NDRG4

Official Full Name

NDRG family member 4

Organism

Homo sapiens

GeneID

65009

Background

This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein that is required for cell cycle progression and survival in primary astrocytes and may be involved in the regulation of mitogenic signalling in vascular smooth muscles cells. Alternative splicing results in multiple transcripts encoding different isoforms.[provided by RefSeq, Jun 2011]

Synonyms

BDM1; SMAP8; SMAP-8;

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Detailed Information

N-myc downstream regulated gene 4 (NDRG4) is a new member of the NDRG family of genes discovered in recent years, and its expression is regulated by various factors. Studies have shown that the NDRG4 gene is closely related to the development of heart and brain and the maintenance of certain malignant tumors. As a candidate tumor suppressor gene, NDRG4 is expected to contribute to the study of tumor prevention and treatment.

The Basic Structure and Characteristics of the NDRG4 Gene

The NDRG4 gene and the other three genes NDRG1, NDEG2, and NDRG3 together form the NDRG gene family. The amino acid sequence of the encoded protein is 57%-65% homologous. The NDRG1 gene and the NDRG3 gene are highly homologous, while the NDRG2 gene and the NDRG4 gene belongs to another homologous subtype. Unlike ubiquitous expression of NDRG1 protein, NDRG2 protein is highly expressed in adult skeletal muscle and brain tissue, and NDRG3 protein is mainly expressed in brain and testis. The NDRG4 protein is highly expressed in the heart and brain tissue and is involved in cell differentiation and synapse formation. NDRG4-B protein is expressed only in brain tissue, while NDRG4-H protein is expressed in both brain and heart tissues, and NDRG4-Bvar protein is expressed as a minor product. Moreover, the expression level of NDRG4 protein is more abundant in the adult heart and brain tissue, but is significantly lower in the brain tissue of patients with Alzheimer's disease. The mRNA transcription levels of the three NDRG4 subtypes are regulated by alternative splicing and may also be involved in promoter selection.

Figure 1. Proposed pathway model for NDRG4 involved in myoblast differentiation. (Zhu, M., et al. 2017)

Expression Regulation of NDRG4 Gene

Tbx2 is a member of the transcription factor T-box family of genes and plays an important role in the development of embryonic cardiac heart. The Tbx2 gene may cross-regulate transcription with other T-box family genes, and together inhibit the production of the NDRG family of NDRG2, NDRG4 proteins and corresponding adhesion factors, thereby regulating cardiac development. In addition, studies have shown that reducing the activity of the Tbx5 gene in the heart can down-regulate the expression of the NDRG4 gene. Conversely, the high expression of the Tbx5 gene due to Tbx20 gene knockdown can up-regulate NDRG4 gene expression, suggesting that the NDRG4 gene may be a downstream regulatory target of Tbx5.

NDRG4 and Tumor

The cellular and biochemical functions of the NDRG4 gene in astrocytes and glioblastoma multiforme (GBM) cells were studied. The results showed that the expression of the NDRG4 gene was up-regulated in GBM and was required for the survival of astrocytes and GBM cell lines in vitro as well as GBM xenograft cells. Overexpression of NDRG4 does not affect cell survival. Conversely, NDRG4 knockout causes cell arrest in G1 phase leading to apoptosis. The initial G1 arrest is associated with decreased expression of the cell cycle protein D1 and increased expression of the p27Kip1 gene, and subsequent apoptosis is associated with decreased expression of the sex-linked inhibitor of apoptosis protein (XlAP) and survivin. In addition, NDRG4 gene knockdown also reduced the tumorigenic capacity of GBM cell lines after implantation into the head of a nude mouse. In conclusion, these results indicate that the NDRG4 gene plays an important role in maintaining GBM cell cycle and cell survival. Therefore, it is different from the tumor suppressor effect of the homologous gene NDRG2 in astrocytes and GBM cells, suggesting that the tumor suppressor effect of NDRG4 gene also has tumor cell source specificity.

References:

Zhu, M. , Zheng, R. , Guo, Y. , Zhang, Y. , & Zuo, B. . (2017). Ndrg4 promotes myogenesis via akt/creb activation. Oncotarget, 8(60), 101720-101734.
Zhang, Z. , She, J. , Yang, J. , Bu, X. , Ji, G. , & Zhu, S. , et al. (2018). Ndrg4 in gastric cancer determines tumor cell proliferation and clinical outcome. Molecular Carcinogenesis.
Hongna, L. U., Huang, S., Zhang, X., Wang, D., Zhang, X., & Yuan, X., et al. (2014). Dna methylation analysis of sfrp2, gata4/5, ndrg4 and vim for the detection of colorectal cancer in fecal dna. , 8(4), 1751-1756.

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