Document Detail

Signalling mechanisms and the role of calcineurin in erythropoiesis.
MedLine Citation:
PMID:  10397175     Owner:  NLM     Status:  MEDLINE    
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.
M Magócsi; A Apáti; R Gáti; A Kolonics
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Immunology letters     Volume:  68     ISSN:  0165-2478     ISO Abbreviation:  Immunol. Lett.     Publication Date:  1999 May 
Date Detail:
Created Date:  1999-10-21     Completed Date:  1999-10-21     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7910006     Medline TA:  Immunol Lett     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  187-95     Citation Subset:  IM    
Department of Cell Metabolism, National Institute of Haematology and Immunology, Budapest, Hungary.
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MeSH Terms
Calcineurin / metabolism,  physiology*
Calcium / metabolism
Cell Differentiation
DNA-Binding Proteins / metabolism
Early Growth Response Protein 1
Erythropoiesis / drug effects,  immunology*
Erythropoietin / pharmacology
Hemoglobins / metabolism
Immediate-Early Proteins*
Indoles / pharmacology
Protein-Tyrosine Kinases
Proto-Oncogene Proteins / biosynthesis,  genetics,  metabolism
Proto-Oncogene Proteins c-fos / metabolism
Proto-Oncogene Proteins c-myb
RNA, Messenger / metabolism
Recombinant Proteins / pharmacology
Signal Transduction / drug effects,  immunology*
Trans-Activators / biosynthesis,  genetics,  metabolism
Transcription Factors / metabolism
Tumor Cells, Cultured
Zinc Fingers
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Early Growth Response Protein 1; 0/Egr1 protein, mouse; 0/Hemoglobins; 0/Immediate-Early Proteins; 0/Indoles; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-myb; 0/RNA, Messenger; 0/Recombinant Proteins; 0/Trans-Activators; 0/Transcription Factors; 11096-26-7/Erythropoietin; 18172-33-3/cyclopiazonic acid; 7440-70-2/Calcium; EC Kinases; EC

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