Repression of c-kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation
Repression of c-kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation
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DOI：
10.1128/mcb.25.15.6747-6759.2005
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发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
Kapur, R
中科院分区：
文献类型：
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作者：
Munugalavadla, V;Dore, LC;Kapur, R
干细胞因子（SCF）、促红细胞生成素（Epo）和GATA-1在红细胞发育中起重要作用。我们研究了这些蛋白在G1E细胞中的功能相互作用，G1E细胞是一种GATA-1（-）红母细胞系，以scf依赖的方式增殖，在GATA-1功能恢复后，经历GATA-1增殖阻滞和epo依赖的终末成熟。我们发现，scf诱导的细胞周期进程是通过激活Src激酶/c-Myc途径介导的。GATA-1活性的恢复诱导G细胞周期阻滞，同时抑制c-Kit及其下游效应物Vav1、Rac1和Akt。这些信号成分的持续表达在不同程度上抑制了gata -1诱导的细胞周期阻滞，但对gata -1调节的红细胞成熟标志物的表达没有影响。染色质免疫沉淀分析显示GATA-1在体内占据了一个明确的Kit基因调控元件，提示了基因抑制的直接机制。因此，GATA-1除了作为红系基因激活因子的既定功能外，还参与了一种独特的遗传程序，通过抑制c-Kit信号轴多种组分的表达来抑制细胞增殖。我们的研究结果揭示了造血发育中必要的转录和细胞因子信号组分之间分子串扰的一个新方面。
Stem cell factor (SCF), erythropoietin (Epo), and GATA-1 play an essential role(s) in erythroid development. We examined how these proteins interact functionally in G1E cells, a GATA-1(-) erythroblast line that proliferates in an SCF-dependent fashion and, upon restoration of GATA-I function, undergoes GATA-1 proliferation arrest and Epo-dependent terminal maturation. We show that SCF-induced cell cycle progression is mediated via activation of the Src kinase/c-Myc pathway. Restoration of GATA-1 activity induced G, cell cycle arrest coincident with repression of c-Kit and its downstream effectors Vav1, Rac1, and Akt. Sustained expression of each of these individual signaling components inhibited GATA-1-induced cell cycle arrest to various degrees but had no effects on the expression of GATA-1-regulated erythroid maturation markers. Chromatin immunoprecipitation analysis revealed that GATA-1 occupies a defined Kit gene regulatory element in vivo, suggesting a direct mechanism for gene repression. Hence, in addition to its well-established function as an activator of erythroid genes, GATA-1 also participates in a distinct genetic program that inhibits cell proliferation by repressing the expression of multiple components of the c-Kit signaling axis. Our findings reveal a novel aspect of molecular cross talk between essential transcriptional and cytokine signaling components of hematopoietic development.