Paul Clarke

Professor of Cancer Cell Biology

Biography

Paul Clarke is Professor of Cancer Cell Biology. He 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 in response to stress signals, DNA damage and during cell division. We are working in two main areas:–

1. Control of apoptosis during the cell cycle and in response to anti-cancer drugs. We are investigating the control of cell death by the process 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 (Figure 1). 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 have identified the anti-apoptotic protein Mcl-1, which blocks cytochrome c release from mitochondria, as a key regulator of apoptosis during the mitotic arrest caused by anti-cancer drugs such as taxol (paclitaxel) and vinca alkaloids. We are currently investigating the regulation of Mcl-1 and other apoptotic regulators by protein phosphorylation and ubiquitin-proteasome mediated proteolysis during mitosis. This work may enable us to develop new strategies to improve the ability of anti-mitotic drugs to selectively kill cancer cells.

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Figure 1 shows human U2OS cancer 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.

 

2. 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 the fidelity of mitotic chromosome segregation and the development of cancer.

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Figure 2 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.

 

Publications