Abstract
Bcl-2 family proteins play a critical role in the regulation of cell survival by controlling the activation of the cell death executing caspase machinery. Recent work demonstrated that they also provide a link between growth factor signaling and cell survival control. Raf-1 has been identified initially as an essential component of the mitogenic Ras-Raf-MEK-ERK cascade. However, expression of oncogenic Raf-1 also efficiently suppresses apoptotic cell death. This process requires mitochondrial translocation of Raf-1 which can be achieved either by co-expression of the anti-apoptotic protein Bcl-2 or by fusion with the transmembrane domain of the yeast outer mitochondrial membrane protein Mas 70p. It is currently unclear how mitochondrial Raf-1 prevents apoptosis. One possible mechanism involves the phosphorylation of the pro-apoptotic protein Bad resulting in the restoration of Bcl-2 function. Alternatively, the role of Bcl-2 could be limited to the mitochondrial translocation of Raf-1 and survival signaling by Raf-1 is Bcl-2 independent. To test for the mutual requirement of Raf-1 and Bcl-2 in apoptosis suppression the individual proteins were singly tested for survival activity in a genetic background which precludes the expression of the other. The results obtained in these studies demonstrate that ablation of Raf-1 or Bcl-2 expression in fibroblast cells significantly increases the sensitivity towards doxorubicin induced cell death. Reversion of the mutant phenotype could be achieved in either case by introducing a functional bcl-2 gene or a mitochondria targeted version of oncogenic Raf-1, demonstrating that each protein by itself is sufficient to confer protection. Our data thus suggest the existence of two separate pathways of survival signaling at the mitochondria controlled either by Bcl-2 or by Raf-1.
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Acknowledgements
The authors want to thank Dr John Reed for providing virus and expression constructs and Drs TM Michaelidis and H Thoenen for the generous gift of the Bcl-2 knockout mice. We are also grateful to the members of the Troppmair laboratory for plenty of scientific and technical discussions. The help of Frau Silvia Pfränger in the preparation of the figures is greatly acknowledged. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Ra642/6-1).
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Zhong, J., Troppmair, J. & Rapp, U. Independent control of cell survival by Raf-1 and Bcl-2 at the mitochondria. Oncogene 20, 4807–4816 (2001). https://doi.org/10.1038/sj.onc.1204614
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DOI: https://doi.org/10.1038/sj.onc.1204614
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