Caspase- and Serine Protease-dependent Apoptosis by the Death Domain of FADD in Normal Epithelial Cells
| Autor: | Andrew Thorburn, Jacqueline Thorburn, Michael J. Morgan, Laura M. Bender |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
Fas-Associated Death Domain Protein Genetic Vectors Apoptosis Epithelium Article Adenoviridae TNF-Related Apoptosis-Inducing Ligand Humans FADD Molecular Biology Caspase Adaptor Proteins Signal Transducing Death domain Serine protease Membrane Glycoproteins biology Tumor Necrosis Factor-alpha Serine Endopeptidases Gene Transfer Techniques Prostate Signal transducing adaptor protein Cell Biology Molecular biology Protein Structure Tertiary Cell biology Caspases biology.protein Death effector domain Tumor necrosis factor alpha Apoptosis Regulatory Proteins Carrier Proteins |
| Zdroj: | Molecular Biology of the Cell. 14:67-77 |
| ISSN: | 1939-4586 1059-1524 |
| Popis: | The adapter protein FADD consists of two protein interaction domains: a death domain and a death effector domain. The death domain binds to activated death receptors such as Fas, whereas the death effector domain binds to procaspase 8. An FADD mutant, which consists of only the death domain (FADD-DD), inhibits death receptor–induced apoptosis. FADD-DD can also activate a mechanistically distinct, cell type–specific apoptotic pathway that kills normal but not cancerous prostate epithelial cells. Here, we show that this apoptosis occurs through activation of caspases 9, 3, 6, and 7 and a serine protease. Simultaneous inhibition of caspases and serine proteases prevents FADD-DD–induced death. Inhibition of either pathway alone does not prevent cell death but does affect the morphology of the dying cells. Normal prostate epithelial cells require both the caspase and serine protease inhibitors to efficiently prevent apoptosis in response to TRAIL. In contrast, the serine protease inhibitor does not affect TRAIL-induced death in prostate tumor cells suggesting that the FADD-DD–dependent pathway can be activated by TRAIL. This apoptosis pathway is activated in a cell type–specific manner that is defective in cancer cells, suggesting that this pathway may be targeted during cancer development. |
| Databáze: | OpenAIRE |
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