MEK Kinase 1 Induces Mitochondrial Permeability Transition Leading to Apoptosis Independent of Cytochrome cRelease
| Autor: | Spencer B. Gibson, Erika M. Gibson, Jacylyn Villanueva, Elizabeth S. Henson |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Cytoplasm
DNA Complementary Time Factors Recombinant Fusion Proteins Blotting Western Green Fluorescent Proteins MAP Kinase Kinase Kinase 1 Apoptosis Cytochrome c Group Caspase 3 Protein Serine-Threonine Kinases Transfection Biochemistry Mitochondrial apoptosis-induced channel Cell Line Mice Tumor Cells Cultured Animals Humans Molecular Biology Inhibitor of apoptosis domain biology Cytochrome c Intrinsic apoptosis Cell Biology Fibroblasts Flow Cytometry Mitochondria Cell biology Luminescent Proteins Spectrometry Fluorescence Mitochondrial permeability transition pore Caspases biology.protein Apoptosome HeLa Cells Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 277:10573-10580 |
| ISSN: | 0021-9258 |
| Popis: | Induction of apoptosis often converges on the mitochondria to induce permeability transition and release of apoptotic proteins into the cytoplasm resulting in the biochemical and morphological alteration of apoptosis. Activation of a serine threonine kinase MEK kinase 1 (MEKK1) is involved in the induction of apoptosis. Expression of a kinase-inactive MEKK1 blocks genotoxin-induced apoptosis. Upon apoptotic stimulation, MEKK1 is cleaved into a 91-kDa kinase fragment that further induces an apoptotic response. Mutation of a consensus caspase 3 site in MEKK1 prevents its induction of apoptosis. The mechanism of MEKK1-induced apoptosis downstream of its cleavage, however, is unknown. Herein we demonstrate that full-length and cleaved MEKK1 leads to permeability transition in the mitochondria. This permeability transition occurs through opening of the permeability transition (PT) pore. Inhibiting PT pore opening and reactive oxygen species production effectively reduced MEKK1-induced apoptosis. Overexpression of MEKK1, however, failed to release cytochrome c from the mitochondria or activate caspase 9. Since Bcl2 regulates changes in mitochondria and blocks MEKK1-induced apoptosis, we determined that Bcl2 blocks MEKK1-induced apoptosis when targeted to the mitochondria. This occurs downstream of MEKK1 cleavage, since Bcl2 fails to block cleavage of MEKK1. In mouse embryonic fibroblast cells lacking caspase 3, the cleaved but not full-length MEKK1 induces apoptosis and permeability transition in the mitochondria. Overall, this suggests that cleaved MEKK1 leads to permeability transition contributing to MEKK1-induced apoptosis independent of cytochrome c release from the mitochondria. |
| Databáze: | OpenAIRE |
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