Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene.
The Raf kinases play a key role in relaying signals elicited by mitogens or oncogenes. Here, we report that c-raf-1(-/-) embryos are growth retarded and die at midgestation with anomalies in the placenta and in the fetal liver. Although hepatoblast proliferation does not appear to be impaired, c-raf-1(-/-) fetal livers are hypocellular and contain numerous apoptotic cells. Similarly, the poor proliferation of Raf-1(-/-) fibroblasts and hematopoietic cells cultivated in vitro is due to an increase in the apoptotic index of these cultures rather than to a cell cycle defect. Furthermore, Raf-1- deficient fibroblasts are more sensitive than wild- type cells to specific apoptotic stimuli, such as actinomycin D or Fas activation, but not to tumor necrosis factor-alpha. MEK/ERK activation is normal in Raf-1-deficient cells and embryos, and is probably mediated by B-RAF. These results indicate that the essential function of Raf-1 is to counteract apoptosis rather than to promote proliferation, and that effectors distinct from the MEK/ERK cascade must mediate the anti-apoptotic function of Raf-1.
Mikula
M
M
Department of Cell- and Microbiology, Institute of Microbiology and Genetics and Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
Schreiber
M
M
Husak
Z
Z
Kucerova
L
L
Rüth
J
J
Wieser
R
R
Zatloukal
K
K
Beug
H
H
Wagner
E F
EF
Baccarini
M
M
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D005347:Fibroblasts / Q000166:cytology; D005804:Genes, Lethal; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells; D006720:Homozygote; D020672:I-kappa B Proteins / Q000378:metabolism; D008099:Liver / Q000196:embryology*; D051379:Mice; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016296:Mutagenesis; D010641:Phenotype; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D015398:Signal Transduction
D020672:I-kappa B Proteins; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases