My laboratory is examining the role of the intrinsic cellular suicide program known as apoptosis in the pathogenesis of human disease. We are currently focused on the study of two factors, X-linked inhibitor of apoptosis (XIAP) and apoptosis inducing factor (AIF). These molecules directly regulate the apoptotic process, but also possess signaling properties that are distinct from their roles during cell death. XIAP is a highly efficient inhibitor of caspases, the predominant biochemical mediators of apoptosis, but also plays a significant role in regulating signal transduction through the TGF-b, JNK, NF-kB, and copper homeostasis pathways. In contrast, AIF promotes cell death by caspase independent means, but also plays a pro-survival role in vivo by functioning as an NADH-oxidase and regulating mitochondrial function. We have determined that XIAP and AIF associate in living cells with the ability to co-regulate. Both XIAP and AIF are elevated in a variety of human cancers, and our research efforts are currently focused on evaluating their roles in the process of tumorigenesis. We address our research questions by utilizing a variety of techniques spanning the disciplines of molecular biology, biochemistry, and in vivo tumor biology. Selected publications: Mufti, A. R., Burstein, E., Csomos, R. A., Wilkinson, J. C., Dick, R. D., Su, G. L., Brewer, G. J., and Duckett, C. S. (2006) XIAP is a copper binding protein deregulated in Wilson’s disease and other copper toxicosis disorders. Molecular Cell 21, 775-785.
Kamradt, M. C., Lu, M., Werner, M. E., Kwan, T., Chen, F., Strohecker, A., Oshita, S., Wilkinson, J. C., Yu, C., Schafer, J. M., Sam, S., Oliver, P. G., Duckett, C. S., Buchsbaum, D. J., LoBuglio, A. F., Jordan, V. C., and Cryns, V. L. (2005) The small heat shock protein aβ-crystallin is a novel mediator of TRAIL-resistance in cancer that inhibits the activation of caspase-3. The Journal of Biological Chemistry 280(12), 11059-66.
Wilkinson, J. C., Richter, B. W. M., Wilkinson, A. S., Burstein, E., Rumble, J. M., Balliu, B., and Duckett, C. S. (2004) VIAF, a conserved inhibitor of apoptosis (IAP)-interacting factor that modulates caspase activation. The Journal of Biological Chemistry 279(49), 51091-9.
Wilkinson, J. C., Wilkinson, A. S., Scott, F. L., Csomos, R. A., Salvesen, G. S., and Duckett, C. S. (2004) Neutralization of Smac/Diablo by inhibitors of apoptosis (IAPs): a caspase-independent mechanism for apoptotic inhibition. The Journal of Biological Chemistry 279(49), 51082-90.
Wilkinson, J. C., Cepero, E., Boise, L. H., and Duckett, C. S. (2004) Upstream regulatory role for XIAP in receptor-mediated apoptosis. Molecular and Cellular Biology 24(16), 7003-14.
Burstein, E., Ganesh, L., Dick, R.D., Van De Sluis, B., Wilkinson, J.C., Klomp, L.W., Wijmenga, C., Brewer, G.J., Nabel, G.J., and Duckett, C.S. (2004) A novel role for XIAP in copper homeostasis through regulation of MURR1. EMBO Journal 23(1), 244-54.
Beltrami, E., Plescia, J., Wilkinson, J.C., Duckett, C.S., and Altieri, D.C. (2004) Acute ablation of survivin uncovers p53-dependent mitotic checkpoint functions and control of mitochondrial apoptosis. The Journal of Biological Chemistry 279(3), 2077-84.
Shin, H., Okada, K., Wilkinson, J. C., Solomon, K. M., Duckett, C. S., Reed, J. C., and Salvesen, G. S. (2003) Identification of ubiquitination sites on the X-linked inhibitor of apoptosis protein. Biochemical Journal 373(3), 965-71. |