The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death
| Autor: | Byoung Rai Lee, Dong-Wook Kim, Dai Wu Seol, Jin Na Shin, Kang Hee Ko, Jae Yoon Park, Tae-Hyoung Kim, Jong Hee Cha, Young Woo Seo, Young Myeong Kim, Cheol Won Yun, Xiao Ming Yin |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Transcriptional Activation
Programmed cell death Recombinant Fusion Proteins Blotting Western Green Fluorescent Proteins Molecular Sequence Data Magnesium Chloride Apoptosis Mitochondrion Biology Ligands Biochemistry Mitochondrial apoptosis-induced channel Cytosol hemic and lymphatic diseases Humans Amino Acid Sequence Molecular Biology Endodeoxyribonucleases Sequence Homology Amino Acid Tumor Necrosis Factor-alpha Cytochrome c Cytochromes c Membrane Proteins Cell Biology Recombinant Proteins Cell biology Mitochondria Protein Structure Tertiary Luminescent Proteins bcl-2 Homologous Antagonist-Killer Protein Mitochondrial permeability transition pore Microscopy Fluorescence Proto-Oncogene Proteins c-bcl-2 biology.protein Apoptosome Signal transduction Tumor Suppressor Protein p53 Carrier Proteins BH3 Interacting Domain Death Agonist Protein HeLa Cells Plasmids Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 278(48) |
| ISSN: | 0021-9258 |
| Popis: | Genotoxic stresses stabilize the p53 tumor suppressor protein which, in turn, transactivates target genes to cause apoptosis. Although Noxa, a “BH3-only” member of the Bcl-2 family, was shown to be a target of p53-mediated transactivation and to function as a mediator of p53-dependent apoptosis through mitochondrial dysfunction, the molecular mechanism by which Noxa causes mitochondrial dysfunction is largely unknown. Here we show that two domains (BH3 domain and mitochondrial targeting domain) in Noxa are essential for the release of cytochrome c from mitochondria. Noxainduced cytochrome c release is inhibited by permeability transition pore inhibitors such as CsA or MgCl2, and Noxa induces an ultra-structural change of mitochondria yielding “swollen” mitochondria that are unlike changes induced by tBid. This indicates that Noxa may activate the permeability transition-related pore to release cytochrome c from mitochondria into cytosol. Moreover, Bak-oligomerization, which is an essential event for tBid-induced cytochrome c release in the extrinsic death signaling pathway, is not associated with Noxa-induced cytochrome c release. This finding suggests that the pathway of Noxa-induced mitochondrial dysfunction is distinct from the one of tBid-induced mitochondrial dysfunction. Thus, we propose that there are at least two different pathways of mitochondrial dysfunction; one mediated through Noxa in response to genotoxic stresses and the other through tBid in response to death ligands. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|