8945. PMID 10722742.
  7. 1 2 Royal Society of Edinburgh: Election of Fellows 2004 (accessed 19 October 2007)
  8. 1 2 3 4 University of Glasgow School for Cancer Studies: Dr. Karen H. Vousden (accessed 18 October 2007)
  9. 1 2 Bowditch G. Scotland's top 50 powerful women, The Scotsman (31 August 2004) (accessed 18 October 2007)
  10. 1 2 Nexxus: Professor Karen Vousden (accessed 19 October 2007) Archived July 14, 2011, at the Wayback Machine.
  11. ↑ Vousden, Karen (1982). Use of suppressor gene mutations to study transfer RNA redundancy in Coprinus (PhD thesis). Queen Mary and Westfield College.(subscription required)
  12. ↑ Vousden, K. H.; Marshall, C. J. (1984). "Three different activated ras genes in mouse tumours; evidence for oncogene activation during progression of a mouse lymphoma". The EMBO Journal 3 (4): 913–917. PMC 557447. PMID 6327295.
  13. ↑ Schiller, J. T.; Vass, W. C.; Vousden, K. H.; Lowy, D. R. (1986). "E5 open reading frame of bovine papillomavirus type 1 encodes a transforming gene". Journal of Virology 57 (1): 1–6. PMC 252691. PMID 3001335.
  14. 1 2 3 4 Cancer Research UK: Karen Vousden (accessed 18 October 2007) Archived September 28, 2006, at the Wayback Machine.
  15. ↑ Anon (2002). "Nature jobs changes". Nature 417 (6887): 99–99. doi:10.1038/nj6883-99a.
  16. ↑ Scotland Cancer Research UK 2007 (accessed 18 October 2007)
  17. ↑ Cancer Research UK Beatson Institute: Karen Vousden - Tumour Suppression (accessed 18 October 2007)
  18. ↑ Hawley-Nelson, P.; Vousden, K. H.; Hubbert, N. L.; Lowy, D. R.; Schiller, J. T. (1989). "HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes". The EMBO Journal 8 (12): 3905–3910. PMC 402081. PMID 2555178.
  19. ↑ Lechner, M. S.; Mack, D. H.; Finicle, A. B.; Crook, T.; Vousden, K. H.; Laimins, L. A. (1992). "Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription". The EMBO Journal 11 (8): 3045–3052. PMC 556787. PMID 1379175.
  20. 1 2 Royal Society: Professor Karen Vousden FRS - Cancer’s achilles heel? (accessed 18 October 2007) Archived October 13, 2007, at the Wayback Machine.
  21. ↑ Nakano, K.; Vousden, K. H. (2001). "PUMA, a Novel Proapoptotic Gene, is Induced by p53". Molecular Cell 7 (3): 683–694. doi:10.1016/S1097-2765(01)00214-3. PMID 11463392.
  22. ↑ Yu, J.; Zhang, L. (2003). "No PUMA, no death: Implications for p53-dependent apoptosis". Cancer Cell 4 (4): 248–249. doi:10.1016/S1535-6108(03)00249-6. PMID 14585351.
  23. 1 2 3 4 Garber, K. (2005). "Missing the Target: Ubiquitin Ligase Drugs Stall". JNCI Journal of the National Cancer Institute 97 (3): 166–167. doi:10.1093/jnci/97.3.166.
  24. ↑ Kubbutat, M. H. G.; Jones, S. N.; Vousden, K. H. (1997). "Regulation of p53 stability by Mdm2". Nature 387 (6630): 299–303. doi:10.1038/387299a0. PMID 9153396.
  25. ↑ Wilson, J. M.; Henderson, G.; Black, F.; Sutherland, A.; Ludwig, R. L.; Vousden, K. H.; Robins, D. J. (2007). "Synthesis of 5-deazaflavin derivatives and their activation of p53 in cells". Bioorganic & Medicinal Chemistry 15 (1): 77–86. doi:10.1016/j.bmc.2006.10.011. PMID 17064912.
  26. ↑ Bensaad, K.; Tsuruta, A.; Selak, M. A.; Vidal, M. N. C.; Nakano, K.; Bartrons, R.; Gottlieb, E.; Vousden, K. H. (2006). "TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis". Cell 126 (1): 107–120. doi:10.1016/j.cell.2006.05.036. PMID 16839880.
  27. ↑ Academy of Medical Sciences: Professor Karen Vousden FRS FMedSci (accessed 18 October 2007)
  28. ↑ EMBO EMBC Annual Report 2004 (accessed 19 October 2007) Archived August 31, 2006, at the Wayback Machine.
  29. ↑ Institute of Cancer Research: Academic Dean's Report 2006 (accessed 18 October 2007)
  30. ↑ Biochemical Society Awards in 2008, The Biochemist October 2007, p. 50 (accessed 18 October 2007)
  31. ↑ The London Gazette: (Supplement) no. 59282. p. 8. 31 December 2009.
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