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. Mutations in this gene have been reported to be causative the autosomal-recessive version of Charcot-Marie-Tooth disease known as CMT4D. It has been reported that NDRG1 localizes to the endosomes and is a Rab4a effector involved in vesicular recycling.
As reviewed by Fang et al., NDRG1 is involved in embryogenesis and development, cell growth and differentiation, lipid biosynthesis and myelination, stress responses, immunity, DNA repair and cell adhesion among other functions. NDRG1 is localised in the cytoplasm, nucleus and mitochondrion, at probabilities of 47.8%, 26.1% and 8.7%, respectively. In response to DNA damage NDRG1 translocates from the cytoplasm to the nucleus, where it may inhibit cell growth and promote DNA repair mechanisms. It is suggested that NDRG1 acts as a stress response gene or potentially as a transcription factor.
As reviewed by Kovacevic et al., NDRG1 is a potent, iron-regulated growth and metastasis suppressor that was found to be negatively correlated with cancer progression in a number of tumors, including prostate, pancreatic, breast, and colon cancers. NDRG1 has marked anti-oncogenic activity, being associated with decreased cell proliferation, migration, invasion, and angiogenesis. The molecular functions of NDRG1 affect numerous signaling pathways that regulate cancer cell proliferation, invasion, angiogenesis, and migration. Specifically, NDRG1 inhibits the oncogenic RAS, c-Src, phosphatidylinositol 3-kinase (PI3K), WNT, ROCK1/pMLC2, and nuclear factor-light chain enhancer of activated B cell (NF-B) pathways, while promoting expression of key tumor-suppressive molecules including phosphatase and tensin homolog, E-cadherin, and mothers against decapentaplegic homolog 4 (SMAD4). Through its effects on E-cadherin and beta-catenin, which form the adherens junction and promote cell adhesion, NDRG1 also inhibits the epithelial to mesenchymal transition, an initial key step in metastasis.
In one of its functions at a molecular level, NDRG1 binds and stabilizes methyltransferases, chiefly O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein. Thus, higher expression of NDRG1 can promote MGMT protein stability and activity. Dominick et al. showed NDRG1 and MGMT protein expression was increased by 2-fold to 3-fold for each of three strains of mice (Snell, GHKRO, and PAPPA-KO) with increased longevity. These authors strongly suggest a link between the increase in the MGMT DNA repair pathway and a delay in the aging process in these mouse strains. This is consistent with the DNA damage theory of aging.
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