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Protein Kinase C-ϵ Is Necessary for Erythropoietin's Up-regulation of c-myc and for Factor-dependent DNA Synthesis

Erythropoietin regulates the transcription of the protooncogenes c-myc and c-myb by discrete protein kinase C (PKC)-dependent and protein serine/threonine phosphatase-dependent pathways, respectively (Spangler, R., Bailey, S. C., and Sytkowski, A. J. (1991) J. Biol. Chem. 266, 681-684; Patel H. R, Choi H.-S, and Sytkowski A. J. (1992) J. Biol. Chem. 267, 21300-21302). In the present study we demonstrate that up-regulation of c-myc requires the PKC-ϵ isoform and that this pathway is required for erythropoietin-induced DNA synthesis (growth) but apparently not for β-globin expression (differentiation). Treatment of Rauscher murine erythroleukemia cells resulted in phosphorylation of phospholipase C-γ1 and activation of PKC-ϵ as evidenced by its translocation from soluble to particulate subcellular fractions. Artificial down-regulation of PKC-ϵ with antisense oligodeoxynucleotides blocked erythropoietin's up-regulation of c-myc in a concentration-dependent manner. In contrast, antisense oligodeoxynucleotides to PKC-α, -β, -γ, -δ, and -ζ had no effect. Although down-regulation of PKC-ϵ blocked the increase in c-myc expression, it did not inhibit erythropoietin induction of β-globin expression, a marker of erythroid differentiation. However, down-regulation of PKC-ϵ did block factor-dependent DNA synthesis quantified by measurement of [3H]thymidine incorporation into newly synthesized DNA of normal murine erythroid cells. The results are consistent with discrete intracellular signals regulating erythroid cell growth and differentiation.