Expression and regulation of NFAT (nuclear factors of activated T cells) in human CD34+ cells: down-regulation upon myeloid differentiation.
The calcineurin-dependent, cyclosporin A (CsA)-sensitive transcription factor nuclear factor of activated T cells (NFAT) represents a group of proteins, which is well-characterized as a central regulatory element of cytokine expression in activated T cells. In contrast, little is known about the expression or function of NFAT family members in myeloid cells; moreover, it is unclear whether they are expressed by hematopoietic stem/progenitor cells. Here, we show that NFATc2 (NFAT1) is expressed at high levels in CD34+ cells and megakaryocytes but not in cells committed to the neutrophilic, monocytic, or erythroid lineages. Cytokine-induced in vitro differentiation of CD34+ cells into neutrophil granulocytes results in the rapid suppression of NFATc2 RNA and protein. NFATc2 dephosphorylation/rephosphorylation as well as nuclear/cytoplasmic translocation in CD34+ cells follow the same calcineurin-dependent pattern as in T lymphocytes, suggesting that NFATc2 activation in these cells is equally sensitive to inhibition with CsA. Finally, in vitro proliferation, but not differentiation, of CD34+ cells cultured in the presence of fms-like tyrosine kinase 3 ligand (FLT3L), stem cell factor, granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-3, and G-CSF is profoundly inhibited by treatment with CsA in a dose-dependent manner. These results suggest a novel and unexpected role for members of the NFAT transcription factor family in the hematopoietic system.
Kiani
Alexander
A
Department of Medicine I, University Hospital Carl Gustav Carus, University of Dresden Technical Center, Germany. alexander.kiani@uniklinikum-dresden.de
Habermann
Ivonne
I
Haase
Michael
M
Feldmann
Silvia
S
Boxberger
Sabine
S
Sanchez-Fernandez
Maria A
MA
Thiede
Christian
C
Bornhäuser
Martin
M
Ehninger
Gerhard
G
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000276:immunology*; D019703:Calcineurin / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008533:Megakaryocytes / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018952:Antigens, CD34; D016207:Cytokines; D004268:DNA-Binding Proteins; D006133:Growth Substances; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016572:Cyclosporine; D019703:Calcineurin