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J. Biol. Chem., Vol. 283, Issue 52, 36665-36675, December 26, 2008

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DYRK3 Dual-specificity Kinase Attenuates Erythropoiesis during Anemia^*

Olga Bogacheva, Oleg Bogachev, Madhu Menon, Arvind Dev, Estelle Houde, Elizabeth I. Valoret, Haydn M. Prosser^¶, Caretha L. Creasy, Susan J. Pickering^¶, Evelyn Grau^¶, Kim Rance^¶, George P. Livi, Vinit Karur, Connie L. Erickson-Miller, and Don M. Wojchowski¹

From the Stem and Progenitor Cell Biology Program, Molecular Medicine Division, Maine Medical Center Research Institute, Scarborough, Maine 04074, GlaxoSmithKline, Collegeville, Pennsylvania 19426, and ^¶GlaxoSmithKline, CM195AW Harlow, United Kingdom

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 CD71^posTer119^pos 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.

Received for publication, October 10, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants RO1 DK059472 and P20 RR18789 (in particular its core facility resources; National Center for Research Resources). E. Valoret, H. Prosser, C. Creasy, S. Pickering, E. Grau, K. Rance, G. Livi, and C. Erickson-Miller are (or have been) employees of GlaxoSmithKline. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Stem and Progenitor Cell Biology Program, Maine Medical Center Research Institute, 81 Research Dr., Scarborough, ME 04074. Fax: 207-885-8179; E-mail: wojchd{at}mmc.org.

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