DYRK3 Dual-specificity Kinase Attenuates Erythropoiesis during Anemia
DYRK3 Dual-specificity Kinase Attenuates Erythropoiesis during Anemia
复制标题
DOI：
10.1074/jbc.m807844200
复制
发表时间：
2008-12-26
影响因子：
4.8
通讯作者：
Wojchowski, Don M.
中科院分区：
文献类型：
--
作者：
Bogacheva, Olga;Bogachev, Oleg;Wojchowski, Don M.
在贫血期间，红细胞生成受到几种因素的支持，包括KIT配体、抑瘤素-M、糖皮质激素和促红细胞生成素。对限制这一进程的因素了解较少。使用双特异性酪氨酸调节激酶3（DYRK 3）敲除和转基因小鼠进行的实验表明，红细胞生成在贫血期间选择性减弱。DYRK 3仅限于红系祖细胞和睾丸。DYRK 3（-/-）小鼠在稳态时表现出基本正常的血液学特征，并正常繁殖。然而，在溶血性贫血的反应中，由于DYRK 3缺乏，网织红细胞的产生增加了几倍。在5-氟尿嘧啶诱导的贫血期间，DYRK 3（-/-）小鼠的网织红细胞和红细胞形成均升高。在短期移植实验中，DYRK 3（-/-）祖细胞也支持增强的成红细胞形成，并且在表达受损的促红细胞生成素受体EPOR-HM等位基因的5-氟尿嘧啶处理的小鼠中也观察到由于DYRK 3缺陷引起的红细胞生成优势。如离体分析，DYRK 3（-/-）成红细胞表现出增强的CD 71（pos）Ter 119（pos）细胞形成和3 HdT掺入。相比之下，转基因pA 2gata 1-DYRK 3小鼠在溶血性贫血期间产生较少的网织红细胞，并且pA 2gata 1-DYRK 3祖细胞在离体晚期原成红细胞形成中受损。最后，如在红系K562细胞中所研究的，DYRK 3被证明有效地抑制NFAT（活化T细胞的核因子）转录应答途径，并与NFATc 3共免疫沉淀。研究结果表明，DYRK 3在贫血期间选择性地减弱（并可能分配）红细胞生成。
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-fluorou-racil-treated mice expressing a compromised erythropoietin receptor EPOR-HM allele. As analyzed ex vivo, DYRK3(-/-) erythroblasts exhibited enhanced CD71(pos)Ter119(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 activatedT cells) transcriptional response pathways and to co-immunoprecipitate with NFATc3. Findings indicate that DYRK3 attenuates (and possibly apportions) red cell production selectively during anemia.