Interaction between the mitochondrial protein BNIP3 and caspase-2 enhances cell death and DNA fragmentation
| 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.degree.discipline | Biochemistry and Medical Genetics | en_US |
| dc.degree.level | Master of Science (M.Sc.) | en_US |
| 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 | |
| dc.format.extent | 184 bytes | |
| dc.format.mimetype | application/pdf | |
| dc.format.mimetype | text/plain | |
| dc.identifier.uri | http://hdl.handle.net/1993/2524 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.title | Interaction between the mitochondrial protein BNIP3 and caspase-2 enhances cell death and DNA fragmentation | en_US |
| dc.type | master thesis | en_US |