JAK-STAT and AKT pathway-coupled genes in erythroid progenitor cells through ontogeny.
JAK-STAT and AKT pathway-coupled genes in erythroid progenitor cells through ontogeny.
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DOI：
10.1186/1479-5876-10-116
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发表时间：
2012-06-07
影响因子：
7.4
通讯作者：
Schechter AN
中科院分区：
文献类型：
--
作者：
Cokic VP;Bhattacharya B;Beleslin-Cokic BB;Noguchi CT;Puri RK;Schechter AN
据报道，磷脂酰肌醇3-激酶（PI 3 K）-AKT信号通路调节促红细胞生成素（EPO）诱导的早期红系祖细胞的存活、增殖和成熟。红系细胞增殖和存活也与JAK-STAT途径的激活有关。本研究的目的是观察EPO激活JAK-STAT和PI 3 K/AKT通路在造血CD 34+祖细胞向红系祖细胞发育中的作用，以及在个体发育过程中区分人红系祖细胞中的早期EPO靶基因。从胎儿和成人造血组织中分离的造血CD 34+祖细胞分化为红系祖细胞。我们使用微阵列分析来检测JAK-STAT和PI 3 K/AKT相关基因，以及这些人红系祖细胞中的广泛基因表达调节。在微阵列研究中，共有1755个基因在胎儿肝脏中表达，3844个在脐带血中表达，1770个在成人骨髓中表达，1325个基因在外周血来源的红系祖细胞中表达。红系祖细胞共有1011个共同基因。使用Influencity Pathways Analysis软件，我们评估了与血液系统发育、细胞生长和增殖相关的基因的网络途径。KITLG、EPO、GATA 1、PIM 1和STAT 3基因代表血液系统发育相关基因中的主要连接点。一些JAK-STAT信号通路相关基因在整个个体发育过程中稳定上调（PIM 1、SOCS 2、MYC、PTPN 11），而其他基因下调（PTPN 6、皮亚斯、SPRED 2）。此外，一些JAK-STAT通路相关基因仅在个体发育的某些阶段差异表达（STAT、GRB 2、CREBB）。除了PI 3 K-AKT信号通路中持续上调的（AKT 1、PPP 2CA、CHUK、NFKB 1）和下调的（FOXO 1、PDPK 1、PIK 3CG）基因之外，我们还观察到间歇性调节的基因表达（NFKBIA、YWHAH）。这一广泛的概述基因表达在红细胞生成揭示转录因子差异表达的个体发育的某些阶段。最后，我们的研究结果表明，EPO介导的红系祖细胞的增殖和存活主要通过调节JAK-STAT途径相关的STAT、GRB 2和PIK 3基因以及AKT途径偶联的NFKBIA和YWHAH基因来发生。
It has been reported that the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway regulates erythropoietin (EPO)-induced survival, proliferation, and maturation of early erythroid progenitors. Erythroid cell proliferation and survival have also been related to activation of the JAK-STAT pathway. The goal of this study was to observe the function of EPO activation of JAK-STAT and PI3K/AKT pathways in the development of erythroid progenitors from hematopoietic CD34+ progenitor cells, as well as to distinguish early EPO target genes in human erythroid progenitors during ontogeny. Hematopoietic CD34+ progenitor cells, isolated from fetal and adult hematopoietic tissues, were differentiated into erythroid progenitor cells. We have used microarray analysis to examine JAK-STAT and PI3K/AKT related genes, as well as broad gene expression modulation in these human erythroid progenitor cells. In microarray studies, a total of 1755 genes were expressed in fetal liver, 3844 in cord blood, 1770 in adult bone marrow, and 1325 genes in peripheral blood-derived erythroid progenitor cells. The erythroid progenitor cells shared 1011 common genes. Using the Ingenuity Pathways Analysis software, we evaluated the network pathways of genes linked to hematological system development, cellular growth and proliferation. The KITLG, EPO, GATA1, PIM1 and STAT3 genes represent the major connection points in the hematological system development linked genes. Some JAK-STAT signaling pathway-linked genes were steadily upregulated throughout ontogeny (PIM1, SOCS2, MYC, PTPN11), while others were downregulated (PTPN6, PIAS, SPRED2). In addition, some JAK-STAT pathway related genes are differentially expressed only in some stages of ontogeny (STATs, GRB2, CREBB). Beside the continuously upregulated (AKT1, PPP2CA, CHUK, NFKB1) and downregulated (FOXO1, PDPK1, PIK3CG) genes in the PI3K-AKT signaling pathway, we also observed intermittently regulated gene expression (NFKBIA, YWHAH). This broad overview of gene expression in erythropoiesis revealed transcription factors differentially expressed in some stages of ontogenesis. Finally, our results show that EPO-mediated proliferation and survival of erythroid progenitors occurs mainly through modulation of JAK-STAT pathway associated STATs, GRB2 and PIK3 genes, as well as AKT pathway-coupled NFKBIA and YWHAH genes.