A novel role for STAT1 in regulating murine erythropoiesis: deletion of STAT1 results in overall reduction of erythroid progenitors and alters their distribution
A novel role for STAT1 in regulating murine erythropoiesis: deletion of STAT1 results in overall reduction of erythroid progenitors and alters their distribution
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DOI：
10.1182/blood-2003-09-3237
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发表时间：
2005-01-15
期刊：
影响因子：
20.3
通讯作者：
Barber, DL
中科院分区：
文献类型：
--
作者：
Halupa, A;Bailey, ML;Barber, DL
促红细胞生成素（EPO）激活许多不同的信号转导级联的参与其受体。小鼠中EPO、EPO受体（EPO-R）或JAK 2基因的缺失会导致胚胎因致命性贫血而死亡。EPO激活红系细胞系中的信号转导和转录激活因子1（STAT 1）、STAT 3和STAT 5a/B转录因子。研究集中在STAT 5作为EPO依赖性JAK 2活化的主要靶点。然而，STAT 5a/B（-/-）小鼠是存活的，在胚胎发生期间显示非致命性贫血，并且在成年红细胞生成中延迟分化。重要的是，EPO-R细胞质酪氨酸是体内活力的标志。有趣的是，STAT 1的磷酸化不需要细胞质酪氨酸。这导致我们检查STAT 1缺陷小鼠是否改变了红细胞生成。在STAT 1（-/-）小鼠中观察到红细胞生成的变化，骨髓源性红细胞集落形成单位（CFU-Es）减少，脾爆发形成单位（BFU-Es）和CFU-Es代偿性增加。两种类型的脾衍生细胞显示EPO高反应性。在STAT 1缺陷小鼠中观察到总CFU-Es减少1.6倍，而总BFU-Es相当。STAT 1缺陷型红系细胞的流式细胞术显示分化程度较低的表型，与早期成红细胞凋亡增加相关。来自苯肼致敏小鼠的STAT 1缺陷型成红细胞显示出增强的STAT 5a/B、Erk 1/2和蛋白激酶B（PK B）/Akt的磷酸化。这些结果说明STAT 1在红细胞生成的调控中起重要作用。(C)2005年，美国血液学会。
Erythropoietin (EPO) activates many distinct signal transduction cascades on engagement of its receptor. Deletion of the EPO, EPO receptor (EPO-R), or JAK2 genes in mice results in embryonic lethality due to a fatal anemia. EPO activates signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5a/b transcription factors in erythroid cell lines. Studies have focused on STAT5 as the primary target of EPO-dependent JAK2 activation. However, STAT5a/b(-/-) mice are viable, displaying a nonfatal anemia during embryogenesis, and delayed differentiation in adult erythropoiesis. Importantly, EPO-R cytoplasmic tyrosines are dispensable for viability in vivo. Interestingly, no cytoplasmic tyrosines are required for phosphorylation of STAT1. This led us to examine whether STAT1-deficient mice have altered erythropoiesis. A shift in erythropoiesis was observed in STAT1(-/-) mice, with reduced bone marrow-derived erythroid colony-forming units (CFU-Es) and a compensatory increase in splenic burst-forming units (BFU-Es) and CFU-Es. Both types of splenic-derived cells displayed EPO hyperresponsiveness. A 1.6-fold reduction in total CFU-Es was observed in STAT1-deficient mice, whereas total BFU-Es were comparable. Flow cytometry of STAT1-deficient erythroid cells revealed a less differentiated phenotype, associated with increased apoptosis of early erythroblasts. STAT1-deficient erythroblasts from phenylhydrazine-primed mice displayed enhanced phosphorylation of STAT5a/b, Erk1/2, and protein kinase B (PKB)/Akt. These results illustrate that STAT1 plays an important role in the regulation of erythropoiesis. (C) 2005 by The American Society of Hematology.