NDRG1

Official Full Name

N-myc downstream regulated 1

Organism

Homo sapiens

GeneID

10397

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 involved in stress responses, hormone responses, cell growth, and differentiation. The encoded protein is necessary for p53-mediated caspase activation and apoptosis. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4D, and expression of this gene may be a prognostic indicator for several types of cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

Synonyms

GC4; RTP; DRG1; NDR1; NMSL; TDD5; CAP43; CMT4D; DRG-1; HMSNL; RIT42; TARG1; PROXY1;

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Detailed Information

N-myc downstream regulated gene 1 (NDRG1), also known as differentiation related gene 1 (DRG-1), calcium activated protein 43 (Cap43), response induced by stress 42 (Rit42), reducing agent and tunicamycin responsive protein (RTP), belonging to the NDRG (N-myc downstream regulated gene) family, named after the proto-oncogenes MYCN and MYC inhibit their expression. NDRG1 is involved in epithelial cell differentiation. It is regulated by androgen and is associated with the pathogenesis of peripheral nervous system disease HMSN-Lom (Hereditary Motor and Sensory Neuropathy-Lom). Currently, NDRG1 has received extensive attention due to its metastatic inhibition in a variety of tumors.

Figure 1. Schematic summarizing the WNT signaling pathway and the effect of the metastasis suppressor NDRG1 on β-catenin distribution and function. (Jin, R., et al. 2014)

Expression of NDRG1

NDRG1 mRNA is ubiquitously expressed in human tissues and organs, especially in prostate, kidney and ovary. NDRG1 is mainly expressed in epithelial cells. Its subcellular localization mainly includes cytoplasm, cell membrane, nucleus, mitochondrial inner membrane and cytoskeleton. Studies have found that different NDRG1 subcellular localization may influence its role in tumor progression. In colorectal cancer, nuclear NDRG1 expression was significantly higher than that of normal intestinal mucosal cells, and no nuclear expression was found in normal intestinal mucosa cells, whereas patients with lymph node metastasis had higher expression of cytoplasm and membrane NDRG1 than non-metastatic patients. It is suggested that NDRG1 may participate in lymph node metastasis through translocation expression. Since the NDRG1 amino acid sequence does not have a nuclear localization signal, it is thought that its intracellular localization may be related to the interaction of other proteins such as Hsp70 and Hsp90 or autophosphorylation status.

Regulation Mechanism of NDRG1

The study found that NDRG1 expression is regulated by a variety of factors, including MYCN, histone acetylation, hypoxia, intracellular iron levels, and intracellular calcium influx. The 5' promoter region of NDRG1 contains a CpG island, and its methylation affects NDRG1 expression. Studies have found that in breast cancer, hypermethylation of the NDRG1 promoter region can cause silencing of its gene expression and is associated with tumor metastasis and lymph node invasion. Recently, studies have also shown that in prostate cancer, the methylation of the CpG island in the NDRG1 promoter region down-regulates its expression and promotes tumor cell proliferation and invasion.

Some researchers have studied the effect of protein level regulation on the expression of NDRG1, and found that NDRG1 has post-translational modifications caused by small ubiquitin⁃like modifier (SUMO), and is preferentially modified by SUMO⁃2. It mainly binds to the Lys14 site. Subcellular localization of NDRG1 modified by SUMO⁃2 was not affected, but its stability was significantly reduced. After overexpression of SUMO⁃2 modified NDRG1, p21 expression was down-regulated, which in turn affected cell cycle. Studies have found that iron chelators can up-regulate NDRG1 expression to produce a selective and potent anti-tumor effect. In addition, recent studies have found that valproic acid (VPA), a clinically useful histone deacetylase inhibitor, can also exert an anti-tumor effect by up-regulating NDRG1 expression.

Mechanism of Action of NDRG1

When NDRG1 is overexpressed, it stabilizes intercellular adhesions induced by transforming growth factor-β(TGF-β) by membrane-bound E-cadherin and β⁃catenin, and inhibits epithelial mesenchymal transition (EMT). It was found that NDRG1 inhibits the phosphorylation of β⁃catenin in Ser33/37 and Thr41 by increasing the expression of GRK⁃3β binding protein FRAT1, and inhibits the nuclear translocation of β⁃catenin by inhibiting PAK4, increasing β⁃catenin in quality. The level of non-phosphorylation of the membrane. This blocks the WNT⁃β⁃catenin pathway, thereby inhibiting EMT. It has also been found that up-regulation of NDRG1 reverses the EMT process, restores epithelial phenotypic marker expression, and restores the sensitivity of lung cancer cells to cisplatin and inhibits invasion and metastasis of lung cancer cells.

References:

Li, Y., Pan, P., Qiao, P., & Liu, R. (2015). Downregulation of n-myc downstream regulated gene 1 caused by the methylation of cpg islands of ndrg1 promoter promotes proliferation and invasion of prostate cancer cells. International Journal of Oncology, 47(3), 1001-8.
Lee, J. E. , & Kim, J. H. . (2015). Sumo modification regulates the protein stability of ndrg1. Biochemical and Biophysical Research Communications, 459(1), 161-165.
Jin, R. , Liu, W. , Menezes, S. , Yue, F. , Zheng, M. , & Kovacevic, Z. , et al. (2014). The metastasis suppressor ndrg1 modulates the phosphorylation and nuclear translocation of ?-catenin through mechanisms involving frat1 and pak4. Journal of Cell Science, 127(14), 3116-3130.

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