DYRK3 dual-specificity kinase attenuates erythropoiesis during anemia.

Academic Article

Abstract

  • 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.
  • 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
  • Status

    Publication Date

  • December 26, 2008
  • Published In

    Keywords

  • Alleles
  • Anemia
  • Animals
  • Antigens, CD
  • Bone Marrow Transplantation
  • Cell Line
  • Erythropoiesis
  • Fluorouracil
  • Humans
  • K562 Cells
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Protein-Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Receptors, Transferrin
  • Transgenes
  • Digital Object Identifier (doi)

    Start Page

  • 36665
  • End Page

  • 36675
  • Volume

  • 283
  • Issue

  • 52