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Dr Thomas Sayers
SAIC-Frederick Inc.
NCI-Frederick
P.O. Box B, Frederick, MD 21701, USA
Email: sayers@ncifcrf.gov
Tel: 301-846-5729
Fax: 301-846-1673
Homepage:
| Research |
We have been interested for a number of years in proteases predominantly produced by Natural Killer cells (NK) and Cytotoxic T cells (CTL), which are important cells of the immune system. These proteases have a very limited cellular distribution and have been termed Granzymes (granule enzymes). They are localized in large lysosomal granules in the cytoplasm of NK cells and CTL. The granzymes are constitutively expressed in NK cells yet are usually only expressed at high levels in T cells following activation and differentiation. The granzymes are a family of serine proteases with diverse substrate specificities as determined by synthetic substrates. In humans, 5 distinct members of this family have been defined to date. Granzyme A has trypsin-like activity (tryptase) and is a disulfide linked homodimer of about 60 kDa. The other human granzymes are monomers of around 30 kDa and include Granzyme B (asp-ase), Granzyme H (chymase), Granzyme K (tryptase) and Granzyme M (met-ase). The biological importance of these enzymes is still not completely defined. However, there has been much interest in Granzyme B, since it was the first asp-ase discovered yet in recent years the caspase family have also been characterized as asp-ases. Therefore there are a number of studies suggesting that Granzyme B on transfer from effector lymphocytes such as NK or CTL cells promotes the apoptotic death of tumor or virally infected cells. Although some of the other granzymes may also be involved in triggering cell death via apoptosis, this had not been firmly established. We are also very interested in enzymes that promote cell death particularly the caspases and also the function of the proteasome complex in influencing apoptosis.
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| Collaborations |
Dr. Mark Smyth, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Dr. Joseph Trapani, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Dr. Jan Paul Medema, University of Leiden, Holland
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| Publications |
Sayers, T.J., Brooks, A.D., Ward, J.M., Hoshino, T., Bere, W.E., Wiegand, G.W., Kelley, J.M., and Smyth, M.J.: The restricted expression of granzyme M (Gzm M, Met-ase) in human lymphocytes. J. Immunol. 166: 765-771, 2001.
Sayers, T. J., Lloyd, A. R., McVicar, D. W., O'Connor, M. D., Kelly, J. M., Carter, C. R. D., Wiltrout, T. A., Wiltrout, R. H., and Smyth, M. J.: Cloning and Expression of a second human NK cell granule tryptase, HNK-Tryp-2/granzyme 3. J. Leukoc. Biol. 59: 763-768, 1996.
Sayers, T. J., Wiltrout, T. A., Smyth, M. J., Ottaway, K. S., Pilaro, A. M., Sowder, R., Henderson, L. E., Sprenger, H., and Lloyd, A. R.: Purification and cloning of a novel serine protease, RNK-tryp 2, from the granules of a rat natural killer cell leukemia. J. Immunol. 152: 2289-2297, 1994.
Smyth, M. J., Wiltrout, T., Trapani, J. A., Ottaway, K. S., Sowder, R., Henderson, L. E., Kam, C-M., Powers, J. C., Young, H. A., and Sayers, T. J.: Purification and cloning of a novel serine protease, RNK-Met-1, from the granules of a rat natural killer cell leukemia. J. Biol. Chem. 267: 22418-24425, 1992.
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