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Professor Paul Clarke

Professor of Cancer Cell Biology

Address:

Biomedical Research Institute

Level 5, Ninewells Hospital and Medical School

Telephone: +44 (0) 1382 425580 (internal ext. 35580)

p.r.clarke@dundee.ac.uk


  • Biography
    • Paul Clarke joined the University of Dundee as a Senior Lecturer in 1998 and was awarded a personal chair in 2005. He has been Research Coordinator for the Biomedical Research Centre (2002-2007) and Head of Research for the College of Medicine, Dentistry and Nursing (2007-2008). Previously he was at the University of Manchester (1994-1998) and was a research fellow in the group of E. Karsenti at the European Molecular Biology Laboratory, Heidelberg (1991-1994). As a student, he read Biochemistry at Bristol and carried out research for his PhD with D. G. Hardie at Dundee. Professor Clarke has received a Royal Society-Wolfson Research Merit Award (2003-2008) and research fellowships from The Wellcome Trust and Cancer Research UK. His research group is funded by Cancer Research UK, Association for International Cancer Research, Biotechnology and Biological Sciences Research Council, and Tenovus Scotland.
  • Research

    • The control of cell proliferation and cell survival is critical for the normal development and tissue homeostasis of multicellular organisms. Defects in these processes underlie a number of major human diseases. Cancer is associated with loss of controls over cell division and evasion of cell death. In order to understand how cancer develops and how it may be treated more effectively, we need to understand the molecular mechanisms controlling these processes. Our goal is to understand what determines determine the balance between cell cycle controls and the induction of cell death by apoptosis in response to stress signals, DNA damage and during cell division. We are working in two main areas:–

    1. Regulation and functions of Ran GTPase. Ran is a member of the Ras superfamily that plays important roles at several stages of the cell division cycle in all eukaryotic cells. During interphase, Ran is concentrated in the nucleus, mainly in the GTP-bound form, and plays an important role in controlling the direction of transport of proteins and RNA between the nucleus and cytoplasm. During mitosis, when the nuclear envelope breaks down in vertebrate cells, Ran-GTP plays roles in the stabilisation of microtubules nucleated at centrosomes and in the organisation of the mitotic spindle. At the end of mitosis, Ran directs the rebinding of precursor vesicles to the chromatin and controls the reassembly of the nuclear envelope. We are investigating the control of Ran and its nucleotide exchange factor RCC1 during the cell cycle, and their potential roles in cancer.

    RAN mutant MitosisFigure 1 shows the localisation of a Ran mutant Q69L) expressed in live U2OS cells as a fusion with green fluorescent protein (green). Chromatin is labelled by a histone-red fluorescent protein fusion (red). The GFP-RanQ69L mutant is dispersed in the cytoplasm and is concentrated at the nuclear pore complexes within the nuclear envelope in interphase (left). In mitosis, GFP-RanQ69L is excluded from chromosomes and is localised partly to the mitotic spindle (right). Images by Dr James Hutchins. See Hutchins, J.R., Moore, W.J. and Clarke, P.R. (2009) Dynamic localisation of Ran GTPase during the cell cycle. BMC Cell Biol. 18, 66.


    2. Control of apoptosis. We are investigating the control of apoptosis in response to stress signals, DNA damage and during cell division. Apoptosis involves caspases, a family of proteases that cleave key proteins to bring about the biochemical and morphological changes associated with apoptosis (Fig.2). Activation of the initiator protease caspase-9 involves its association with Apaf-1 in a large complex, the apoptosome. Formation of the apoptosome is stimulated by cytochrome c released from mitochondria. Caspase-9 activates caspase-3 and -7, effector proteases that cause the destruction of a cell by apoptosis. We are studying the regulation of caspase-9 activation by Bcl-2 family proteins and by signalling pathways. We have found that caspase-9 is phosphorylated and inhibited by multiple protein kinases activated by survival factors and oncogene products that suppress apoptosis. We are currently investigating the control of apoptosis during mitotic arrest in response to anti-cancer drugs.

    Figure 2Figure 2 shows human U2OS cells in interphase (green, cytochrome c; red, nuclear pore proteins; blue, DNA) and, inset, undergoing apoptosis from mitosis (red, active caspase-3; yellow, phosphorylated histone H3 Ser10; blue, DNA). Images by Dr Helen Sanderson. See Allan, L.A. and Clarke, P.R. (2009) Apoptosis and autophagy: Regulation of caspase-9 by phosphorylation. FEBS J 276, 6063-6073.

  • Selected publications
    1. Zhang, C. and Clarke, P.R. (2000) Chromatin-independent nuclear envelope assembly induced by Ran GTPase in Xenopus egg extracts. Science 288, 1429-1432. Abstract or Full Text available.
    2. Moore, W.J., Zhang, C. and Clarke, P.R. (2002) Targeting of RCC1 to chromosomes is required for proper mitotic spindle assembly in human cells. Curr. Biol. 12, 1442-1447.
    3. Allan, L.A., Morrice, N, Brady, S., Magee, G., Pathak, S. and Clarke, P.R. (2003) Inhibition of caspase-9 by phosphorylation at Thr125 by ERK MAPK. Nature Cell Biol. 5, 647-654.
    4. Hutchins, J.R.A., Moore, W.J., Hood, F.E., Wilson, J.S.J., Andrews, P.D., Swedlow, J.R. and Clarke, P.R. (2004) Phosphorylation regulates the dynamic interaction of RCC1 with chromosomes during mitosis. Curr. Biol. 14, 1099-1104.
    5. Brady, S.C., Allan, L.A. and Clarke, P.R. (2005) Regulation of caspase-9 through phosphorylation by protein kinase C zeta in response to hyperosmotic stress. Mol. Cell. Biol. 25, 10543-10555.
    6. Clarke, P.R. (2005) The Crm de la Crème of mitosis. Nature Cell Biol. 7, 551-552.
    7. Clarke, P.R. (2005) A gradient signal orchestrates the mitotic spindle. Science 309, 1334-1335.
    8. Sanderson, H.S and Clarke P.R. (2006) Cell Biology: Ran, mitosis and the cancer connection. Curr. Biol. 16, R466-R468.
    9. Clarke, P.R. and Sanderson, H.S. (2006) A mitotic role for BRCA1/BARD1 in tumor suppression? Cell 127, 453-455.
    10. Allan, L.A. and Clarke, P.R. (2007) Phosphorylation of caspase-9 by CDK1/cyclin B1 protects mitotic cells against apoptosis. Mol. Cell 26, 301-310.
    11. Clarke, P.R. (2007) Anchoring RCC1 by the tail. Nature Cell Biol. 9, 485-487.
    12. Clarke, P.R. (2008) Signaling to nuclear transport. Dev. Cell 14, 316-318.
    13. Clarke, P.R., Zhang, C., (2008) Spatial and temporal coordination of mitosis by Ran GTPase. Nat. Rev. Mol. Cell. Biol. 9. 464-77.
    14. Seifert, A., Allan, L.A., Clarke, P.R. (2008) DYRK1A phosphorylates caspase 9 at an inhibitory site and is potently inhibited in human cells by harmine. FEBS J. 275, 6268-80.
    15. Clarke, P.R., Allan, L.A., (2009) Cell-cycle control in the face of damage - a matter of life or death. Trends Cell Biol. 19, 89-98.