Control of Mammalian Cell Proliferation
At its simplistic level, cancer can be thought of as unrestrained cell division. We have a long-standing interest in the mechanisms controlling cell proliferation and how they can be misregulated in cancer. Our interests range from the molecular mechanisms underlying viral subvertion of proliferation control (Yarmishyn et al; Child & Mann) to cyclin/cyclin-dependent kinases and protein phosphorylation (Child et al; Anderson et al). We are interested in the links between DNA damage and cell cycle progression (Suwaki et al) and in identifying novel chemotherapeutics to block excessive proliferation, as exemplified by our collaboration with Prof Ramon Vilar to study the effects of organometal complexes as cytotoxics and/or quadruplex nucleic acid stabilizers (Suntharalingam et al).
We are pursuing chemical genetic approaches to understand protein kinase function. Most protein kinases utilise ATP as the phosphate donor and have highly conserved catalytic sites. This makes many protein kinase inhibitors promiscuous in their specificity. We are using site directed mutagenesis to subtly alter the catalytic site of specific protein kinases so that they can accept analogues of ATP that are not normally used (Elphick et al). This approach allows the molecular construction of unique kinase/ATP analogue pairs and can be used for the identification of the substrates of the modified kinase (Lee et al; Elphick et al A, B).
To facilitate protein kinase substrate identification wie are collaborating with Prof Ramon Vilar and Dr Joachim Steinke in the Chemistry Department at Imperial College London to develop novel matrices for specifically isolating phosphoproteins and thir derivatives. In collaboration with Prof Alan Armstrong, we are developing novel kinase inhibitors and activity-based probes to assess the functions of specific enzymes in vivo.
Novel Methods to Identify Therapeutics
We are applying our molecular biological and chemical genetic expertise to develop new ways to identify targets in cancer and develop therapeutics.We have recently developed a new method for identifying chemical fragments that bind to a defined protein surface (Nonoo et al) and we are actively using this methodology to screen for modulators of protein-protein interactions, an under-exploited class of drug targets. In addition we have an ongoing programme developing inhibitors to the cell cycle regulatory phosphatases of the cdc25 family (Mak et al).
Current Lab Members
- Charlotte Allen
- Sarah Byrne
- Michelle Cheung
- Marina Fedorova
- Siak Lim
- Jiazhi Liu
- Verity Stafford
- George Stephen
- Emmanuelle Thinon
Eiji Hara, Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo
Prof Mauricio Barahona, Maths, Imperial College London
Kwee Yong, UCL Cancer Centre
John Quinn, UCL Cancer Centre
Michal Optyeka, University of Palacky
Richard Bishop, International Livestock Research Institute, Nairobi
Gordon Peters, Cancer Research UK London Research Institute
Dr Ed Tate, Chemistry, Imperial College London
Prof Alan Armstrong, Chemistry, Imperial College London
Prof Ramon Vilar, Chemistry, Imperial College London
Dr Joachim Steinke, Imperial College London
Dr Rudiger Woscholski, Chemistry, Imperial College London
Prof David Klug, Chemistry, Imperial College London
Prof Sophia Yaliraki, Chemistry, Imperial College London
Paivi Ojala, Univerisity of Helsinki