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The Raf‐1 Protein Mediates Insulin‐Like Growth Factor‐Induced Proliferation of Erythroid Progenitor Cells

Previous studies from this and other laboratories have shown that insulin‐like growth factor‐1 (IGF‐I) and insulin‐like growth factor‐2 (IGF‐II) support erythroid colony formation in cultures supplemented with serum substitute and recombinant erythropoietin. Subpopulations of IGF‐I‐ and IGF‐II‐dependent, erythropoietin‐independent colony‐forming unit‐erythroid (CFU‐E)‐derived colonies and BFU‐E‐derived colonies were identified under serum‐substituted conditions for adult bone‐marrow‐derived erythroid progenitors which proliferate in the absence and presence of exogenous anti‐erythropoietin receptor monoclonal antibody and in serum‐substituted medium that was preadsorbed with anti‐erythropoietin IgG. To assess whether Raf‐1 is required for the formation of IGF‐dependent, erythropoietin‐independent human erythroid colonies, 5‐15 μM sense or antisense oligomer to raf‐1 were added to serum‐substituted cultures containing either 2 U/ml recombinant human erythropoietin (rHuEpo) alone or 0‐1,000 ng/ml IGF‐I or IGF‐II with/without 2 U/ml rHuEpo. Both erythropoietin‐induced and IGF‐induced erythroid colony formation were completely blocked by antisense (but not sense) oligomers to raf‐1. Purified human CFU‐Es were examined for Raf‐1 message and protein. Total RNA was extracted, and raf‐1 mRNA was detected on Northern blots. Furthermore, a 74 kD protein, corresponding to Raf‐1, was also detected in CFU‐Es purified from human adult sources. Together, these studies support the hypothesis that the Raf‐1 protein mediates both erythropoietin‐induced and IGF‐induced signal transduction in human erythroid progenitor cells.