M Keyse

Biography

Stephen M. Keyse received a Bachelors degree in Pharmacy (BPharm Hons) at the University of Bathin 1978 and went on to obtain a Ph.D in Photobiology from that University in 1983. During postdoctoral training with Rex M. Tyrrell at the Swiss Institute for Experimental Cancer Research (ISREC) in Lausanne, he studied UV-induced DNA damage, repair and mutagenesis and developed an interest in the regulation of gene expression in response to conditions of oxidative-stress. Returning to the UK in 1989, this work was continued in the laboratory of Richard D. Wood at the ICRF (now CR-UK) Clare Hall Laboratories in London. In 1991 he was appointed as a group leader within the CR-UK Molecular Pharmacology Unit, then based at the University of Edinburgh. Since the relocation of the CR-UK unit to the University of Dundee in late 1992, he has been head of the CR-UK Stress Response Laboratory, first within the Biomedical Research Centre and now as part of the Cancer Research Division of the Medical Research Institute at Ninewells Hospital & Medical School. He was granted tenure by ICRF in 1996 and was awarded a personal chair at the University of Dundee in 2005.

Research Interest

MAP kinase cascades are key components of the signalling networks that sense cellular exposure to growth factors and environmental stress. These include the classical Ras/ERK MAP kinase pathway, which is activated by a variety of hormones and growth factors and when constitutively activated can contribute to cancer development. A second group of MAP kinases are strongly activated by cellular stress. This group includes the c-Jun amino terminal kinases (JNKs) and p38 MAP kinase isoforms. The balance of signalling through these distinct MAP kinase cascades is critically important in determining cellular responses to external stimuli in terms of either cell survival/proliferation or cell death. It is now clear that the duration and magnitude of signalling through MAP kinase pathways is a critical determinant of biological effect. All MAP kinases are activated by phosphorylation of both threonine and tyrosine residues within the conserved signature sequence T-X-Y by a dual specificity MAP kinase kinase (MEK or MKK). A balance between the activity of this enzyme and specific protein phosphatases plays an important role in determining the duration and magnitude of MAP kinase activity. For many years we have been involved in the isolation and characterisation of dual-specificity (Thr/Tyr) MAP kinase phosphatases (DUSPs or MKPs) in mammalian cells. Ten such genes have been identified and certain of these are regulated at the transcriptional level in response to many of the stimuli that activate MAP kinase signalling. This indicates that they act as negative feedback regulators of MAP kinase activity. In addition, these enzymes exhibit substrate selectivity towards different MAP kinase isoforms and are differentially localised within cells. We use a variety of biochemical, cell biological and genetic tools to study how these enzymes shape both physiological and pathophysiological responses to MAPK signalling. We are particularly interested in their role(s) in those human cancers in which tumour growth is driven by activating mutations in upstream components of the Ras/ERK pathway.