The focus of our laboratory is the study of apoptosis, a biochemically ordered process in which cells are induced to initiate a cellular suicide program in response to physiologic cues, cellular damage, or virus infection. In normal cells the apoptotic pathway is very tightly controlled, but deregulation of the cell death cascade contributes to the pathogenesis of many human diseases including cancer, neurodegenerative diseases and lymphoproliferative and autoimmune disorders.
Our laboratory is interested in the control of cell survival is focused on the iap (inhibitor of apoptosis) gene family encodes a group of factors with diverse cellular functions that range from suppression of apoptotic cell death by direct inhibition of apoptotic effector proteases to the control of mitotic spindle formation in conjunction with mitosis-regulated kinases. Our work is focused on X-linked IAP (XIAP), a potent inhibitor of apoptosis that has been shown to play roles in apoptosis inhibition, cell cycle control, activation of stress-induced transcription factors and stress-activated kinases, cytokine signaling, protein degradation through the ubiquitin pathway and even the metabolic control of intracellular copper levels. A major effort in our laboratory is to reconcile these apparently diverse properties of XIAP. Through the characterization of XIAP-deficient mice, mutagenesis analysis, imaging studies of intracellular trafficking and the identification of novel XIAP-associated proteins, we are beginning to understand which of these functions can, and cannot, be uncoupled from each other. Our long-term goal is to describe an integrated picture of XIAP in which its disparate functions can be reconciled.
Mufti, A.R., Burstein, E., Csomos, R.A., Graf, P.C.F., Wilkinson, J.C., Dick, R.D., Challa., M., Son, J.-K., Bratton, S.B., Su, G.L., Brewer, G.J., Jakob., U. and Duckett, C.S. XIAP is a copper binding protein deregulated in Wilson’s Disease and other copper toxicosis disorders. Mol. Cell 21:775-785, (2006).
Wilkinson, J.C., Wilkinson, A.S., Csomos, R.A., Galbán, S. and Duckett, C.S. AIF is a target for ubiquitination through interaction with XIAP. Mol. Cell. Biol 28:237-247, (2008).
O’Riordan, M.X.D., Bauler, L.D., Scott, F.L. and Duckett, C.S. Inhibitor of apoptosis (IAP) proteins in eukaryotic evolution and development: a model of thematic conservation. Dev. Cell 15:497-508, (2008).
Galbán, S., Brady, G.F. and Duckett, C.S. Caspases and IAPS: A dance of death ensures cell survival. Mol. Cell 32:462-463 (2008).
Wright, C.W. and Duckett, C.S. ARNT modulates CD30-mediated NF-kB transactivation through regulation of RelB. Science 323:251-255, (2009).
Csomos, R.A., Wright, C.W., Galbán, S., Oetjen, K.A. and Duckett, C.S. Two distinct signalling cascades target the NF-kB regulatory factor c-IAP1 for Degradation. Biochem J 420:83-91 (2009).
Rumble, J.M., Oetjen, K.A., Stein, P.L., Schwartzberg, P.L., Moore, B.B. and Duckett, C.S. Phenotypic differences between mice deficient in XIAP and SAP, two factors targeted in X-linked lymphoproliferative syndrome (XLP). Cell Immunol. 2009;259(1):82-9. Epub 2009 Jun 13.