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Molecular Cell Biology laboratory
Prof. Seamus J. Martin
Email: martinsj@tcd.ie The
primary focus of my lab is the dissection of the molecular
components of the machinery that orchestrates 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. Thus,
understanding
apoptosis at a molecular level will provide new insights into many
fundamental biological processes and will very likely result in new
ways of treating conditions where either too few (cancer, autoimmune
disease) or too many (AIDS, neurodegeneration) cells die.In a broader context, I am interested in how apoptosis is regulated during the development and functioning of the immune system and other organs. As the key regulators of apoptosis emerge, the prospect of targeting these molecules for disease intervention becomes real. We eventually hope to apply the information we have gleaned, concerning the molecular control of apoptosis, for the purposes of developing novel strategies to modulate the cell death responses in disease contexts. |
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| We have several areas of
research interest at present: 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. |
 Mitochondrial fragmentation |
 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 |
Selected Publications:
Martin, S. J. & Green, D. R. (1995). Protease activation during apoptosis: death by a thousand cuts? Cell 82, 349-352. PubMed.
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 J. 14, 5191-5200. PubMed.
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. J Exp Med 182, 1545-1556. PubMed.
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 J. 15, 2407-2416. PubMed.
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. PubMed.
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. J. Cell Biol. 144, 281-292. PubMed.
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 J. 20, 6627-6636. PubMed.
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. J. Biol. Chem. 276, 7320-7326. PubMed.
Martin, S. J. (2002). Destabilizing influences in apoptosis: sowing the seeds of IAP destruction. Cell 109, 793-796. PubMed.
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. J Exp Med 197, 625-632. PubMed.
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 J. 23, 2134-2145. PubMed.
Kroemer, G. & Martin, S. J. (2005). Caspase-independent cell death. Nat Med 11, 725-730. PubMed.
Adrain, C. & Martin, S. J. (2006). Cell biology. Double knockout blow for caspases. Science 311, 785-786. PubMed.
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. Mol. Cell 21, 761-773. PubMed.
Cullen, S. P., Adrain, C., Luthi, A. U., Duriez, P. J. & Martin, S. J. (2007). Human and murine granzyme B exhibit divergent substrate preferences. J. Cell Biol. 176, 435-444. PubMed.
Sheridan, C., Delivani, P., Cullen, S. P. & Martin, S. J. (2008). Bax- or Bak-induced mitochondrial fission can be uncoupled from cytochrome C release. Mol. Cell 31, 570-585. PubMed.
Taylor, R. C., Cullen, S. P. & Martin, S. J. (2008). Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9, 231-241. PubMed.
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Laboratory Members
Dr. Susan Logue, Post-doc Dr. Arnaud Autret, Post-doc Sean Cullen, Post-doc Alexander Luthi, PhD student Clare Sheridan, PhD student John Walsh, PhD student Inna Afonina, PhD student Mohamed Elgendy, PhD student Katrin Viikov, PhD student Anna Sharafutdinova, PhD student |
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