Date of Award

5-2004

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

Supervisor

Professor David W. Andrews

Abstract

The molecular mechanism by which the Bd-2 family of proteins regulates the complex process of apoptosls is unknown. One insight into the function of these proteins is their requirement for membrane localization to regulate cell death. Bd-2, the prototype of the family, is localized the endoplasmic reticulum (ER) and mitochondria. By examining the contribution of ER localized Bcl-2 in the regulation of apoptosis; two spatially distinct cell death pathways were identified. One pathway is characterized by the early loss of inner mitochondrial membrane potential and is inhibited by ER localized Bc1-2. The other pathway, not inhibited by ER localized Bcl-2, is characterized by the mitochondrial translocation of the cytoplasmic pro-apoptotic protein Bax. On mitochondria Bax oligomerizes inducing the release of cytochrome c. This mitochondrial pathway is influenced by the expression of the oncogene Myc, specifically, Myc is required for the transition from monomeric, membrane bound, Bax to oligomeric active Bax. This activation ofBax is not mediated by changes to its membrane topology as both monomeric and oligomeric membrane bound Bax adopts a multi-spanning membrane topology with helices a5, a6 and a9 partially inserted into the lipid bilayer. These studies have demonstrated that the function ofBcl-2 at the ER is dependent on apoptotic agonist; Bax activity at mitochondria is influenced by a Myc regulated factor and activation of Bax is not mediated by changes in this proteins membrane topology. Combined these studies have provided valuable insight into both the complexity and molecular mechanisms of Bd-2 proteins in the regulation of apoptosis.

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Biochemistry Commons

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