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dc.contributor.author Brown, Tracy en_US
dc.date.accessioned 2007-07-12T17:47:51Z
dc.date.available 2007-07-12T17:47:51Z
dc.date.issued 2000-05-01T00:00:00Z en_US
dc.identifier.uri http://hdl.handle.net/1993/2524
dc.description.abstract BNIP3 is a cell death-inducing mitochondrial protein that is part of a Bcl-2 subfamily with NIX and ceBNIP3. BNIP3-induced cell death morphologically resembles necrosis that is characterized by rapid plasma membrane damage and mitochondrial dysfunction in the early stages, followed by DNA fragmentation and chromatin condensation characteristic of apoptotic cell death in the later stages. DNA fragmentation during most types of apoptosis is predominantly due to caspase-3 activation. However, BNIP3-induced cell death is independent of caspase-3 activity, thus the mechanism of BNIP3-induced DNA fragmentation remains unknown. Co-immunoprecipitation analysis revealed an interaction between BNIP3, NIX, and caspase-2. The interaction is unique in that it is not mediated through the caspase-2 prodomain. Caspases-1, -8, and -9, which have homologous prodomains to caspase-2, do not bind BNIP3 or NIX, indicating specificity for caspase-2. Further structural analysis indicated that the transmembrane domain and NH2-terminus of BNIP3, which mediate binding to Bcl-2 and Bcl-XL, are not required for binding caspase-2. An ' in vitro' caspase assay detected activation of endogenous caspase-2 in BNIP3-transfected cells. This activation corresponded with enhanced cell death and DNA fragmentation in cells co-expressing BNIP3 and caspase-2. Furthermore, both a broad-spectrum caspase inhibitor and a caspase-2-specific inhibitor blocked NIP3-induced DNA fragmentation 'in vivo', and cleavage of a caspase-2-specific substrate 'in vitro', indicating a role for caspase-2 in BNIP3-induced cell death. Taken together, our results suggest that BNIP3 induces DNA fragmentation and subsequent cell death through a novel mechanism involving the specific recruitment and activation of caspase-2. en_US
dc.format.extent 4071955 bytes
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dc.language en en_US
dc.language.iso en_US
dc.title Interaction between the mitochondrial protein BNIP3 and caspase-2 enhances cell death and DNA fragmentation en_US
dc.degree.discipline Biochemistry & Medical Genetics en_US
dc.degree.level Master of Science (M.Sc.) en_US


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