Imperial College London

DrDavidMann

Faculty of Natural SciencesDepartment of Life Sciences

Reader in Cell Cycle Control
 
 
 
//

Contact

 

+44 (0)20 7594 5302d.mann

 
 
//

Location

 

605Sir Ernst Chain BuildingSouth Kensington Campus

//

Summary

 

Overview

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 thedf 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).

Protein Phosphorylation

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.  dThis 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.

Protein Myristoylation

Protein myristoylation is the post- or co-translational modification of proteins with a C14 fatty acid (reviewed in Wright et al).  This modification has been shown to be essential for thev correct functioning and/or subcellular localisation of many proteins and is important in cancer - for example, the tyrosine kinase src looses its transforming ability if it lacks N terminal myristoylation.  In collaboration with Dr Ed Tate (Department of Chemistry), we are applying chemical genetic tagging to identify myristoylated proteins in mammalian cells and assess their relevance to normal and disease physiology.

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.aWe 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

Collaborators

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