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.
Bogacheva
Olga
O
Stem and Progenitor Cell Biology Program, Molecular Medicine Division, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA.
Bogachev
Oleg
O
Menon
Madhu
M
Dev
Arvind
A
Houde
Estelle
E
Valoret
Elizabeth I
EI
Prosser
Haydn M
HM
Creasy
Caretha L
CL
Pickering
Susan J
SJ
Grau
Evelyn
E
Rance
Kim
K
Livi
George P
GP
Karur
Vinit
V
Erickson-Miller
Connie L
CL
Wojchowski
Don M
DM
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