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 a
nd die at midgestation with anomalies in the placenta and in the fetal live
r. 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 hematopoie
tic 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-de
ficient fibroblasts are more sensitive than wildtype cells to specific apop
totic stimuli, such as actinomycin D or Fas activation, but not to tumor ne
crosis factor-alpha. MEK/ERK activation is normal in Raf-l-deficient cells
and embryos, and is probably mediated by B-Raf, These results indicate that
the essential function of Raf-l is to counteract apoptosis rather than to
promote proliferation, and that effecters distinct from the MEK/ERK cascade
must mediate the anti-apoptotic function of Raf-1.