Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes
Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes
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DOI：
10.1073/pnas.94.6.2609
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发表时间：
1997-03-18
影响因子：
11.1
通讯作者：
Look, AT
中科院分区：
文献类型：
--
作者：
Ikushima, S;Inukai, T;Look, AT
E2A-HLF(肝脏白血病因子)癌蛋白是通过将E2A的反式激活结构域融合到HLF的bZIP结构域而在前B细胞中产生的，在白血病细胞转化中起抗凋亡转录因子的作用。当将E2A-HLF引入依赖IL-3的小鼠前B淋巴细胞中时，E2A-HLF可以阻止生长因子剥夺诱导的细胞凋亡。提示IL-3通过激活一个转录因子来介导细胞存活，该转录因子的活性可以被嵌合的癌蛋白组成地取代。我们认为4个bZIP转录因子是这种可能的IL-3调节因子的候选因子。在小鼠前B细胞系(Baf-3和Fl5.12)中，Nfl3/E4bp4的表达和结合活性受IL-3的调节，Northern印迹分析表明，Nfl3/E4bp4在缺乏IL-3的情况下，是一个‘延迟-早期’的IL-3反应基因，需要去新生蛋白的合成人NFIL3/E4BP4基因的增强表达促进了依赖IL-3的Pro-B细胞的存活，但不能促进其生长。我们的结果表明，NFIL3/E4BP4(由IL-3/腺病毒E4启动子结合蛋白调节的核因子)参与了一种独特的生长因子调节的信号通路，该信号通路负责早期B细胞前体细胞的存活，并且该信号通路被E2A-HLF改变导致儿童B系白血病。
The E2A-HLF (hepatic leukemia factor) oncoprotein, generated in pro-B lymphocytes by fusion of the trans-activation domain of E2A to the basic region/leucine zipper (bZIP) domain of HLF, functions as an anti-apoptotic transcription factor in leukemic cell transformation, When introduced into interleukin 3 (IL-3)-dependent mouse pro-B lymphocytes, E2A-HLF prevents apoptosis induced by growth factor deprivation, suggesting that IL-3 mediates cell survival through activation of a transcription factor whose activity can be constitutively replaced by the chimeric oncoprotein, We considered four bZIP transcription factors as candidates for this putative IL-3-regulated factor, each of which binds avidly to the DNA consensus sequence recognized by E2A-HLF and is related to the Caenorhabditis elegans CES-2 (cell death specification protein) neuron-specific mediator of cell death, The expression and binding activity of the Nfil3 protein (also called E4bp4), but not of Hlf, Dbp, or Tef, was found to be regulated by IL-3 in mouse pro-B cell lines (Baf-3 and FL5.12), Northern blot analysis showed that Nfl3/E4bp4 is regulated as a ''delayed-early'' IL-3-responsive gene, requiring de novo protein synthesis, In the absence of IL-3, enforced expression of the human NFIL3/E4BP4 cDNA promoted the survival but not the growth of IL-3-dependent pro-B cells, Our results implicate NFIL3/E4BP4 (nuclear factor regulated by IL-3/adenovirus E4 promoter binding protein) in a distinct growth factor-regulated signaling pathway that is responsible for the survival of early B-cell progenitors, and whose alteration by E2A-HLF leads to childhood B lineage leukemia.