The repression of human differentiation-related gene NDRG2 expression by Myc via miz-1-dependent interaction with the NDRG2 core promoter
The repression of human differentiation-related gene NDRG2 expression by Myc via miz-1-dependent interaction with the NDRG2 core promoter
复制标题
Myc 通过 miz-1 依赖的与 NDRG2 核心启动子的相互作用抑制人类分化相关基因 NDRG2 的表达
DOI：
10.1074/jbc.m605820200
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发表时间：
2006-12-22
影响因子：
4.8
通讯作者：
Yao, Libo
中科院分区：
文献类型：
--
作者：
Zhang, Jian;Li, Fuyang;Yao, Libo
N-myc下游调节基因1（ndrg 1）在N-myc基因敲除小鼠中通过一种未知的调节机制高度表达。NDRG 2基因是人类NDRG基因家族的成员之一，编码与NDRG 1高度同源的蛋白质。然而，由于小鼠ndrg 2和ndrg 3不受Myc的影响，因此不确定人NDRG 2的表达是否受Myc的调控。在本研究中，我们提供了新的证据表明，人NDRG 2的表达下调Myc通过转录抑制。随着分化细胞中Myc表达的减少，观察到高水平的NDRG 2，而在血清刺激后Myc表达增加后，显示低水平的NDRG 2。c-Myc的异位表达显著降低了细胞Ndrg 2蛋白和mRNA水平。我们进一步确定了NDRG 2的核心启动子区，这是所需的Myc阻遏NDRG 2转录，我们验证了Myc与核心启动子区在体外和体内的相互作用。此外，c-Myc介导的NDRG 2抑制需要与Miz-1相关，并可能需要其他表观遗传因子（如组蛋白脱乙酰酶）的募集。Myc对NDRG 2基因表达的调控作用提示NDRG 2在细胞分化中的调控作用。
The N-myc downstream-regulated gene 1 (ndrg1) is highly expressed in N-myc knock-out mice through an unknown regulatory mechanism. As one member of the human NDRG gene family, NDRG2 encodes a protein highly homologous to Ndrg1. However, it is uncertain whether the expression of human NDRG2 is regulated by Myc because mouse ndrg2 and -3 are not affected by Myc. In this study, we provide the novel evidence that the expression of human NDRG2 is down-regulated by Myc via transcriptional repression. A high level of NDRG2 was observed as Myc expression was reduced in differentiated cells, whereas a low level of NDRG2 was shown following increased Myc expression upon serum stimulation. The ectopic expression of c-Myc dramatically reduces the cellular Ndrg2 protein and mRNA level. We further identified the core promoter region of NDRG2 that is required for Myc repression on NDRG2 transcription, and we verified the interaction of Myc with the core promoter region both in vitro and in vivo. Moreover, the c-Myc-mediated repression of NDRG2 requires association with Miz-1, and possibly the recruitment of other epigenetic factors, such as histone deacetylases, to the promoter. The regulatory function of Myc on NDRG2 gene expression implicated the role of the Ndrg2 in regulating cell differentiation.