The mechanisms that mediate cellular sensitivity to apoptotic stimuli are poorly understood. Considerable data suggests that reactive oxygen intermediates (R01s) may play a critical role in this regard. For example, the PI has demonstrated that increases in intracellular 02- appears to protect cells from Fas-mediated death. In this proposal, the PI plans to: 1) use various agents to alter intracellular 02- production in a variety of different cells types stimulated to die so that the generalizability of this observation can determined; 2) examine the effects of redox balance on caspase activity; 3) determine if Bcl-2 alters redox state in cells; 4) evaluate the effects of altered redox state on apoptosis sensitivity of tumor cells in vivo; and 5) determine if activation-associated changes in lymphocyte sensitivity to apoptotic stimuli is redox state dependent.
| Hampton, Mark B; Stamenkovic, Ivan; Winterbourn, Christine C (2002) Interaction with substrate sensitises caspase-3 to inactivation by hydrogen peroxide. FEBS Lett 517:229-32 |
| Yu, Q; Stamenkovic, I (2001) Angiopoietin-2 is implicated in the regulation of tumor angiogenesis. Am J Pathol 158:563-70 |
| Mitsiades, N; Poulaki, V; Tseleni-Balafouta, S et al. (2000) Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 60:4122-9 |
| Yu, Q; Stamenkovic, I (1999) Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev 13:35-48 |
