The inositol phosphatase SHIP-1 is negatively regulated by Fli-1 and its loss accelerates leukemogenesis
The inositol phosphatase SHIP-1 is negatively regulated by Fli-1 and its loss accelerates leukemogenesis
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肌醇磷酸酶 SHIP-1 受到 Fli-1 的负向调节，其缺失会加速白血病的发生。
DOI：
10.1182/blood-2009-10-250217
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发表时间：
2010-07-22
期刊：
影响因子：
20.3
通讯作者：
Ben-David, Yaacov
中科院分区：
文献类型：
--
作者：
Lakhanpal, Gurpreet K.;Vecchiarelli-Federico, Laura M.;Ben-David, Yaacov
Ets转录因子Fli-1的激活是Friend鼠白血病病毒（F-MuLV）诱导的红白血病的关键遗传事件。Fli-1过表达通过激活Ras途径导致促红细胞生成素依赖性成红细胞增殖、增强的存活和终末分化抑制。然而，Fli-1激活该信号转导通路的机制尚未确定。含Src同源2（SH2）结构域的肌醇-5-磷酸酶-1（SHIP-1）的下调与促红细胞生成素刺激的红白血病细胞相关，并与转化细胞增殖增加相关。在这项研究中，我们已经表明，F-MuLV感染的SHIP-1基因敲除小鼠显示加速红白血病进展。此外，RNA干扰（RNAi）介导的红白血病细胞中SHIP-1的抑制激活磷脂酰肌醇3-激酶（PI 3-K）和细胞外信号调节激酶/丝裂原活化蛋白激酶（ERK/MAPK）途径，阻断红细胞分化，加速促红细胞生成素诱导的增殖，并导致PI 3-K依赖性Fli-1上调。染色质免疫沉淀和荧光素酶测定证实，Fli-1直接结合到一个Ets DNA结合位点内的SHIP-1启动子和抑制SHIP-1转录。这些数据提供了证据表明，SHIP-1是Fli-1的直接靶点，SHIP-1和Fli-1在负反馈回路中相互调节，并且Fli-1对SHIP-1的抑制在F-MuLV转化红系祖细胞中起重要作用。
The activation of Fli-1, an Ets transcription factor, is the critical genetic event in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia. Fli-1 overexpression leads to erythropoietin-dependent erythroblast proliferation, enhanced survival, and inhibition of terminal differentiation, through activation of the Ras pathway. However, the mechanism by which Fli-1 activates this signal transduction pathway has yet to be identified. Down-regulation of the Src homology 2 (SH2) domain-containing inositol-5-phosphatase-1 (SHIP-1) is associated with erythropoietin-stimulated erythroleukemic cells and correlates with increased proliferation of transformed cells. In this study, we have shown that F-MuLV-infected SHIP-1 knockout mice display accelerated erythroleukemia progression. In addition, RNA interference (RNAi)-mediated suppression of SHIP-1 in erythroleukemia cells activates the phosphatidylinositol 3-kinase (PI 3-K) and extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathways, blocks erythroid differentiation, accelerates erythropoietin-induced proliferation, and leads to PI 3-K-dependent Fli-1 up-regulation. Chromatin immunoprecipitation and luciferase assays confirmed that Fli-1 binds directly to an Ets DNA binding site within the SHIP-1 promoter and suppresses SHIP-1 transcription. These data provide evidence to suggest that SHIP-1 is a direct Fli-1 target, SHIP-1 and Fli-1 regulate each other in a negative feedback loop, and the suppression of SHIP-1 by Fli-1 plays an important role in the transformation of erythroid progenitors by F-MuLV.