Human NM23/nucleoside diphosphate kinase regulates gene expression through DNA binding to nuclease-hypersensitive transcriptional elements
Human NM23/nucleoside diphosphate kinase regulates gene expression through DNA binding to nuclease-hypersensitive transcriptional elements
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DOI：
10.1023/a:1005541114029
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发表时间：
2000-06-01
影响因子：
3
通讯作者：
Kaetzel, DM
中科院分区：
文献类型：
--
作者：
Postel, EH;Berberich, SJ;Kaetzel, DM
NM 23-H2/NDP激酶B已被鉴定为序列特异性DNA结合蛋白，对c-MYC基因启动子的核酸酶超敏元件具有亲和力（Postel et al，1993）。Nm 23-H2通过相同元件在体外和体内激活c-MYC转录的能力证明了这种相互作用的生物学意义。突变分析已经确定Arg 34、Asn 69和Lys 135对于DNA结合是关键的，但对于NDP激酶反应不是必需的。然而，具有催化作用的重要His 118残基是序列特异性DNA结合所必需的，这表明序列特异性DNA识别和磷酰基转移是独立的性质。Nm 23-H2还具有位点特异性切割DNA的活性，涉及共价蛋白质-DNA复合物。Nm 23-H2以DNA序列依赖的方式识别其他靶基因进行激活，包括髓过氧化物酶、CD 11b和CCR 5，所有这些基因都参与骨髓特异性分化。此外，Nm 23-H1和Nm 23-H2均与血小板衍生生长因子PDGF-A基因启动子序列中的核酸酶超敏元件特异性结合，与正或负转录调控相关。这些数据支持了一个模型，其中NM 23/NDP激酶通过DNA结合和随后的结构转换来调节基因表达。
NM23-H2/NDP kinase B has been identified as a sequence-specific DNA-binding protein with affinity for a nuclease-hypersensitive element of the c-MYC gene promoter (Postel et al, 1993). The ability of Nm23-H2 to activate c-MYC transcription in vitro and in vivo via the same element demonstrates the biological significance of this interaction. Mutational analyses have identified Arg34, Asn69 and Lys135 as critical for DNA binding, but not required for the NDP kinase reaction. However, the catalytically important His118 residue is dispensible for sequence-specific DNA binding, suggesting that sequence-specific DNA recognition and phosphoryl transfer are independent properties. Nm23-H2 also has an activity that cleaves DNA site-specifically, involving a covalent protein-DNA complex. In a DNA sequence-dependent manner, Nm23-H2 recognizes additional target genes for activation, including myeloperoxidase, CD11b, and CCR5, all involved in myeloid-specific differentiation. Moreover, both NM23-H1 and Nm23-H2 bind to nuclease hypersensitive elements in the platelet-derived growth factor PDGF-A gene promoter sequence-specifically, correlating with either positive or negative transcriptional regulation. These data support a model in which NM23/NDP kinase modulates gene expression through DNA binding and subsequent structural transactions.