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Volume 271, Number 23, Issue of June 7, 1996 pp. 13484-13490
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Ca²⁺/Calmodulin-dependent and -independent Down-regulation of c-myb mRNA Levels in Erythropoietin-responsive Murine Erythroleukemia Cells
THE ROLE OF CALCINEURIN

(Received for publication, January 30, 1996)

András Schaefer , Mária Magócsi ^¶ , Ulrich Stöcker , Anette Fandrich and Hans Marquardt

From the  Department of Toxicology, Hamburg University Medical School and Fraunhofer Department of Toxicology and Environmental Medicine, Grindelallee 117, D-20146 Hamburg, Federal Republic of Germany and the ^¶ National Institute of Hematology, Blood Transfusion and Immunology, H-1113 Budapest, Daróczi út 24, Hungary

Down-regulation of c-myb mRNA levels by [Ca²⁺]_i-increasing agents (A23187, thapsigargin, cyclopiazonic acid) and erythropoietin was comparatively studied in the erythropoietin-responsive murine erythroleukemia cell line, ELM-I-1. The Ca²⁺-induced suppression of c-myb mRNA could be inhibited by the calmodulin antagonists trifluoperazine and calmidazolium, as well as by cyclosporin A, an inhibitor of the Ca²⁺/calmodulin-dependent protein phosphatase 2B (calcineurin). KN-62, an inhibitor of Ca²⁺/calmodulin-dependent protein kinases, did not antagonize the Ca²⁺-mediated decrease in c-myb mRNA. In cyclosporin A-treated ELM-I-1 cells, a close correlation could be demonstrated between the antagonization of the Ca²⁺ effect on c-myb mRNA levels and inhibition of the calcineurin phophatase activity. On the other hand, FK506, which did not inhibit calcineurin activity in ELM-I-1 cells, failed to prevent the Ca²⁺-mediated decrease in c-myb mRNA. The erythropoietin-induced down-regulation of c-myb mRNA levels could be demonstrated also in the presence of EGTA and was resistant to calmodulin antagonists and cyclosporin A. In addition, no increase in [Ca²⁺]_i was observed in ELM-I-1 cells in response to erythropoietin. Cyclosporin A inhibited the Ca²⁺-induced hemoglobin production, while the erythropoietin-mediated increase in hemoglobin synthesis was not affected. The results indicate that the Ca²⁺-induced decrease in c-myb mRNA and increase in hemoglobin synthesis is mediated by calcineurin, while these effects of erythropoietin occur independently of Ca²⁺ in ELM-I-1 cells. Calcineurin may be involved in the regulation of c-myb expression in erythroid precursor cells and Ca²⁺ signals via calcineurin may positively modulate the differentiation inducing action of erythropoietin.

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