Stephen Dilworth joined Middlesex University in September 2010 as Professor of Cancer Biology. He gained his first degree and a Masters in Natural Sciences from St Johns College Cambridge, and then a PhD from Imperial College, London University. His thesis work was conducted at the Imperial Cancer Research Fund in London, from where he moved back to Cambridge University as a Research Associate for six years. He then joined the Royal Postgraduate Medical School in London (the RPMS, later merged into the Imperial College School of Medicine) as a Lecturer, where he established his own research group, and advanced to a Reader in Tumour Virology.
Stephen's research work has focussed on identifying the essential changes that occur in cells as they become cancerous. This started with his PhD work studying the oncogenic viral proteins made by the mouse polyoma virus, to which he returned when setting up his own group at the RPMS. During his 30 years working in this area, he isolated the first monoclonal antibodies directed against these viral proteins, and isolated a number of proteins that interact with the middle T-antigen, including a tyrosine phosphorylated protein that was later identified as an essential component of the mechanism used by tumour cells to avoid programmed cell death. His group also identified the ShcA protein as a middle T binding protein which led to the realisation that MT acts in the same way as a cell growth factor receptor, a key discovery in unravelling how receptors act in human cancer formation. His work continues in this area, but he has also made significant contributions in the field of cell nucleus assembly, including chromatin formation, and the signals that specify proteins to accumulate within the nucleus. Many of the antibodies made by his group are currently used in cancer screening assays.
Education and Qualifications
|1968-1974||Marsh Hill Boy's Grammar School, Birmingham|
A-Levels. 3 grade A, 1 grade B. (Biology, Chemistry, Physics and Mathematics)
|1975-1978||St. John's College, Cambridge. B.A. (Hons.) Class: First. |
Subject: Natural Sciences
|1978 - 1982||External PhD Student, Imperial College, London|
|1983||P.H.D. Thesis title: Polyoma virus T-antigens. |
Work performed at ICRF, LIF Branch.
At ICRF I characterised the T-antigens encoded by polyoma virus. I helped mapg the coding regions used to synthesise each protein, and produced the first monoclonal antibodies (MAbs) directed against the T-antigens. I then used these MAbs to characterise the MT-kinase complex and the polypeptides phosphorylated by the activity. This was an important pre-requisite to identifying both pp60c-srcand PI3K associated with MT. The MAbs also allowed us to perform direct sub-cellular location studies on MT for the first time. Finally, the MAbs were used to purify sufficient large T-antigen to allow biochemical characterisation of its DNA binding activity.
A change in scientific direction followed in a move to Cambridge where the molecular mechanisms behind the replication and assembly of the eukaryotic nucleus were studied. I isolated a series of MAbs directed against the components of chromatin assembly in X.laevisembryos, and used these to define the complexes involved in producing nucleosomes during development. These antibodies were then used to examine further aspects of chromatin assembly, including the role of H1 analogues, and chromatin decondensation. I was also part of the team that cloned the nucleosome assembly factor, nucleoplasmin, and identified and characterised the now canonical bi-partite nuclear migration sequence.
In 1988 I moved to the RPMS in London, and established my own research group returning to the investigation of the transforming action of the middle T-antigen of polyoma virus. New MAbs have generated a comprehensive antigenic map of MT which was used to identify, and define the molecular characteristics of a novel pp60c-src binding site in MT through development of an in vitro system that recreates the complete MT complex within the test tube. This has led to the definition of the sequences in pp60c-src that are recognised by MT.
Some of our main achievements have been through the identification of new MT binding proteins, including the ShcA polypeptides. We used our MAbs to establish the binding site on MT for Shc, then characterised the consequences of this interaction, which involve the phosphorylation of Shc, binding Grb2 and mSos, and activation of p21ras, and the MAP Kinase cascade. This was instrumental in our realisation of the now generally accepted fact that MT was mimicking the actions of tyrosine kinase associated growth factor receptors. We have been able to use MT as a receptacle for other tyrosine containing sequences, and have used this system to establish how the important phosphorylation sites in ShcA function in both transformation and differentiation induction. This identified another new MT associated protein in Gab1. Current work involves characterising the membrane location sequence in MT and defining the requirements for cellular transformation. MT has been found to be located in discrete complexes on the cell membrane, and this localisation is essential for transformation.
Refereed and published conference proceedings
Reviews in Books
Too many to list, but including presentations at most of the DNA Tumour Virus Meetings held every year, FEBS Meetings, including FEBS2009, Biochemical Society Meetings, BSCB/BSDB Meetings and Genes and Cancer Meetings.
During my time at the RPMS and ICSM, over £2,000,000 in research grants has been raised. The group held two CRC Project Grants continuously for over 12 years, and has also received grants from the EC Biomed 2 Cancer Programme to study Protein Phosphatase 2A. The role of tyrosine phosphorylation sites in Shc signal transduction was funded by grants from the BBSRC, as was a proteomic project to identify and characterize novel MT binding proteins that is just producing results. In addition to this, we are collaborating with other CR UK Groups, particularly Prof. Laskey's, to develop clinically useful diagnostic monoclonal antibodies, and currently hold small awards from local funding schemes. Other grants have been gained in the past from the Royal Society, The Nuffield Foundation and the local SHA.
Planned Grant Applications include one each to the CR UK and BBSRC to examine the way the hydrophobic domain of MT targets discrete signalling complexes in the membrane and an application to determine the other components of this signalling complex.
|1999-2002||BBSRC||Signalling Pathways activated by Shc phosphorylation||£163,500|
|1999-2003||AICR||The membrane spanning domain in GFR signalling and MT||£119,416|
|2001-2006||BELSPO||Transmembrane transport and protein phosphorylation in the regulation of cell function||£67,000|
|2004-2007||BBSRC||Signal output by the adaptor protein Grb2: regulation by ShcA and phosphorylation.||£178,000|
|2004-2007||BBSRC||Proteomic analysis of the novel proteins associated with the polyoma virus T-antigens and their role in cell function.||£279,000|
|2004-2010||BBSRC||Functional analysis of the nuclear receptor co repressor RIP140 Co-PI||£200,000|
|2007-2011||BELSPO||Signal Integration Mechanisms in Health and Disease||£66,000|
|2008-2011||IOG Trust||Changes to the PP2A Interactome||£18,000|
Outside the University, I was a member of the North West Cancer Research Fund Scientific Committee for 7 years from 2001 to 2007.