Signalling mechanisms and the role of calcineurin in erythropoiesis

Mária Magócsi, Ágota Apáti, Róbert Gáti, Attila Kolonics

Research output: Contribution to journalArticle

9 Citations (Scopus)


Erythropoietin (Epo) is the principal regulator of the production of circulating erythrocytes by controlling the proliferation, the differentiation and the survival of the erythroid progenitor cells. Early down-regulation of c-myb expression in erythroleukemia cells is a common feature of the action of Epo and chemical inducers-of differentiation such as DMSO. Previously we have shown that in our Epo-responsive murine erythroleukemia cell line ELM-I-1, [Ca2+](i) increasing agents can mimic the effect of Epo on c-myb expression and activate nuclear signal transduction processes involved in the induction of hemoglobin synthesis. These results also indicated that the Ca2+-induced down-regulation of c- myb expression and hemoglobin synthesis are mediated by the Ca2+/calmodulin dependent serine/threonine-specific protein phosphatase PP2B, calcineurin, but the Epo induced processes are not mediated by PP2B. In spite of this, we demonstrated in this paper that in ELM-I-1 cells the Epo-induced down- regulation of c-myb expression and hemoglobin production can be effectively enhanced by the simultaneously added [Ca2+](i)-increasing agent, cyclopiazonic acid (CPA). This observation further supports the existence of at least two independent signalling pathways in the mechanism of Epo and [Ca2+](i) increasing agents and the strong correlation between c-myb expression and hemoglobin production in differentiating cells. Although the c-AMP-response element binding protein (CREB) could be the common target of both calcium-dependent and -independent dephosphorylation, our results do not support the involvement of CREB in the regulation of c-myb gene expression. In addition to the calcineurin mediated down-regulation of c-myb expression, we have found a negative regulatory effect in the Ca2+-mediated transcriptional activation of certain genes. In response to [Ca2+](i)- increasing agents in ELM-I-1 cells, both, egr-1 and c-fos mRNA expression increased significantly after the inhibition of calcineurin by cyclosporine A. Cyclosporin A exerted stimulatory effects on the egr-1 and c-fos expression also at lower (150-400 nM) intracellular Ca2+ levels. This potential co-regulation of c-myb, egr-1 and c-fos expression by calcineurin suggests that the negative modulation of egr-1 and c-fos expression may also be important for the induction of erythroid differentiation by [Ca2+](i)- increasing agents. This negative modulation may also contribute to the Epo- induced differentiation in the case of a moderate increase of [Ca2+](i).

Original languageEnglish
Pages (from-to)187-195
Number of pages9
JournalImmunology letters
Issue number1
Publication statusPublished - May 3 1999


  • Calcineurin
  • Calcium
  • Cell proliferation
  • Differentiation
  • Erythropoietin
  • Signal transduction
  • Transcription factors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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