Survival signaling by C-RAF: mitochondrial reactive oxygen species and Ca2+ are critical targets
| Autor: | Martin Hermann, Andrey V. Kuznetsov, Martin Wurm, Stefan F. Scheidl, Julija Smigelskaite, Andrea J. Deutschmann, Jakob Troppmair, Robert Sucher, Manickam Janakiraman, Christine Doblander |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Mitochondrial ROS
Cell Survival Recombinant Fusion Proteins Apoptosis Oxidative phosphorylation Biology Mitochondrial apoptosis-induced channel Antioxidants Oncogene Proteins v-raf Mice tert-Butylhydroperoxide medicine Staurosporine Animals Homeostasis Humans Myeloid Cells c-Raf Calcium Signaling RNA Small Interfering Molecular Biology chemistry.chemical_classification Reactive oxygen species Microscopy Confocal Superoxide Dismutase Cell Biology Articles Cell biology Mitochondria Proto-Oncogene Proteins c-raf Mitochondrial permeability transition pore chemistry Proto-Oncogene Proteins c-bcl-2 Interleukin-3 Apoptosis Regulatory Proteins Reactive Oxygen Species medicine.drug |
| Zdroj: | Molecular and cellular biology. 28(7) |
| ISSN: | 1098-5549 |
| Popis: | Survival signaling by RAF occurs through largely unknown mechanisms. Here we provide evidence for the first time that RAF controls cell survival by maintaining permissive levels of mitochondrial reactive oxygen species (ROS) and Ca(2+). Interleukin-3 (IL-3) withdrawal from 32D cells resulted in ROS production, which was suppressed by activated C-RAF. Oncogenic C-RAF decreased the percentage of apoptotic cells following treatment with staurosporine or the oxidative stress-inducing agent tert-butyl hydroperoxide. However, it was also the case that in parental 32D cells growing in the presence of IL-3, inhibition of RAF signaling resulted in elevated mitochondrial ROS and Ca(2+) levels. Cell death is preceded by a ROS-dependent increase in mitochondrial Ca(2+), which was absent from cells expressing transforming C-RAF. Prevention of mitochondrial Ca(2+) overload after IL-3 deprivation increased cell viability. MEK was essential for the mitochondrial effects of RAF. In summary, our data show that survival control by C-RAF involves controlling ROS production, which otherwise perturbs mitochondrial Ca(2+) homeostasis. |
| Databáze: | OpenAIRE |
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