Regulation of death receptor-mediated apoptosis by Bcl-2 and caspase inhibition
Date of Award
Doctor of Philosophy (Ph.D.)
Microbiology and Immunology
First Committee Member
Lawrence H. Boise, Committee Chair
Apoptosis, or programmed cell death, is an essential mechanism by which normal embryonic development and homeostasis are maintained. Defects leading to increased or decreased cell death can contribute to a number of detrimental outcomes, including autoimmunity, neurodegenerative diseases, and cancer. The signaling pathways initiated during the apoptotic process as well as how these pathways are regulated are therefore of great significance in the fight against disease. Elucidation of the defects in cell death which occur will lead to new avenues of research with the ultimate goal being the rational design of novel therapeutic strategies. Our work has shown that while cell death initiated by cell surface receptors termed death receptors cannot be rescued by either the expression of anti-apoptotic members of the Bcl-2 family alone or addition of the synthetic peptide caspase inhibitor zVAD-fmk alone, the combination is sufficient to inhibit these cell deaths. These data suggest that anti-apoptotic members of the Bcl-2 family can cooperate with the synthetic peptide caspase inhibitor zVAD-fmk to suppress death receptor-mediated apoptosis. The data we have obtained lead us to propose a model in which these receptors can initiate two distinct apoptotic pathways. One pathway involves the direct activation of effector caspases while the other involves perturbations of the mitochondria. zVAD-fmk dampens the initial activation of the apoptotic cascade at the level of caspase-8 activation at the receptor complex. This dampening effect does not allow for the direct activation of effector caspases, and therefore drives the cell down a cell death pathway involving disruption of normal mitochondrial function, which is inhibited by Bcl-2 or Bcl-x L. Importantly, both activated T cells and members of a particular subfamily of herpesvirus (and perhaps more virus families) contain endogenous caspase-8 inhibitors called FLIPS and anti-apoptotic Bcl-2 family members. We hypothesize that these two protein families cooperate during the regulation of T cell homeostasis as well as during the course of viral infection and could serve as targets for therapy in autoimmunity and virus-associated malignancies.
Johnson, Bryan Walter, "Regulation of death receptor-mediated apoptosis by Bcl-2 and caspase inhibition" (2002). Dissertations from ProQuest. 1821.