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Serpins Biology Group

Staff Members

Head

Dr Paul Coughlin

PhD student

Anita Horvath

Research Assistant

Melinda Missen

Research activities

This research group has been established in 2000 under the direction of Dr Paul Coughlin since he returned from the University of Cambridge Department of Haematology. Dr Coughlin is a Wellcome Trust Senior International Fellow whose principal research work has been to establish the role of intracellular serpins in regulating the growth and differentiation of haemopoietic progenitor cells. The long term aim of this work is to give new insights into the control of blood cell development. The role of intracellular serpins in common blood diseases such as aplastic anaemia, myelodysplastic syndromes, leukaemia and myeloproliferative disorders will also be addressed.

Members of the serpin family of genes are essential regulators of proteolytic networks. Biochemical and structural studies of antithrombin and antitrypsin have defined their normal roles and explained how their dysfunction leads to thrombosis and emphysema. These studies demonstrate that serpins are capable of undergoing dramatic conformational changes which modulate protein function.

We have established a programme of research centred on the antichymotrypsin-like protein, serpin 2A and its close relations. Members of this family show tightly regulated expression in haemopoietic stem cells and activated T lymphocytes. Evidence suggests that these proteins are involved in regulation of cell growth by interacting with cell cycle regulators in a redox sensitive manner. It is likely that proteolytic processing also modulates these interactions.

Research is also being conducted on the role of serpins in human haemopoiesis. We are studying the pattern of expression of serpins and proteases in haemopoietic stem cells and committed progenitors. In particular, we are examining the role of elastase and its regulators in haemopoiesis.

Current research projects in the serpins biology group

1. Biochemical, biophysical and structural analysis of serpin 2A

2. Investigation of the biological role of serpin 2A using yeast 2-hybrid analysis

3. Characterisation of proteases and serpins expressed in human haemopoietic progenitors

Publications

  1. Coughlin,P.B., Tetaz,T. and Salem, H.H. Identification and purification of a novel serine proteinase inhibitor. J. Biol. Chem. 1993, 268:9541-9547.


  2. Coughlin, P.B., Jiuru, S., Cerruti,L., Salem,H.H. and Bird,P. Cloning and molecular characterization of a human intracellular serine proteinase inhibitor. Proc. Nat. Acad. Sci. USA. 1993, 90:9417-9421.


  3. Coughlin,P.B., Nichol,L, Jiuru,S., Salem,H.H., Bird,P. and Sutherland,G. Chromosomal mapping of human proteinase inhibitor 6 (PI6) gene to 6p25 by fluorescent in situ hybridisation. Genomics. 1995, 26:431-433.


  4. Jiuru,S., Coughlin,P.B., Salem,H.H. and Bird,P. Production and characterization of recombinant human proteinase inhibitor 6. Biochym. et Biophys. Acta. 1995, 1252:28-34.


  5. Scott,F.L., Coughlin,P.B., Bird,C., Cerruti, L., Hayman,J.A. and Bird,P. Proteinase inhibitor 6 (PI-6) cannot be secreted suggesting it is a new type of cellular serpin. J. Biol.Chem. 1996, 271: 1605-1612.


  6. Sun,J.R., Bird,C.H., Sutton,V., McDonald,L., Coughlin,P.B., Dejong,T.A., Trapani,J.A. and Bird,P.I. A cytosolic granzyme-B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes. J. Biol Chem. 1996, 271: 27802-27809.


  7. Fitton,H.L., Walker,I.D., Jones,L., Brown,K. and Coughlin,P. Five antithrombin variants, four associated with thrombosis. Blood. Coag. & Fibrinolys. 1997, 8: 145-148.


  8. Scott,F.L., Paddle-Ledinek,J.E., Cerrutti,L., Coughlin,P.B., Salem,H.H. and Bird,P.I. Proteinase inhibitor 6 (PI-6) expression in human skin: induction of PI-6 and a PI-6/proteinase complex during keratinocyte differentiation. Exp. Cell. Res. 1998, 245: 263-271.


  9. Streatfield-James,R., Williamson,D., Pike,R., Tewkesbury,D., Carrell,R.W. and Coughlin,P.B. Angiotensinogen cleavage by renin: importance of a structurally constrained N-terminus. FEBS Lett. 1998, 436: 267-70.


  10. Carrell,R.W. and Coughlin,P.B. Serpins. In The Encyclopedia of Molecular Biology (Ed Creighton,T.E.) J.Wiley & Sons Inc., N.Y. (in press).


  11. Coughlin, P.B., Morris, EC and Hampson, L. The role of granzymes and serpins in regulating cell growth and death. In Cell Death in Health and Disease 2000, Ch 5: 55-64. (Ed Bryant, J) Bios Scientific Publishers, Oxford.