| Autor: |
Timo Korpela, Igor Dudich, Natalie Tokhtamisheva, Elena Dudich, Juan-Antonio Palop-Cubillo, Yury Okruzhnov, Edward Borisovitch Tatulov, Lidia Nikolaevna Semenkova, Jesús García-Foncillas |
| Rok vydání: |
2003 |
| Předmět: |
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| Zdroj: |
European Journal of Biochemistry. 270:4388-4399 |
| ISSN: |
0014-2956 |
| DOI: |
10.1046/j.1432-1033.2003.03836.x |
| Popis: |
Previous results have shown that the oncoembryonic marker α-fetoprotein (AFP) is able to induce apoptosis in tumor cells through activation of caspase 3, bypassing Fas-dependent and tumor necrosis factor receptor-dependent signaling. In this study we further investigate the molecular interactions involved in the AFP-mediated signaling of apoptosis. We show that AFP treatment of tumor cells is accompanied by cytosolic translocation of mitochondrial cytochrome c. In a cell-free system, AFP mediates processing and activation of caspases 3 and 9 by synergistic enhancement of the low-dose cytochrome c-mediated signals. AFP was unable to regulate activity of caspase 3 in cell extracts depleted of cytochrome c or caspase 9. Using high-resolution chromatography, we show that AFP positively regulates cytochrome c/dATP-mediated apoptosome complex formation, enhances recruitment of caspases and Apaf-1 into the complex, and stimulates release of the active caspases 3 and 9 from the apoptosome. By using a direct protein–protein interaction assay, we show that pure human AFP almost completely disrupts the association between processed caspases 3 and 9 and the cellular inhibitor of apoptosis protein (cIAP-2), demonstrating its release from the complex. Our data suggest that AFP may regulate cell death by displacing cIAP-2 from the apoptosome, resulting in promotion of caspase 3 activation and its release from the complex. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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