The Journal of Experimental Medicine
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Published online 11 November 2002 doi:10.1084/jem.20020562
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© Rockefeller University Press, 0022-1007/2002/11/1347/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 10, November 18, 2002 1347-1353

Raf-1 Antagonizes Erythroid Differentiation by Restraining Caspase Activation

Andrea Kolbus1, Sandra Pilat1, Zvenyslava Husak2, Eva Maria Deiner1, Gabriele Stengl1, Hartmut Beug1 and Manuela Baccarini2

1 Research Institute of Molecular Pathology, Institute of Microbiology and Genetics, Vienna Biocenter, 1030 Vienna, Austria
2 Department of Cell and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, 1030 Vienna, Austria

Address correspondence to Manuela Baccarini, Department of Cell and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, Dr. Bohr Gasse 9, 1030 Vienna, Austria. Phone: +43 1 4277-54607; Fax: +43 1 4277-9546; E-mail: manuela{at}gem.univie.ac.at

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.

Key Words: kinase • gene inactivation • erythropoiesis • fetal liver • apoptosis


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