The repression of human differentiation-related gene NDRG2 expression by Myc via Miz-1-dependent interaction with the NDRG2 core promoter.
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.
Zhang
Jian
J
Institute of Molecular Biology and the State Key Laboratory of Cancer Biology, Fourth Military Medical University, 710032 Xi'an, China.
Li
Fuyang
F
Liu
Xinping
X
Shen
Lan
L
Liu
Junye
J
Su
Jin
J
Zhang
Wei
W
Deng
Yanchun
Y
Wang
Lifeng
L
Liu
Na
N
Han
Wei
W
Zhang
Jing
J
Ji
Shaoping
S
Yang
Angang
A
Han
Hua
H
Yao
Libo
L
D000818:Animals; D018938:Caco-2 Cells; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000737:chemistry*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D020298:U937 Cells
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; C466228:NDRG2 protein, human; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C107961:ZBTB17 protein, human