Date on Master's Thesis/Doctoral Dissertation

12-2012

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Committee Chair

Li, Chi

Author's Keywords

Apoptosis; oxidative stress Bcl-2; outer mitochondria membrane; Bcl-xL

Subject

Apoptosis; Proteins

Abstract

Bcl-2 proteins are major regulators of cellular responses to various apoptotic stimuli. Among them, overexpression of the anti-apoptotic BcI-2 protein BcI-xL modulates organelle-specific apoptotic pathways. To understand the mechanisms by which endogenous BcI-xL regulates apoptosis, mouse embryonic fibroblasts (MEFs) deficient in BcI-xL expression (Bcl-x-KO) was generated. Studies of BcI-xL exclusively targeted to an organelle in Bcl-x-KO MEFs indicate that the mitochondria- and ER-Iocalized BcI-xL play distinct roles in apoptosis resistance and Ca2+ homeostasis. Specifically, mitochondrial BcI-xL can regulate apoptosis independently of ER BcI-xL, and when localized exclusively at the ER, BcI-xL impinges on Ca2+ homeostasis but does not affect apoptosis unless BcI-xL is present in additional cellular compartments. Furthermore, I investigated how Bcl-2 proteins, especially Bcl-xL, might regulate oxidative stress-induced apoptosis. My studies reveal a signaling pathway, in which the oxidative stress inducer hydrogen peroxide (H202) activates Noxa, leading to a decrease in Mcl-1 expression levels and subsequent increase in apoptosis in the absence of BcI-xL expression. Finally, I studied the exact roles of lysosomal membrane permeabilization in apoptosis cascade triggered by oxidative stress and how LMP is regulated by the complex Bcl-2 protein network. My studies elucidate a novel molecular mechanism that couples lysosomal membrane permeabilization with mitochondrial membrane permeabilization and ultimate cell death during oxidative stress-induced apoptosis.

Download

Share

COinS