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 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.
Stem and Progenitor Cell Biology Program, Molecular Medicine Division, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA.
Olga
O
Bogacheva
Oleg
O
Bogachev
Madhu
M
Menon
Arvind
A
Dev
Estelle
E
Houde
Elizabeth I
EI
Valoret
Haydn M
HM
Prosser
Caretha L
CL
Creasy
Susan J
SJ
Pickering
Evelyn
E
Grau
Kim
K
Rance
George P
GP
Livi
Vinit
V
Karur
Connie L
CL
Erickson-Miller
Don M
DM
Wojchowski
D000483:Alleles; D000740:Anemia / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002460:Cell Line; D004920:Erythropoiesis; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011990:Receptors, Transferrin / Q000378:metabolism; D019076:Transgenes
D015703:Antigens, CD; C068126:CD71 antigen; D011990:Receptors, Transferrin; C408131:DYRK3 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D005472:Fluorouracil