Inhibitory effects of homeodomain-interacting protein kinase 2 on the aorta-gonad-mesonephros hematopoiesis
Inhibitory effects of homeodomain-interacting protein kinase 2 on the aorta-gonad-mesonephros hematopoiesis
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DOI：
10.1016/j.yexcr.2006.09.022
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发表时间：
2007-01-01
影响因子：
3.7
通讯作者：
Taga, Tetsuya
中科院分区：
文献类型：
--
作者：
Ohtsu, Naoki;Nobuhisa, Ikuo;Taga, Tetsuya
连续性造血开始于小鼠胚胎的性腺-中肾（AGM）区域。我们以前的研究表明，STAT 3，一个gp 130下游转录因子，是AGM造血所必需的，同源域相互作用蛋白激酶2（HIPK 2）磷酸化STAT 3的丝氨酸-727。HIPK 2是已知参与转录抑制和细胞凋亡的丝氨酸/苏氨酸激酶。在本研究中，我们研究了HIPK 2在小鼠胚胎造血中的作用。HIPK 2转录本在胚胎造血组织如小鼠AGM区和胎肝中发现。在培养的AGM细胞中，在贴壁细胞中检测到HIPK 2蛋白。通过将野生型和突变体HIPK 2构建体引入AGM培养物中进行HIPK 2的功能分析。在AGM培养物中，HIPK 2的强制表达抑制了CD 45（+）造血细胞的产生。这种抑制需要HIPK 2的激酶结构域和核定位信号，但激酶活性是不稳定的。HIPK 2过表达AGM衍生的非贴壁细胞在基质细胞培养中不形成鹅卵石样集落。此外，HIPK 2在AGM培养物中的过表达阻碍了CD 45（低）c-Kit（+）细胞的扩增，其表现出未成熟造血祖细胞表型。这些数据表明，HIPK 2在小鼠胚胎AGM造血中起负调控作用。(c)2006年爱思唯尔公司All rights reserved.
Definitive hematopoiesis starts in the aorta-gonad-mesonephros (AGM) region of the mouse embryo. Our previous studies revealed that STAT3, a gp130 downstream transcription factor, is required for AGM hematopoiesis and that homeodomain-interacting protein kinase 2 (HIPK2) phosphorylates serine-727 of STAT3. HIPK2 is a serine/threonine kinase known to be involved in transcriptional repression and apoptosis. In the present study, we examined the role of HIPK2 in hematopoiesis in mouse embryo. HIPK2 transcripts were found in fetal hematopoietic tissues such as the mouse AGM region and fetal liver. In cultured AGM cells, HIPK2 protein was detected in adherent cells. Functional analyses of HIPK2 were carried out by introducing wild-type and mutant HIPK2 constructs into AGM cultures. Production of CD45(+) hematopoietic cells was suppressed by forced expression of HIPK2 in AGM cultures. This suppression required the kinase domain and nuclear localization signals of HIPK2, but the kinase activity was dispensable. HIPK2-overexpressing AGM-derived nonadherent cells did not form cobblestone-like colonies in cultures with stromal cells. Furthermore, overexpression of HIPK2 in AGM cultures impeded the expansion of CD45(low)c-Kit(+) cells, which exhibit the immature hematopoietic progenitor phenotype. These data indicate that HIPK2 plays a negative regulatory role in AGM hematopoiesis in the mouse embryo. (c) 2006 Elsevier Inc. All rights reserved.