Abstract
Previous studies have indicated an important role for the Raf family of protein kinases in controlling cellular responses to extracellular stimuli and activated oncogenes, through their ability to activate the MEK/ERKs. To investigate the specific role of A-Raf in this process we generated A-Raf deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells by gene targeting and characterized their ability to undergo proliferation, differentiation, apoptosis, ERK activation, and transformation by oncogenic Ras and Src. The A-Raf deficient cells are not disrupted for any of these processes, despite the fact that this protein is normally expressed at high levels in both cell types. This implies either that A-Raf plays no role in MEK/ERK activation, that its function is fully compensated by other Raf proteins or MEK kinases or that its role in MEK/ERK activation is highly tissue-specific. Interestingly, B-Raf and Raf-1 activity towards MEK as measured by the immunoprecipitation kinase cascade assay are both significantly increased in the A-Raf deficient MEFs.
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Acknowledgements
We thank Susan Giblett for embedding and sectioning the teratomas, Mabel Iwobi for the PCR data, Martin McMahon for providing the pZAS4ras and pZAS4src vectors and Lee Topping for help with statistics. We are also grateful to the Division of Biomedical Services at Leicester for their technical assistance. This work was supported by a BBSRC studentship to K Mercer, a Royal Society fellowship to C Pritchard, and project grants from the Medical Research Council and the Cancer Research Campaign. We thank these organisations for their invaluable support.
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Mercer, K., Chiloeches, A., Hüser, M. et al. ERK signalling and oncogene transformation are not impaired in cells lacking A-Raf. Oncogene 21, 347–355 (2002). https://doi.org/10.1038/sj.onc.1205101
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DOI: https://doi.org/10.1038/sj.onc.1205101
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