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Volume 271, Number 43, Issue of October 25, 1996 pp. 27025-27030
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Protein Kinase C- Is Necessary for Erythropoietin's Up-regulation of c-myc and for Factor-dependent DNA Synthesis
EVIDENCE FOR DISCRETE SIGNALS FOR GROWTH AND DIFFERENTIATION

(Received for publication, March 26, 1996, and in revised form, May 24, 1996)

From the Laboratory for Cellular and Molecular Biology, Division of Hematology and Oncology, New England Deaconess Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215

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- isoform and that this pathway is required for erythropoietin-induced DNA synthesis (growth) but apparently not for -globin expression (differentiation). Treatment of Rauscher murine erythroleukemia cells resulted in phosphorylation of phospholipase C-1 and activation of PKC- as evidenced by its translocation from soluble to particulate subcellular fractions. Artificial down-regulation of PKC- with antisense oligodeoxynucleotides blocked erythropoietin's up-regulation of c-myc in a concentration-dependent manner. In contrast, antisense oligodeoxynucleotides to PKC-, -, -, -, and - had no effect. Although down-regulation of PKC- blocked the increase in c-myc expression, it did not inhibit erythropoietin induction of -globin expression, a marker of erythroid differentiation. However, down-regulation of PKC- 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.

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