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Molecular Determinants of the Caspase-promoting Activity of Smac/DIABLO and Its Role in the Death Receptor Pathway
Open accessAbstract
Smac/DIABLO is a mitochondrial protein that is released along with cytochrome c during apoptosis and promotes cytochrome c-dependent caspase activation by neutralizing inhibitor of apoptosis proteins (IAPs). We provide evidence that Smac/DIABLO functions at the levels of both the Apaf-1-caspase-9 apoptosome and effector caspases. The N terminus of Smac/DIABLO is absolutely required for its ability to interact with the baculovirus IAP repeat (BIR3) of XIAP and to promote cytochrome c-dependent caspase activation. However, it is less critical for its ability to interact with BIR1/BIR2 of XIAP and to promote the activity of the effector caspases. Consistent with the ability of Smac/DIABLO to function at the level of the effector caspases, expression of a cytosolic Smac/DIABLO in Type II cells allowed TRAIL to bypass Bcl-xL inhibition of death receptor-induced apoptosis. Combined, these data suggest that Smac/DIABLO plays a critical role in neutralizing IAP inhibition of the effector caspases in the death receptor pathway of Type II cells.
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Cites
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The Role of Mitochondria in Apoptosis
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IAP proteins: blocking the road to death's door
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IAPs: from caspase inhibitors to modulators of NF-κB, inflammation and cancer
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The inhibitors of apoptosis (IAPs) as cancer targets
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Differential apoptotic pathways in human keratinocyte HaCaT cells exposed to UVB and UVC
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Metadata
- Authors
- Srinivasula, S. M., Datta, P., Fan, X.-J., Fernandes-Alnemri, T., Huang, Z., & Alnemri, E. S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-11
- Volume
- 275
- Issue
- 46
- Pages
- 36152-36157
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2079930944
- Cited by
- 356
- References
- 1
- FWCI
- 14.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
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