Karen Vousden

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Karen Heather Vousden

CBE, FRS, FRSE, FMedSci
Born (1957-07-19) 19 July 1957 (age 66) [1]
Alma mater Queen Mary and Westfield College [1]
Known forWork on p53 tumour suppressor protein [2] [3] and Mdm2 protein [4]
Spouse
Robert Ludwig
​
(m. 1986)​
[1]
Awards
Scientific career
FieldsCancer [6] [7]
Institutions
Thesis Use of suppressor gene mutations to study transfer RNA redundancy in Coprinus  (1982)

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. From 2003 to 2016, she was the director of the Cancer Research UK Beatson Institute in Glasgow, UK, moving back to London in 2016 to take up the role of Chief Scientist at CRUK and Group Leader at the Francis Crick Institute.

Contents

Education

After attending Gravesend Grammar School for Girls,[ citation needed ] 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 (1981–85) and Douglas Lowy [13] at the National Cancer Institute, Bethesda, United States (1985–87). [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 (1995–97), director of the Molecular Virology and Carcinogenesis Laboratory (1997–98), interim director of the ABL-Basic Research Program (1998–99) and chief of the Regulation of Cell Growth Laboratory, Division of Basic Sciences (1999–2002). [8] [10]

From 2003 to 2016, she was the director of the Cancer Research UK Beatson Institute in Glasgow, UK, where she oversaw a £15 million expansion. [14] [15] [16] She also led the institute's Tumour Suppression research group. [17] She also served on the Life Sciences jury for the Infosys Prize in 2014.

Since 2016, she has moved back to London to take up the role of CRUK Chief Scientist and Group Leader at the Francis Crick Institute. [18] In 2018, she was elected a foreign associate of the National Academy of Sciences.

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. [19] 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. [20]

p53 suppressor protein

Vousden's recent research has centred on p53, [21] a gene which 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. Her 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). [22] [23]

Structure of Mdm2 Mdm2.png
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. [4] [24] [25]

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. [24] 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. [24] [26] Mdm2 inhibitors have also been discovered by researchers at Hoffmann–La Roche and the Karolinska Institute. [24]

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. [27]

Key publications

Awards and honours

Vousden is a fellow of the Royal Society (2003), [21] Royal Society of Edinburgh (2004) [5] and the Academy of Medical Sciences (2006); [28] she was also elected a member of the European Molecular Biology Organization in 2004. [29] The Institute of Cancer Research awarded her an Honorary Doctorate in Science (Medicine) in 2006. [30] She gave the Sir Frederick Gowland Hopkins Memorial Lecture of the Biochemical Society in 2008. [31] She was awarded the Royal Medal from the Royal Society of Edinburgh in 2009. Vousden was appointed Commander of the Order of the British Empire (CBE) in the 2010 New Year Honours. [32]

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

In 2021, Karen Vousden was recognized with the first Pezcoller Foundation-Marina Larcher Fogazzaro-EACR Women in Cancer Award.

Related Research Articles

p53 Mammalian protein found in Homo sapiens

p53, also known as Tumor protein P53, cellular tumor antigen p53, or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

p73 Protein-coding gene in the species Homo sapiens

p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized by the presence of different isoforms of the protein. This is explained by splice variants, and an alternative promoter in the DNA sequence.

<span class="mw-page-title-main">Mdm2</span> Protein-coding gene in the species Homo sapiens

Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene. Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation.

p14ARF is an alternate reading frame protein product of the CDKN2A locus. p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein). It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2. These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively. p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic, and it is polyubiquinated at the N-terminus.

p53 upregulated modulator of apoptosis Protein-coding gene in the species Homo sapiens

The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family. In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene. The expression of PUMA is regulated by the tumor suppressor p53. PUMA is involved in p53-dependent and -independent apoptosis induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2 family members, thus freeing Bax and/or Bak which are then able to signal apoptosis to the mitochondria. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death.

<span class="mw-page-title-main">Promyelocytic leukemia protein</span> Protein-coding gene in the species Homo sapiens

Promyelocytic leukemia protein (PML) is the protein product of the PML gene. PML protein is a tumor suppressor protein required for the assembly of a number of nuclear structures, called PML-nuclear bodies, which form amongst the chromatin of the cell nucleus. These nuclear bodies are present in mammalian nuclei, at about 1 to 30 per cell nucleus. PML-NBs are known to have a number of regulatory cellular functions, including involvement in programmed cell death, genome stability, antiviral effects and controlling cell division. PML mutation or loss, and the subsequent dysregulation of these processes, has been implicated in a variety of cancers.

<span class="mw-page-title-main">RASSF1</span> Protein-coding gene in the species Homo sapiens

Ras association domain-containing protein 1 is a protein that in humans is encoded by the RASSF1 gene.

<span class="mw-page-title-main">TP53BP1</span> Protein-coding gene in the species Homo sapiens

Tumor suppressor p53-binding protein 1 also known as p53-binding protein 1 or 53BP1 is a protein that in humans is encoded by the TP53BP1 gene.

<span class="mw-page-title-main">DNAJA3</span> Protein-coding gene in the species Homo sapiens

DnaJ homolog subfamily A member 3, mitochondrial, also known as Tumorous imaginal disc 1 (TID1), is a protein that in humans is encoded by the DNAJA3 gene on chromosome 16. This protein belongs to the DNAJ/Hsp40 protein family, which is known for binding and activating Hsp70 chaperone proteins to perform protein folding, degradation, and complex assembly. As a mitochondrial protein, it is involved in maintaining membrane potential and mitochondrial DNA (mtDNA) integrity, as well as cellular processes such as cell movement, growth, and death. Furthermore, it is associated with a broad range of diseases, including neurodegenerative diseases, inflammatory diseases, and cancers.

<span class="mw-page-title-main">ING1</span> Protein-coding gene in the species Homo sapiens

Inhibitor of growth protein 1 is a protein that in humans is encoded by the ING1 gene.

<span class="mw-page-title-main">Ubiquitin C</span> Mammalian protein found in Homo sapiens

Polyubiquitin-C is a protein encoded by the UBC gene in humans. Polyubiquitin-C is one of the sources of ubiquitin, along with UBB, UBA52, and RPS27A.

<span class="mw-page-title-main">60S ribosomal protein L11</span> Protein found in humans

60S ribosomal protein L11 is a protein that in humans is encoded by the RPL11 gene.

<span class="mw-page-title-main">CCNG1</span> Protein-coding gene in the species Homo sapiens

Cyclin-G1 is a protein that in humans is encoded by the CCNG1 gene.

<span class="mw-page-title-main">CDKN2A</span> Protein-coding gene in the species Homo sapiens

CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family member p16 and p14arf. Both act as tumor suppressors by regulating the cell cycle. p16 inhibits cyclin dependent kinases 4 and 6 and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase. p14ARF activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2A are associated with familial melanoma, glioblastoma and pancreatic cancer. The CDKN2A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">FBXO31</span> Protein-coding gene in the species Homo sapiens

F-box only protein 31 is a protein that in humans is encoded by the FBXO31 gene.

In molecular biology mir-605 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

<span class="mw-page-title-main">TP53-inducible glycolysis and apoptosis regulator</span> Protein-coding gene in the species Homo sapiens

The TP53-inducible glycolysis and apoptosis regulator (TIGAR) also known as fructose-2,6-bisphosphatase TIGAR is an enzyme that in humans is encoded by the C12orf5 gene.

<span class="mw-page-title-main">PYR-41</span> Chemical compound

PYR-41 is a cell permeable irreversible inhibitor of ubiquitin-activating enzyme E1. It was also reported to increase sumoylation in cells.

Owen Sansom, FRSE., FMedSci is the Director of the Cancer Research UK Beatson Institute. He is known for his work determining the molecular hallmarks of colorectal cancer (CRC), including demonstrating the roles of the tumour suppressor protein APC and the WNT signalling pathway, as well as the involvement of intestinal stem cells in tumourigenesis

References

  1. 1 2 3 4 5 "Vousden, Prof. Karen Heather, (Mrs R. Ludwig)" . Who's Who . Vol. 2016 (online Oxford University Press  ed.). Oxford: A & C Black.(Subscription or UK public library membership required.)
  2. ↑ 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.
  3. ↑ Yee, K. S.; Vousden, K. H. (2005). "Complicating the complexity of p53". Carcinogenesis. 26 (8): 1317–1322. doi: 10.1093/carcin/bgi122 . PMID   15888490.
  4. 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.
  5. 1 2 Royal Society of Edinburgh: Election of Fellows 2004 Archived 23 September 2007 at the Wayback Machine (accessed 19 October 2007)
  6. ↑ Evan, Gerard I.; Vousden, Karen H. (2001). "Proliferation, cell cycle and apoptosis in cancer". Nature. 411 (6835): 342–348. Bibcode:2001Natur.411..342E. doi:10.1038/35077213. PMID   11357141. S2CID   4414024.
  7. ↑ Peters G, Vousden KH, eds. Oncogenes and Tumour Suppressors (Oxford University Press; 1997) ( ISBN   0199635951)
  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 14 July 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. OCLC   940246473. ProQuest   301407293.(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. doi:10.1002/j.1460-2075.1984.tb01905.x. 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. doi:10.1128/JVI.57.1.1-6.1986. PMC   252691 . PMID   3001335.
  14. 1 2 3 4 Cancer Research UK: Karen Vousden (accessed 18 October 2007) Archived 28 September 2006 at the Wayback Machine
  15. ↑ Anon (2002). "Nature jobs changes". Nature. 417 (6887): 99. doi: 10.1038/nj6883-99a .
  16. ↑ Scotland Cancer Research UK 2007 (accessed 18 October 2007)[ dead link ]
  17. ↑ Cancer Research UK Beatson Institute: Karen Vousden – Tumour Suppression Archived 13 July 2015 at the Wayback Machine (accessed 18 October 2007)
  18. ↑ Francis Crick Institute: Karen Vousden Biography
  19. ↑ 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. doi:10.1002/j.1460-2075.1989.tb08570.x. PMC   402081 . PMID   2555178.
  20. ↑ 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. doi:10.1002/j.1460-2075.1992.tb05375.x. PMC   556787 . PMID   1379175.
  21. 1 2 Royal Society: Professor Karen Vousden FRS – Cancer’s achilles heel? (accessed 18 October 2007) Archived 13 October 2007 at the Wayback Machine
  22. ↑ 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.
  23. ↑ 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.
  24. 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 . PMID   15687356.
  25. ↑ Kubbutat, M. H. G.; Jones, S. N.; Vousden, K. H. (1997). "Regulation of p53 stability by Mdm2". Nature. 387 (6630): 299–303. Bibcode:1997Natur.387..299K. doi:10.1038/387299a0. PMID   9153396. S2CID   4329670.
  26. ↑ 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.
  27. ↑ 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. S2CID   15006256.
  28. ↑ Academy of Medical Sciences: Professor Karen Vousden FRS FMedSci Archived 19 July 2011 at the Wayback Machine (accessed 18 October 2007)
  29. ↑ EMBO EMBC Annual Report 2004 (accessed 19 October 2007) Archived 31 August 2006 at the Wayback Machine
  30. ↑ Institute of Cancer Research: Academic Dean's Report 2006 Archived 11 June 2011 at the Wayback Machine (accessed 18 October 2007)
  31. ↑ Biochemical Society Awards in 2008, The Biochemist October 2007, p. 50 (accessed 18 October 2007)
  32. ↑ "No. 59282". The London Gazette (Supplement). 31 December 2009. p. 8.
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