Raf-1 antagonizes erythroid differentiation by restraining caspase activation.
The Raf kinases are key signal transducers activated by mitogens or oncogenes. The best studied Raf isoform, Raf-1, was identified as an inhibitor of apoptosis by conventional and conditional gene ablation in mice. c-raf-1(-)(/)(-) embryos are growth retarded and anemic, and die at midgestation with anomalies in the placenta and fetal liver. Here, we show that Raf-1-deficient primary erythroblasts cannot be expanded in culture due to their accelerated differentiation into mature erythrocytes. In addition, Raf-1 expression is down-regulated in differentiating wild-type cells, whereas overexpression of activated Raf-1 delays differentiation. As recently described for human erythroid precursors, we find that caspase activation is necessary for the differentiation of murine fetal liver erythroblasts. Differentiation-associated caspase activation is accelerated in erythroid progenitors lacking Raf-1 and delayed by overexpression of the activated kinase. These results reveal an essential function of Raf-1 in erythropoiesis and demonstrate that the ability of Raf-1 to restrict caspase activation is biologically relevant in a context distinct from apoptosis.
Kolbus
Andrea
A
Research Institute of Molecular Pathology, Institute of Microbiology and Genetics, Vienna Biocenter, 1030 Vienna, Austria.
Pilat
Sandra
S
Husak
Zvenyslava
Z
Deiner
Eva Maria
EM
Stengl
Gabriele
G
Beug
Hartmut
H
Baccarini
Manuela
M
D000595:Amino Acid Sequence; D000818:Animals; D020169:Caspases / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology*; D004912:Erythrocytes / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000502:physiology*
D019908:Proto-Oncogene Proteins c-raf; D020169:Caspases