Molecular Cell Biology laboratory, Trinity College Dublin

Prof. Seamus J. Martin

Email: martinsj@tcd.ie

Biographical Information Seamus Martin is the holder of the Smurfit Chair of Medical Genetics at Trinity College Dublin (since 1999). He has an international reputation in the field of programmed cell death (apoptosis), which is highly relevant to cancer and immunity to infectious agents, and is one of the most highly cited scientists in the world on this topic. Seamus is a PhD graduate of The National University of Ireland (1990) and has held post-doctoral fellowships at University College London, UK, and The University of California, San Diego, USA. He is a co-author of the 11th and 12th editions of the major Immunology textbook ‘Essential Immunology’ and is an editorial board member and receiving editor of several journals including Science Signaling, Cell Reports, Oncogene and Cell Death and Differentiation. He has received several prestigious national and international awards for his research including; Wellcome Trust International Prize Fellowship (1994-1996) Wellcome Trust Senior Fellowship (1996-2001), Science Foundation Ireland Principal Investigator Awards (2002-2007 and 2008-2013), The BA Charles Darwin Award (2005), and The GlaxoSmithKline Award of The Biochemical Society UK (2006). He was elected to the Royal Irish Academy in 2006 and to the European Molecular Biology Organisation (EMBO) in 2009.

Research Interests The primary focus of our lab is the natural cell death process known as apoptosis or programmed cell death.  Apoptosis is a mode of cell death that is under molecular control and can be triggered by a multitude of stimuli—both physiological as well as pathological.  Cells die by apoptosis during development, tissue homeostasis, fine-tuning of the immune system, and due to the normal wear and tear that multicellular organisms experience in everyday life.  Apoptosis is also observed as a part of the damage-limitation response seen during infectious disease and is seen during many other pathological conditions, such as cancer and neurodegeneration.  Understanding apoptosis at a molecular level is likely to provide new insights into many fundamental biological processes and result in new ways of treating conditions where either too few (cancer, autoimmune disease) or too many (AIDS, neurodegeneration) cells die.

What we work on Regulation of cell death and immunity by caspases A family of proteases (called Caspases) are responsible for dismantling the cellular architecture during apoptosis.  We have previously explored how caspases become activated during apoptosis, the order of caspase activation events, and how caspase activation results in the apoptotic phenotype.  We are currently investigation the role of caspases in immune-related contexts. BH3-only proteins as triggers of the cell death machinery     BH3-only proteins act as upstream regulators of apoptosis that connect specific death signals to the cell death machinery.  We are focused towards understanding how certain BH3-only proteins are regulated by oncogenes such as Ras and B-Raf.  The role of Granzyme B and other granzymes in CTL and NK-initiated apoptosis The cytotoxic granules of Natural Killer and cytotoxic T lymphocytes contain a battery of destructive proteases, called granzymes, that these cells use to kill their targets.  We are exploring how granzymes kill, their molecular targets, and also other roles that these proteases play uppon delivery into the target cell. Regulation of mitochondrial fission/fusion dynamics by members of the Bcl-2 family Apart from their role in the regulation of the onset of cell death, certain members of the Bcl-2 family may have additional roles in other cell processes such as mitochondrial fission/fusion dynamics.  This is an area of active investigation in the lab.   Interested in working in our group? We are always interested in recruiting talented and motivated people to the lab. Please contact Seamus (martinsj@tcd.ie) for further details.

Mitochondrial Fission

With James D. Watson at Genetics Symposium, TCD, 2008

Relevant links The CASBAH (Caspase Substrate dataBAse Homepage)  www.casbah.ie Highly cited labs in Apoptosis esi-topics.com/apoptosis/authors/b1c.html Lab Rankings in Apoptosis Research www.caspases.org Lab Rankings in Protease Research www.proteases.org Martin Lab Press Release http://www.youtube.com/watch?v=U_qtQH4Ias4

Selected Publications:

Martin, S. J. & Green, D. R. (1995). Protease activation during apoptosis: death by a thousand cuts? Cell, 82, 349-352.

Martin, S. J., Newmeyer, D. D., Mathias, S., Farschon, D. M., Wang, H. G., Reed, J. C., Kolesnick, R. N. & Green, D. R. (1995). Cell-free reconstitution of Fas-, UV radiation- and ceramide-induced apoptosis. EMBO Journal, 14, 5191-5200.

Martin, S. J., Reutelingsperger, C. P., McGahon, A. J., Rader, J. A., van Schie, R. C., LaFace, D. M. & Green, D. R. (1995). Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. Journal of Experimental Medicine, 182, 1545-1556.

Martin, S. J., Amarante-Mendes, G. P., Shi, L., Chuang, T. H., Casiano, C. A., O'Brien, G. A., Fitzgerald, P., Tan, E. M., Bokoch, G. M., Greenberg, A. H. & Green, D. R. (1996). The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32, via a novel two-step mechanism. EMBO Journal, 15, 2407-2416.

Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D. R. & Verma, I. M. (1996). Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science, 274, 787-789.

Slee, E. A., Harte, M. T., Kluck, R. M., Wolf, B. B., Casiano, C. A., Newmeyer, D. D., Wang, H. G., Reed, J. C., Nicholson, D. W., Alnemri, E. S., Green, D. R. & Martin, S. J. (1999). Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. Journal of Cell Biology, 144, 281-292.

Adrain, C., Creagh, E. M. & Martin, S. J. (2001). Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2. EMBO Journal, 20, 6627-6636.

Slee, E. A., Adrain, C. & Martin, S. J. (2001). Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. Journal Biological Chemistry, 276, 7320-7326.

Martin, S. J. (2002). Destabilizing influences in apoptosis: sowing the seeds of IAP destruction. Cell, 109, 793-796.

Murphy, B. M., O'Neill, A. J., Adrain, C., Watson, R. W. & Martin, S. J. (2003). The apoptosome pathway to caspase activation in primary human neutrophils exhibits dramatically reduced requirements for cytochrome C. Journal of Experimental Medicine, 197, 625-632

Hill, M. M., Adrain, C., Duriez, P. J., Creagh, E. M. & Martin, S. J. (2004). Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes. EMBO Journal, 23, 2134-2145.

Delivani, P., Adrain, C., Taylor, R. C., Duriez, P. J. & Martin, S. J. (2006). Role for CED-9 and Egl-1 as regulators of mitochondrial fission and fusion dynamics. Molecular Cell, 21, 761-773.

Kroemer, G. & Martin, S. J. (2005). Caspase-independent cell death. Nature Medicine, 11, 725-730.

Adrain, C. & Martin, S. J. (2006). Cell biology. Double knockout blow for caspases. Science, 311, 785-786

Cullen, S. P., Adrain, C., Luthi, A. U., Duriez, P. J. & Martin, S. J. (2007). Human and murine granzyme B exhibit divergent substrate preferences. Journal of Cell Biology, 176, 435-444.

Sheridan, C., Delivani, P., Cullen, S. P. & Martin, S. J. (2008). Bax- or Bak-induced mitochondrial fission can be uncoupled from cytochrome C release. Molecular Cell, 31, 570-585.

Talor, R. C., Cullen, S. P. & Martin, S. J. (2008). Apoptosis: controlled demolition at the cellular level. Nature Reviews, Molecular Cell Biology, 9, 231-241.

Walsh, J. G., Cullen, S. P., Sheridan, C., Luthi A. U., Gerner, C. and S. J. Martin. (2008) Executioner caspases –3 and –7 are functionally-distinct proteases. Proceedings of the National Academy of Science. USA. 105, 12815-12819.

Lüthi, A.U., Cullen, S.P., McNeela, E.A., Duriez, P.J., Afonina, I.S., Sheridan, C., Brumatti, G., Taylor, R.C., Kersse, K., Vandenabeele, P., Lavelle, E.C. and S. J. Martin. (2009) Suppression of IL-33 Bioactivity through Proteolysis by Apoptotic Caspases. Immunity, 31, 84-98.

Logue S.E., Elgendy, M. and S. J. Martin (2009) Expression, purification and use of recombinant annexin V for the detection of apoptotic cells. Nature Protocols, 4, 1383-1395.

Adrain, C. and S. J. Martin. (2009) Apoptosis: calling time on apoptosome activity. Science Signaling, 2, p.62, 1-3.

Autret, A. and S. J. Martin. (2009) Emerging role for members of the Bcl-2 family in mitochondrial morphogenesis. Molecular Cell, 36, 355-36.

Afonina, I., Cullen S. P and S. J. Martin. (2010) Cytotoxic and non cytotoxic roles of the CTL/NK proteases granzyme B. Immunological Reviews, 235, 105-116.

Sheridan, C., Brumatti G., Elgendy, M., Brunet, M. and S. J. Martin. (2010) An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs. Oncogene, 29, 6428-6441.

Martin, S.J. (2010) Opening the cellular poison cabinet. Science, 330, 1330-1331.

Martin, S.J. (2011) Mitochondrial fusion : Bax to the Fussure. Developmental Cell, 20, 142-143.

Elgendy, M., Sheridan, C., Brumatti, G. and Martin, S.J. (2011) Oncogenic Ras-Induced Expression of Noxa and Beclin-1 Promotes Autophagic Cell Death and Limits Clonogenic Survival. Molecular Cell, 42(1), 23-25.

Afonina, I.S., Tynan, G.A., Logue, S.E., Cullen, S.P., Bots, M., Lüthi, A.U., Reeves, E.P., McElvaney, N.G., Medema, J.P., Lavelle, E.C. and Martin, S.J. (2011) Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1α. Molecular Cell, 44(2), 265-78.

Cullen, S.P., Henry, C.M. and Martin S.J. (2011) Staying alive : defensive strategies in the BCL-2 family playbook. Molecular Cell, 44(4), 509-10.

Hollville, E. and Martin S.J. (2012) Greasing the Path to BAX/BAK Activation. Cell, 148

 

Laboratory Members 2012 Dr. Sean Cullen, Post-doc Dr. Mathilde Brunet, Post-doc Dr. Emilie Hollville, Post-Doc Dr. Antonino Glaviano, Post-Doc Inna Afonina, PhD student Conor Henry, PhD student Conor Kearney, PhD student Richard Carroll, PhD student Danielle Clancy, PhD student

Martin Lab Members 2012

Laboratory Members 2010 (Left to Right) Dr. Sean Cullen Dr. Susan Logue Dr. Stephanie Speckgelns Dr. John Walsh Conor Kearney Dr. Mathilde Brunet Richard Carroll Dr. Emilie Hollville Inna Afonina Conor Henry

Martin Lab Members 2010

 

 

Lab Retreat 2008 (Left to Right) Dr. Douglas Green, Dr. Paola Tucci Dr. Mohamed Elgendy Inna Afonina Dr. Clare Sheridan Prof. Seamus Martin Dr. Sean Cullen Dr. John Walsh Katrin Viikov Dr. Alexander Luthi

Martin Lab Retreat 2008 Killarney, Ireland