DYRK3 Dual-specificity Kinase Attenuates Erythropoiesis during Anemia

During anemia erythropoiesis is bolstered by several factors including KIT ligand, oncostatin-M, glucocorticoids, and erythropoietin. Less is understood concerning factors that limit this process. Experiments performed using dual-specificity tyrosine-regulated kinase-3 (DYRK3) knock-out and transgen...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-12, Vol.283 (52), p.36665-36675
Main Authors: Bogacheva, Olga, Bogachev, Oleg, Menon, Madhu, Dev, Arvind, Houde, Estelle, Valoret, Elizabeth I., Prosser, Haydn M., Creasy, Caretha L., Pickering, Susan J., Grau, Evelyn, Rance, Kim, Livi, George P., Karur, Vinit, Erickson-Miller, Connie L., Wojchowski, Don M.
Format: Article
Language:English
Subjects:
Alleles
Anemia - metabolism
Animals
Antigens, CD - metabolism
Bone Marrow Transplantation
Cell Line
Erythropoiesis
Fluorouracil - pharmacology
Humans
K562 Cells
Mice
Mice, Knockout
Mice, Transgenic
Molecular Basis of Cell and Developmental Biology
Protein-Serine-Threonine Kinases - physiology
Protein-Tyrosine Kinases - physiology
Receptors, Transferrin - metabolism
Transgenes
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Summary:During anemia erythropoiesis is bolstered by several factors including KIT ligand, oncostatin-M, glucocorticoids, and erythropoietin. Less is understood concerning factors that limit this process. Experiments performed using dual-specificity tyrosine-regulated kinase-3 (DYRK3) knock-out and transgenic mice reveal that erythropoiesis is attenuated selectively during anemia. DYRK3 is restricted to erythroid progenitor cells and testes. DYRK3-/- mice exhibited essentially normal hematological profiles at steady state and reproduced normally. In response to hemolytic anemia, however, reticulocyte production increased severalfold due to DYRK3 deficiency. During 5-fluorouracil-induced anemia, both reticulocyte and red cell formation in DYRK3-/- mice were elevated. In short term transplant experiments, DYRK3-/- progenitors also supported enhanced erythroblast formation, and erythropoietic advantages due to DYRK3-deficiency also were observed in 5-fluorouracil-treated mice expressing a compromised erythropoietin receptor EPOR-HM allele. As analyzed ex vivo, DYRK3-/- erythroblasts exhibited enhanced CD71posTer119pos cell formation and 3HdT incorporation. Transgenic pA2gata1-DYRK3 mice, in contrast, produced fewer reticulocytes during hemolytic anemia, and pA2gata1-DYRK3 progenitors were compromised in late pro-erythroblast formation ex vivo. Finally, as studied in erythroid K562 cells, DYRK3 proved to effectively inhibit NFAT (nuclear factor of activated T cells) transcriptional response pathways and to co-immunoprecipitate with NFATc3. Findings indicate that DYRK3 attenuates (and possibly apportions) red cell production selectively during anemia.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M807844200