NDRG1

NDRG1
Identifiers
AliasesNDRG1, CAP43, CMT4D, DRG-1, DRG1, GC4, HMSNL, NDR1, NMSL, PROXY1, RIT42, RTP, TARG1, TDD5, N-myc downstream regulated 1
External IDsMGI: 1341799 HomoloGene: 55953 GeneCards: NDRG1
Gene location (Human)
Chr.Chromosome 8 (human)[1]
Band8q24.22Start133,237,171 bp[1]
End133,302,022 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

10397

17988

Ensembl

ENSG00000104419

ENSMUSG00000005125

UniProt

Q92597

Q62433

RefSeq (mRNA)

NM_001135242
NM_001258432
NM_001258433
NM_006096

NM_008681

RefSeq (protein)

NP_001128714
NP_001245361
NP_001245362
NP_006087

NP_032707

Location (UCSC)Chr 8: 133.24 – 133.3 MbChr 15: 66.93 – 66.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Protein NDRG1 is a protein that in humans is encoded by the NDRG1 gene.[5][6][7][8]

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.[8] It has been reported that NDRG1 localizes to the endosomes and is a Rab4a effector involved in vesicular recycling.[9]

As reviewed by Fang et al.,[10] 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.

Functions in cancer and metastasis

As reviewed by Kovacevic et al.,[11] 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.

Functions in DNA repair and aging

In one of its functions at a molecular level, NDRG1 binds and stabilizes methyltransferases, chiefly O-6-methylguanine-DNA methyltransferase (MGMT),[12] a DNA repair protein. Thus, higher expression of NDRG1 can promote MGMT protein stability and activity. Dominick et al.[13] 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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000104419 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000005125 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ van Belzen N, Dinjens WN, Diesveld MP, Groen NA, van der Made AC, Nozawa Y, Vlietstra R, Trapman J, Bosman FT (Sep 1997). "A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms". Lab Invest. 77 (1): 85–92. PMID 9251681.
  6. ↑ Kokame K, Kato H, Miyata T (Jan 1997). "Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes". J Biol Chem. 271 (47): 29659–65. doi:10.1074/jbc.271.47.29659. PMID 8939898.
  7. ↑ Zhang J, Chen S, Zhang W, Zhang J, Liu X, Shi H, Che H, Wang W, Li F, Yao L (Jun 2008). "Human differentiation-related gene NDRG1 is a Myc downstream-regulated gene that is repressed by Myc on the core promoter region". Gene. 417 (1–2): 5–12. doi:10.1016/j.gene.2008.03.002. PMID 18455888.
  8. 1 2 "Entrez Gene: NDRG1 N-myc downstream regulated gene 1".
  9. ↑ Kachhap SK, Faith D, Qian DZ, et al. (2007). Heisenberg C, ed. "The N-Myc down regulated Gene1 (NDRG1) Is a Rab4a effector involved in vesicular recycling of E-cadherin". PLoS ONE. 2 (9): e844. doi:10.1371/journal.pone.0000844. PMC 1952073. PMID 17786215.
  10. ↑ Fang BA, Kovačević Ž, Park KC, Kalinowski DS, Jansson PJ, Lane DJ, Sahni S, Richardson DR (2014). "Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy". Biochim. Biophys. Acta. 1845 (1): 1–19. doi:10.1016/j.bbcan.2013.11.002. PMID 24269900.
  11. ↑ Kovacevic Z, Menezes SV, Sahni S, Kalinowski DS, Bae DH, Lane DJ, Richardson DR (2016). "The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways". J. Biol. Chem. 291 (3): 1029–52. doi:10.1074/jbc.M115.689653. PMC 4714189. PMID 26534963.
  12. ↑ Weiler M, Blaes J, Pusch S, Sahm F, Czabanka M, Luger S, Bunse L, Solecki G, Eichwald V, Jugold M, Hodecker S, Osswald M, Meisner C, Hielscher T, Rübmann P, Pfenning PN, Ronellenfitsch M, Kempf T, Schnölzer M, Abdollahi A, Lang F, Bendszus M, von Deimling A, Winkler F, Weller M, Vajkoczy P, Platten M, Wick W (2014). "mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy". Proc. Natl. Acad. Sci. U.S.A. 111 (1): 409–14. doi:10.1073/pnas.1314469111. PMC 3890826. PMID 24367102.
  13. ↑ Dominick G, Bowman J, Li X, Miller RA, Garcia GG (2017). "mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice". Aging Cell. 16 (1): 52–60. doi:10.1111/acel.12525. PMC 5242303. PMID 27618784.

Further reading

  • Kovacevic Z, Richardson DR (2007). "The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer". Carcinogenesis. 27 (12): 2355–66. doi:10.1093/carcin/bgl146. PMID 16920733.
  • Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
  • Kalaydjieva L, Hallmayer J, Chandler D, et al. (1996). "Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24". Nat. Genet. 14 (2): 214–7. doi:10.1038/ng1096-214. PMID 8841199.
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
  • Zhou D, Salnikow K, Costa M (1998). "Cap43, a novel gene specifically induced by Ni2+ compounds". Cancer Res. 58 (10): 2182–9. PMID 9605764.
  • Kurdistani SK, Arizti P, Reimer CL, et al. (1998). "Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage". Cancer Res. 58 (19): 4439–44. PMID 9766676.
  • Piquemal D, Joulia D, Balaguer P, et al. (1999). "Differential expression of the RTP/Drg1/Ndr1 gene product in proliferating and growth arrested cells". Biochim. Biophys. Acta. 1450 (3): 364–73. doi:10.1016/S0167-4889(99)00056-7. PMID 10395947.
  • Guan RJ, Ford HL, Fu Y, et al. (2000). "Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer". Cancer Res. 60 (3): 749–55. PMID 10676663.
  • Kalaydjieva L, Gresham D, Gooding R, et al. (2000). "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom". Am. J. Hum. Genet. 67 (1): 47–58. doi:10.1086/302978. PMC 1287101. PMID 10831399.
  • Park H, Adams MA, Lachat P, et al. (2000). "Hypoxia induces the expression of a 43-kDa protein (PROXY-1) in normal and malignant cells". Biochem. Biophys. Res. Commun. 276 (1): 321–8. doi:10.1006/bbrc.2000.3475. PMID 11006124.
  • Rutherford MN, Bayly GR, Matthews BP, et al. (2001). "The leukemogenic transcription factor E2a-Pbx1 induces expression of the putative N-myc and p53 target gene NDRG1 in Ba/F3 cells". Leukemia. 15 (3): 362–70. doi:10.1038/sj.leu.2402059. PMID 11237058.
  • Zhou RH, Kokame K, Tsukamoto Y, et al. (2001). "Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart". Genomics. 73 (1): 86–97. doi:10.1006/geno.2000.6496. PMID 11352569.
  • Qu X, Zhai Y, Wei H, et al. (2002). "Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family". Mol. Cell. Biochem. 229 (1–2): 35–44. doi:10.1023/A:1017934810825. PMID 11936845.
  • Cangul H, Salnikow K, Yee H, et al. (2002). "Enhanced expression of a novel protein in human cancer cells: a potential aid to cancer diagnosis". Cell Biol. Toxicol. 18 (2): 87–96. doi:10.1023/A:1015376032736. PMID 12046693.
  • Cangul H, Salnikow K, Yee H, et al. (2002). "Enhanced overexpression of an HIF-1/hypoxia-related protein in cancer cells". Environ. Health Perspect. 110 Suppl 5: 783–8. doi:10.1289/ehp.02110s5783. PMC 1241245. PMID 12429530.
  • Lachat P, Shaw P, Gebhard S, et al. (2003). "Expression of NDRG1, a differentiation-related gene, in human tissues". Histochem. Cell Biol. 118 (5): 399–408. doi:10.1007/s00418-002-0460-9. PMID 12432451.
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
  • Segawa T, Nau ME, Xu LL, et al. (2003). "Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells". Oncogene. 21 (57): 8749–58. doi:10.1038/sj.onc.1205992. PMID 12483528.
  • Symes AJ, Eilertsen M, Millar M, et al. (2013). "Quantitative Analysis of BTF3, HINT1, NDRG1 and ODC1 Protein Over-Expression in Human Prostate Cancer Tissue". PLoS ONE. 8 (12): e84295. doi:10.1371/journal.pone.0084295. PMC 3874000. PMID 24386364.
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