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首页> 外文期刊>Molecular and Cellular Biology >DNA-binding specificity and trans-activating potential of the leukemia-associated E2A-hepatic leukemia factor fusion protein.
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DNA-binding specificity and trans-activating potential of the leukemia-associated E2A-hepatic leukemia factor fusion protein.

机译：与白血病相关的E2A-肝白血病因子融合蛋白的DNA结合特异性和反式激活潜力。

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Hybrid transcription factors, resulting from gene fusions in the wake of chromosomal translocations, have been implicated in leukemogenesis, but their precise contributions to oncogenic conversion remain unclear. The E2A-HLF fusion gene, formed by a t(17;19)(q22;p13) in childhood pro-B-cell acute lymphoid leukemia, encodes a hybrid protein that contains the trans-activation domain of E2A (E12/E47) linked to the bZIP DNA-binding and dimerization domain of hepatic leukemia factor (HLF). Here we report that both HLF and E2A-HLF bind to a 10-bp consensus sequence, 5'-GTTACGTAAT-3', with a core dyad-symmetric motif characteristic of the bZIP scissors-grip model of DNA binding. A probe containing this sequence bound chimeric E2A-HLF proteins in nuclear extracts of a leukemic cell line (UOC-B1) containing the t(17;19), as demonstrated by complexes supershifted with antibodies specific for amino-terminal epitopes of E2A or carboxyl-terminal eptiopes of HLF. E2A-HLF functioned as a potent trans activator of reporter gene expression from a plasmid that contained the consensus DNA-binding sequence. Interestingly, wild-type HLF was restricted in its capacity to act as a trans activator, functioning in human fetal kidney cells but not HepG2 hepatocarcinoma cells or NIH 3T3 mouse fibroblasts. The ability of the E2A-HLF hybrid protein to bind DNA in a sequence-specific manner and trans activate the expression of artificial reporter genes suggests that it could subvert transcriptional programs that normally control the growth, differentiation, and survival of lymphoid progenitor cells.
机译：由染色体易位后的基因融合产生的杂合转录因子已与白血病的发生有关，但它们对致癌转化的确切作用尚不清楚。 E2A-HLF融合基因由儿童前B细胞急性淋巴白血病中的at（17; 19）（q22; p13）形成，编码包含E2A反式激活结构域（E12 / E47）的杂合蛋白肝癌因子（HLF）的bZIP DNA结合和二聚化结构域。在这里我们报告HLF和E2A-HLF都绑定到10 bp的共有序列5'-GTTACGTAAT-3'，具有DNA结合的bZIP剪刀抓握模型的核心二重对称基序。含有该序列的探针结合了含有t（17; 19）的白血病细胞系（UOC-B1）的核提取物中的嵌合E2A-HLF蛋白，这是由对E2A或羧基的氨基末端表位具有特异性的抗体超位移的复合物所证明的-HLF的末端表位。 E2A-HLF从包含共有DNA结合序列的质粒中起报告基因表达的有效反式激活子的作用。有趣的是，野生型HLF在其反式激活剂中的功能受到限制，它在人胎儿肾细胞中起作用，但在HepG2肝癌细胞或NIH 3T3小鼠成纤维细胞中没有作用。 E2A-HLF杂合蛋白以序列特异性方式结合DNA并反激活人工报告基因表达的能力表明，它可以破坏通常控制淋巴祖细胞生长，分化和存活的转录程序。

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