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NDRG1 (N-myc downstream regulated 1)

Written2009-10Michel Wissing, Nadine Rosmus, Michael Carducci, Sushant Kachhap
Johns Hopkins Medical Institute, The Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, CRB-I 162E, Baltimore, MD 21231, USA
Updated2015-10Maria A Nagai, Flavia R Mangone
Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo; Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of São Paulo, Av. Dr. Arnaldo, 251, CEP 01296-000, São Paulo, Brazil.

(Note : for Links provided by Atlas : click)

Identity

Alias_namesCAP43
Alias_symbol (synonym)DRG1
RTP
TDD5
NDR1
Other aliasCMT4D
DRG-1
GC4
HMSNL
NMSL
PROXY1
RIT42
Rit42
TARG1
HGNC (Hugo) NDRG1
LocusID (NCBI) 10397
Atlas_Id 41512
Location 8q24.22  [Link to chromosome band 8q24]
Location_base_pair Starts at 133237171 and ends at 133297304 bp from pter ( according to hg19-Feb_2009)  [Mapping NDRG1.png]
Fusion genes
(updated 2016)
C18orf25 (18q21.1) / NDRG1 (8q24.22)DDX24 (14q32.12) / NDRG1 (8q24.22)ERG (21q22.2) / NDRG1 (8q24.22)
NDRG1 (8q24.22) / ATP2A2 (12q24.11)NDRG1 (8q24.22) / CSTF2 (Xq22.1)NDRG1 (8q24.22) / ERG (21q22.2)
NDRG1 (8q24.22) / FOXP1 (3p13)NDRG1 (8q24.22) / LPAR1 (9q31.3)NDRG1 (8q24.22) / NDRG1 (8q24.22)
NDRG1 (8q24.22) / NEAT1 (11q13.1)NDRG1 (8q24.22) / PLEKHA5 (12p12.3)NDRG1 (8q24.22) / SLC25A3 (12q23.1)
NDRG1 (8q24.22) / SNW1 (14q24.3)NDRG1 (8q24.22) / ST3GAL1 (8q24.22)NEDD8-MDP1 (14q12) / NDRG1 (8q24.22)
PSENEN (19q13.12) / NDRG1 (8q24.22)PTGS1 (9q33.2) / NDRG1 (8q24.22)PTMS (12p13.31) / NDRG1 (8q24.22)
PVT1 (8q24.21) / NDRG1 (8q24.22)

DNA/RNA

 
  DNA size: 64.85Kb; mRNA size: 3123 bp (NM_006096.3); 16 exons.
Description NDRG1 was mapped to human chromosome 8q24 and consists of 64,851 basepairs, starting at basepair 133,237,171 and ending at basepair 133,302,022 from the p-terminus. It is a member of the NDRG family, consisting of NDRG1, NDRG2, NDRG3 and NDRG4 (of which three isoforms exist: NDRG-4B, NDRG-4Bvar and NDRG-4H), which are part of the alpha/beta hydrolase superfamily. The members of the NDRG family share 52-65% amino acid identity. The promoter region of all NDRG family members contain CpG islands (Bandyopadhyay et al., 2004). NDRG1 downregulation has been correlated with DNA hypermethylation in some types of human cancer and cell lineages such as prostate, breast and gastric and also in sclerosis-affected brains (Li et al , 2015; Huynh et al , 2014; Han et al , 2013; Chang et al , 2013).
Transcription The DNA of NDRG1 contains 16 exons, see diagram for details about their location. The DNA encodes a 3.0 kb mRNA with a coding region of 1.185 kb.

Protein

Note Molecular weight: 42,835 KDa, 394aa (NP_001128714.1)
 
Description NDRG1 is a ~ 43 kD protein, composed of 394 amino acids, with an iso-electric point of 5.7. NDRG1 has an alpha/beta hydrolase-fold motif, however, without a hydrolytic catalytic activity required to function as hydrolases. The protein has no apparent transmembrane domain (Kokame et al, 1996). NDRG1 has several phosphorylation sites, among others a phosphopantetheine attachment site, protein kinase C, casein kinase II, tyrosine kinase, protein kinase A and calmodulin kinase II. Experimental studies have demonstrated that NRDG1 is phosphorylated by Protein Kinase A and Calmodulin kinase II, and is also a physiological substrate of SGK1 and GSK-3-beta kinase (Figure 1), a kinase involved in cancer growth and progression. he C-terminal region of NDRG1 (residues 339-369) possess three tandem repeats of 10 amino acids, GTRSRSHTSE, (Zhou et al, 2001) not present in the other members of the NDRG family. These repeats with a histidine located between serine and threonine residues act as a binding site for metal ions such as nickel and copper (Zoroddu et al, 2001) (Figure 1). NDRG1 is also target for SOMOylation, preferentially by SUMO-2 isoform, in an acceptor site in residue Lys14. This modification does not affect the subcellular localization of NDRG1 but the protein stability by increasing protein ubiquitination and degradation (Lee and Kim, 2015) (Figure 1).
 
  Figure 1 - Schematic representation of the modular structure of NDRG1 - NDRG1 is target of phosphorylation by PKA, PKC, CaMKII. Residues that are phosphorylated by SGK1 and GSK3 and target of SUMOylation by SUMO-2 are indicated. PKA: Protein Kinase A; PKC: Protein Kinase C; CaMKII: Calmodulin Kinase II; SGK1: serum and glucocorticoid-regulated kinase 1; GSK3- Glycogen synthase kinase 3; SUMO-2: Small Ubiquitin-Like Modifier 2 .
Expression NDRG1 is relatively ubiquitously expressed in normal human cells, and especially highly expressed in prostate, brain, kidney, placenta, ovarian, thyroid, testicular and intestinal cells. NDRG1 is mostly found in epithelial cells. NDRG1 expression has been shown to be controlled by promoter CpG island methylation and histone acetylation. In addition, several transcription factors have been implicated in the NDRG1 transcriptional regulation, including homo- and heterodimers of MYC, MYCN and MAX, androgen receptor (AR), TP53, and HIF1A.
Localisation NDRG1 is primarily a cytoplasmic protein. 47.8% of the NDRG1 is expressed in the cytosol, 26.1% in the nucleus (such as in prostate epithelial cells), and 8.7% in the mitochondria (such as in proximal tubule cells in the kidney). NDRG1 is also found in the adherens junctions. Additionally, in intestinal and lactating breast epithelia NDRG1 is located in the plasma membrane. NDRG1 can also be found in vacuoles, the peroxisome, early and recycling endosomes, and the cytoskeleton.
Function The exact function of NDRG1 is still unclear. The expression of all members of the NDRG1 family has been correlated with different stages of differentiation from birth to adulthood. NDRG1 has been reported to be involved in different biological processes as cell proliferation, differentiation, development, and stress response (Ellen et al., 2008).
There is evidence that NDRG1 expression peaks in the G1 and G2/M phases, and is lowest in the S phase, and that this regulation might be associated to cell growth and differentiation. In fact, NDRG1 has been shown to up regulates p21/WAF1 (Kovacevic et al, 2013) and NDRG1 expression is downregulated under conditions of increased cell proliferation. NDRG1 is also described as a microtubule-associated protein, which may play an important role in maintaining spindle structure during cell division.
The function of NDRG1 may be controlled at least in part by phosphorylation. Phosphorylation at residues Ser330 and Thr346 by SGK-1 is involved in NF-κB signaling pathway inhibition probably affecting cell survival (Murakami et al, 2010).
NDRG1 has also been identified as a stress response gene, upregulated by homocysteine and hypoxia. Hif-1-dependent and independent mechanisms have been implicated in NDRG1 induction. It is also controlled by AP-1 transcription factors. When exposed to stress, for example hypoxia, NDRG1 may play a cytoprotective role in normal healthy cells.
NDRG1 is upregulated during colon epithelial cell differentiation. It is positively or negatively regulated by hormones such as androgens and estradiol, respectively. Small molecules such as N-hydroxy-N'-phenol-octane-1,8-diotic acid diamide, calcium ionophores like BAPTA, metal ions such as Nickel and Cobalt, iron chelators and differentiating agents like retinoic acid induce NDRG1 expression. Additionally, NDRG1 is induced during cellular DNA damage and endoplasmic reticulum stress.
In the Schwann cells, NDRG1 is essential for myelin sheath maintenance. Hence, NDRG1 is a multifunctional protein with roles that may be tissue- and/or cell-type specific.
It has been found to be a Rab4a effector protein that recruits to the recycling endosomes in the Trans Golgi network by binding to the lipid phosphotidylinositol 4-phosphate (PI4P), where it plays a role in the recycling of E-cadherin. NDRG1 also interacts with HSP70. NDRG1 co-localizes with APO A-I and A-II, and may be involved in lipid transport.
Evidences obtained from global gene expression analysis of breast cell lines with high endogenous NDRG1 expression transduced with shRNA against NDRG1 suggested an involvement of NDRG1 with vesicle transport (Askautrud et al, 2014).
In cancer, NDRG1 is reported to be a metastasis suppressor gene which is downregulated in prostate, colon and breast cancers. However, up-regulation of NDRG1 has also been associated to poor prognosis in breast, renal, hepatocellular, and colorectal cancer, suggesting that it may play different role depending on cellular type and context (Nagai. et al, 2001; Nishie et al, 2001; Chua et al, 2007; Strzelczyk et al, 2009).
Signaling Pathways
The widespread localization of NDRG1 might impact its involvement with diverse signaling pathways. It has been demonstrated that NDRG1 interacts directly with NF-κB, PI3K/AKT/ mTOR, Ras/Raf/MEK/ERK, TGF-β; and Wnt/β-catenin pathways independently with each pathway or by promoting a crosstalk between them (Sun J et al, 2013). The nuclear translocation of the DNA binding subunit of NFκB, NFKB1 (p50), complexed with RelA is reduced by NDRG1 as a consequence of the induced degradation of IKBKB (IKK&beta), subunit of the IκB kinase complex (Hosoi et al, 2009). The effect of NDRG1 on NFκB signaling pathway seems to be dependent of phosphorylation at residues Ser330 and Thr346 by SGK1 (Murakami et al, 2010).
The expression of PTEN, a tumor suppressor gene described as inactivated in diverse types of human cancers, is also involved in tumor metastasis suppression and it was demonstrated that PTEN targets NDRG1 in a PI3K dependent manner. It was demonstrated that up regulation of PTEN increase the level of NDRG1 and the inhibition of PTEN by shRNA also inhibits NDRG1 expression. This blockage is reverted when the cells are treated with phospho-Akt inhibitor, evidencing a dependency of PI3K/AKT pathway (Bandyopadhyay, et al, 2004). In prostate epithelial cells NDRG1 expression increased phosphorylation of tumorigenic AKT, ERK1/2 and SMAD2L and decreased PTEN levels (Dixon et al, 2013). NDRG1 also has been associated to up-regulation of SMAD4 that is responsible for nuclear translocation of effector SMADs upon TGFβ receptor activation. Up regulation of SMAD4 has a dual role both in TGFβ signaling, intermediating the induction of p21, and also blocking Ras signaling pathway by inhibiting ERK phosphorylation (Kovacevic et al, 2013) (Figure 2).
 
  Figure 2 - Modulators and Biological functions of NDRG1 - NDRG1 is involved in a variety of signaling pathways been positively or negatively regulated. As a consequence, diverse biological processes are modulated. HIF1, hypoxia inducible factor 1; c-Myc, v-myc avian myelocytomatosis viral oncogene homolog; AR, Androgen receptor; E2, -17β-estradiol; AP1, activator protein-1, p53, tumor suppressor protein p53; PTEN, phosphatase and tensin homolog; VEGF, vascular endothelial growth factor; CXCL8 (IL-8), interleukin-8; p21, cyclin-dependent kinase inhibitor 1A; NFKB, nuclear factor of kappa light polypeptide gene enhancer in B-cells; pERK, extracellular signal-regulated kinases; SMAD4, SMAD family member 4; PI3K, phosphatidylinositol 3-kinase; AKT, v-akt murine thymoma viral oncogene homolog.
Homology NDRG1 amino acid sequence is 53% homologous to NDRG2, 62% to NDRG3, 62% to NDRG4, and 94% homologous to the mouse analog, Ndr-1 (also known as TDD5). NDRG1 homologs have been found in Helianthus, Caenorhabditis, Xenopus and Drosophilia.

Implicated in

Note
  
Entity Prostatic adenocarcinoma, breast cancer, colorectal cancer, renal cell carcinoma, bladder carcinoma, pancreatic cancer, hepatocellular carcinoma, thyroid carcinoma, and glioma.
Prognosis The association of NDRG1 and prognosis of cancer patients is controversial. Some studies have found that downregulation of NDRG1 in cancer worsens the prognosis of cancer. There is an inverse relationship in the levels of NDRG1 expression and the Gleason grade of the tumor in prostate cancer. A high PTEN (a tumor suppressor which positively regulates NDRG1) and NDRG1 expression improves survival rates in patients with breast and prostate cancer. In patients with colorectal cancer, the 2 year survival rate for patients with high NDRG1-expression was 82.4%, while for patients with a low NDRG1-expression it was only 69.6%. In pancreatic cancer patients, the median survival time for patients with high NDRG1-expression was 24.7 months, while the median survival time for patients with low NDRG1-expression was only 10.9 months. High expression of NDRG1 in colon tumors was found to correlate with increased resistance to irinotecan.
On the other hand, the positivity for NDRG1 expression was associated to poor disease free and overall survival of breast cancer patients. Also, the positivity of NDRG1 protein observed in breast cancer patients is associated with important clinic-pathological variables for disease outcome, such as large tumor size, advanced clinical stage, lymph node metastasis and high tumor grade (SBR) (Nagai. et al, 2001). An inverse correlation of NDGR1 and ER and/or PR status has also been described (Leth-Larsen et al, 2009; Fotovati et al, 2006).
Increase in protein level has been observed in thyroid carcinomas. Thyroid lesions showed higher immunohistochemical staining of NDRG1 as compared to normal and benign thyroid lesions that was correlated with more advanced tumor stages. This increase of NDRG1 expression was correlated with more advanced TNM stage (stages III and IV) and an AMES high-risk category in patients with thyroid carcinoma (Gerhard et al, 2010).
In hepatocellular carcinoma upregulation of NDRG1 has been correlated with tumour aggressiveness and poor patients' survival (Chua et al., 2007).
NDRG1 has been associated to breast cancer cells differentiation both in vitro and in vivo. Endogenous expression of NDRG1 was associated to differentiation status of breast cancer cell lines and when these cells were treated with the cellular differentiation inducer, sodium butyrate, a concomitant increase of NDRG1 and β-casein, a marker of breast cell differentiation, expression was observed. Moreover, the blockage of NDRG1 expression was also followed by β-casein reduction. Also in breast cancer samples a close relationship between NDRG1 and β-casein was found (Fotovati et al, 2011).
NDRG1 has been considered as a possible biomarker to guide the decision of treatment of WHO grade II glioma patients. Time to reintervention, assessed for patients without immediate postoperative genotoxic treatment and known progression and survival status, was significantly longer in the high NDRG1 group. This group of tumors presented growth delay improving progression free surviva (Blaes et al, 2014).
Oncogenesis NDRG1 aberrant expression has been reported in different types of cancer, indication that it plays an important role in the tumorigenic process. However, both tumor suppressive and oncogenic functions have been demonstrated for NDRG1, suggesting an impact of its tissue specific function.
An inverse relationship exists between NDRG1 and the oncogenes N-myc and c-myc, suggesting that members of the MYC family suppress expression of NDRG1. Experimental evidence exist that both N-myc and c-myc downregulate NDRG1 gene expression by directly binding to NDRG1 promoter.
NDRG1 is downregulated in colon, breast, prostate and pancreatic neoplasms, by c-myc and N-myc transcription factors. In cancer cells, NDRG1 expression is consistent through all phases in the cell cycle, instead of the biphasic expression in normal cells. PTEN expression is positively related to NDRG1 expression. NDRG1 is induced in cancer cells by histone deacetylase inhibitors and DNA methyl transferase inhibitors indicating that NDRG1 is regulated by chromatin modulation and DNA methylation.
Although NDRG1 has been reported to be downregulated in a variety of cancers, it has been shown to be upregulated in hepatic, pancreatic and kidney cancers. Induction of NDRG1 in these tumors is speculated to be in response to tumor stress or hypoxia and NDRG1 is proposed as a marker of tumor hypoxia. However, in pancreatic cancer, cellular differentiation and not hypoxia was demonstrated to be the determining factor for NDRG1 expression. In renal cancer, induction of NDRG1 in the tumor tissue was restricted to infiltrating macrophages and not cancer cells.
NDRG1 is suggested to be an early target for p53. Loss of p53 expression in cancer is suggested to reduce NDRG1 expression. However, p53 knockout mice show expression of NDRG1, suggesting that there are other mechanisms regulating NDRG1 levels.
NDRG1 expression plays a role in vitro in primary tumor growth in prostate, breast, and bladder cancer: a higher expression of NDRG1 lowers the proliferation rates of these cancers. In pancreatic and bladder cancer cells, this reduction was proven in vivo: in pancreatic cells it was suggested that the reduced proliferation was caused by NDRG1 by modulating tumor stroma and angiogenesis. NDRG1 can recruit onto the recycling endosome in the Trans-Golgi network by binding to phosphotidylinositol 4-phosphate. There, NDRG1 may be involved in the transport of various cargo back to the cells' surface. At the molecular level, NDRG1 may stabilize the E-cadherin molecule by recycling it back to the cells' surface, thereby preventing tumor invasion.
  
  
Entity Hereditary Motor and Sensory Neuropathy-Lom (HMSNL) / Charcot-Marie-Tooth Disease (CMT 4D)
Note Autosomal recessive mutation in NDRG1 is responsible for HMSNL/CMT 4D inheritance. The Gypsy founder mutation, homozygote R148X, also called homozygote C564t is a causative mutation. In patients with CMT disease, apart from the R148X mutation, another disease-causing mutation was identified, namely IVS8-1G>A (g.2290787G>A), which results in skipping of exon 9. The homozygote phenotype of this mutation was very closely related to the phenotype of HMSNL patients.
An increased copy number (chr8: 134265065-134271319) covering NDRG's1 exons 6-8 was detected in CMT individual. Heterozygous individuals for the locus duplication are carriers for the disease while the homozygous are affected. Also, the presence of this duplication leads to a nonsense mutation at codon 223 affecting gene function (Okamoto et al, 2014).
Disease A hereditary autosomal recessive disease, caused by demyelination of peripheral nerves. It is the most common form of demyelinating Charcot-Marie-Tooth disease in the Roma population.
Prognosis Severe disability in adulthood. It begins consistently in the first decade of life with a gait disorder, followed by upper limb weakness in the second decade and, in most subjects, by deafness setting in in the third decade of life. Sensory loss affecting all modalities is present; both this and the motor involvement predominating distally in the limbs. Skeletal deformity, particularly foot deformities, are frequent.
  
  
Entity Atherosclerosis
Note Patients with HMSNL were found to have a high total cholesterol: HDL-C ratio.
Disease Atherosclerosis is an important factor for the development of cardiovascular diseases, like myocardial infarction and angina pectoris. NDRG1 contributes to HDL-C (high-density lipoprotein-cholesterol) levels most likely by its phosphopantetheine-binding domain interacting with the high-density lipoproteins apolipoprotein A-I and A-II
  

Bibliography

Phosphorylation of RTP, an ER stress-responsive cytoplasmic protein
Agarwala KL, Kokame K, Kato H, Miyata T
Biochem Biophys Res Commun 2000 Jun 16;272(3):641-7
PMID 10860807
 
Global gene expression analysis reveals a link between NDRG1 and vesicle transport
Askautrud HA, Gjernes E, Gunnes G, Sletten M, Ross DT, Børresen-Dale AL, Iversen N, Tranulis MA, Frengen E
PLoS One 2014 Jan 31;9(1):e87268
PMID 24498060
 
PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer
Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Tsukada T, Miura K, Takano Y, Saito K, Commes T, Piquemal D, Watabe M, Gross S, Wang Y, Huggenvik J, Watabe K
Cancer Res 2004 Nov 1;64(21):7655-60
PMID 15520163
 
NDRG1 prognosticates the natural course of disease in WHO grade II glioma
Blaes J, Weiler M, Sahm F, Hentschel B, Osswald M, Czabanka M, Thomé CM, Schliesser MG, Pusch S, Luger S, Winkler F, Radbruch A, Jugold M, Simon M, Steinbach JP, Schackert G, Tatagiba M, Westphal M, Tonn JC, Gramatzki D, Pietsch T, Hartmann C, Glimm H, Vajkoczy P, von Deimling A, Platten M, Weller M, Wick W
J Neurooncol 2014 Mar;117(1):25-32
PMID 24395351
 
Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers
Cangul H
BMC Genet 2004 Sep 2;5:27
PMID 15341671
 
Association of NDRG1 gene promoter methylation with reduced NDRG1 expression in gastric cancer cells and tissue specimens
Chang X, Zhang S, Ma J, Li Z, Zhi Y, Chen J, Lu Y, Dai D
Cell Biochem Biophys 2013 May;66(1):93-101
PMID 23099645
 
N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury.
Chen B, Nelson DM, Sadovsky Y.
J Biol Chem. 2006 Feb 3;281(5):2764-72. Epub 2005 Nov 28.
PMID 16314423
 
Overexpression of NDRG1 is an indicator of poor prognosis in hepatocellular carcinoma
Chua MS, Sun H, Cheung ST, Mason V, Higgins J, Ross DT, Fan ST, So S
Mod Pathol 2007 Jan;20(1):76-83
PMID 17170744
 
A microarray-based gastric carcinoma prewarning system.
Cui DX, Zhang L, Yan XJ, Zhang LX, Xu JR, Guo YH, Jin GQ, Gomez G, Li D, Zhao JR, Han FC, Zhang J, Hu JL, Fan DM, Gao HJ.
World J Gastroenterol. 2005 Mar 7;11(9):1273-82.
PMID 15761963
 
Dp44mT targets the AKT, TGF- and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells
Dixon KM, Lui GY, Kovacevic Z, Zhang D, Yao M, Chen Z, Dong Q, Assinder SJ, Richardson DR
Br J Cancer 2013 Feb 5;108(2):409-19
PMID 23287991
 
NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states.
Ellen TP, Ke Q, Zhang P, Costa M.
Carcinogenesis. 2008 Jan;29(1):2-8. Epub 2007 Oct 4. (REVIEW)
PMID 17916902
 
17Beta-estradiol induces down-regulation of Cap43/NDRG1/Drg-1, a putative differentiation-related and metastasis suppressor gene, in human breast cancer cells
Fotovati A, Fujii T, Yamaguchi M, Kage M, Shirouzu K, Oie S, Basaki Y, Ono M, Yamana H, Kuwano M
Clin Cancer Res 2006 May 15;12(10):3010-8
PMID 16707596
 
NDRG1 protein overexpression in malignant thyroid neoplasms
Gerhard R, Nonogaki S, Fregnani JH, Soares FA, Nagai MA
Clinics (Sao Paulo) 2010 Jun;65(8):757-62
PMID 20835551
 
Regulation of the differentiation-related gene Drg-1 during mouse skin carcinogenesis.
Gomez-Casero E, Navarro M, Rodriguez-Puebla ML, Larcher F, Paramio JM, Conti CJ, Jorcano JL.
Mol Carcinog. 2001 Oct;32(2):100-9.
PMID 11746822
 
Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer.
Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB.
Cancer Res. 2000 Feb 1;60(3):749-55.
PMID 10676663
 
Aberrant NDRG1 methylation associated with its decreased expression and clinicopathological significance in breast cancer
Han LL, Hou L, Zhou MJ, Ma ZL, Lin DL, Wu L, Ge YL
J Biomed Sci 2013 Jul 30;20:52
PMID 23899187
 
N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of kappaB kinase beta expression
Hosoi F, Izumi H, Kawahara A, Murakami Y, Kinoshita H, Kage M, Nishio K, Kohno K, Kuwano M, Ono M
Cancer Res 2009 Jun 15;69(12):4983-91
PMID 19491262
 
NDRG1 interacts with APO A-I and A-II and is a functional candidate for the HDL-C QTL on 8q24.
Hunter M, Angelicheva D, Tournev I, Ingley E, Chan DC, Watts GF, Kremensky I, Kalaydjieva L.
Biochem Biophys Res Commun. 2005 Jul 15;332(4):982-92.
PMID 15922294
 
Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease.
Hunter M, Bernard R, Freitas E, Boyer A, Morar B, Martins IJ, Tournev I, Jordanova A, Guergelcheva V, Ishpekova B, Kremensky I, Nicholson G, Schlotter B, Lochmuller H, Voit T, Colomer J, Thomas PK, Levy N, Kalaydjieva L.
Hum Mutat. 2003 Aug;22(2):129-35.
PMID 12872253
 
Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains
Huynh JL, Garg P, Thin TH, Yoo S, Dutta R, Trapp BD, Haroutunian V, Zhu J, Donovan MJ, Sharp AJ, Casaccia P
Nat Neurosci 2014 Jan;17(1):121-30
PMID 24270187
 
The N-Myc down regulated Gene1 (NDRG1) Is a Rab4a effector involved in vesicular recycling of E-cadherin.
Kachhap SK, Faith D, Qian DZ, Shabbeer S, Galloway NL, Pili R, Denmeade SR, DeMarzo AM, Carducci MA.
PLoS One. 2007 Sep 5;2(9):e844.
PMID 17786215
 
N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom.
Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, Blechschmidt K, Angelicheva D, Chandler D, Worsley P, Rosenthal A, King RH, Thomas PK.
Am J Hum Genet. 2000 Jul;67(1):47-58. Epub 2000 May 30.
PMID 10831399
 
Function of Drg1/Rit42 in p53-dependent mitotic spindle checkpoint.
Kim KT, Ongusaha PP, Hong YK, Kurdistani SK, Nakamura M, Lu KP, Lee SW.
J Biol Chem. 2004 Sep 10;279(37):38597-602. Epub 2004 Jul 9.
PMID 15247272
 
Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis
Kokame K, Kato H, Miyata T
GRP78/BiP and novel genes J Biol Chem
PMID 8939898
 
The iron-regulated metastasis suppressor NDRG1 targets NEDD4L, PTEN, and SMAD4 and inhibits the PI3K and Ras signaling pathways
Kovacevic Z, Chikhani S, Lui GY, Sivagurunathan S, Richardson DR
Antioxid Redox Signal 2013 Mar 10;18(8):874-87
PMID 22462691
 
A transmitting tissue- and pollen-expressed protein from sunflower with sequence similarity to the human RTP protein.
Krauter-Canham R, Bronner R, Evrard JL, Hahne G, Friedt W, Steinmetz A.
Plant Sci. 1997; 129: 191-202.
 
Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage.
Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW.
Cancer Res. 1998 Oct 1;58(19):4439-44.
PMID 9766676
 
Expression of NDRG1, a differentiation-related gene, in human tissues.
Lachat P, Shaw P, Gebhard S, van Belzen N, Chaubert P, Bosman FT.
Histochem Cell Biol. 2002 Nov;118(5):399-408. Epub 2002 Oct 10.
PMID 12432451
 
SUMO modification regulates the protein stability of NDRG1
Lee JE, Kim JH
Biochem Biophys Res Commun 2015 Mar 27;459(1):161-5
PMID 25712528
 
Metastasis-related plasma membrane proteins of human breast cancer cells identified by comparative quantitative mass spectrometry
Leth-Larsen R, Lund R, Hansen HV, Laenkholm AV, Tarin D, Jensen ON, Ditzel HJ
Mol Cell Proteomics 2009 Jun;8(6):1436-49
PMID 19321434
 
The growth-inhibitory Ndrg1 gene is a Myc negative target in human neuroblastomas and other cell types with overexpressed N- or c-myc.
Li J, Kretzner L.
Mol Cell Biochem. 2003 Aug;250(1-2):91-105.
PMID 12962147
 
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
Li Y, Pan P, Qiao P, Liu R
Int J Oncol 2015 Sep;47(3):1001-8
PMID 26202882
 
Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis.
Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, Kage M, Aoyagi S, Kinoshita H, Kuwano M.
Cancer Res. 2006 Jun 15;66(12):6233-42.
PMID 16778198
 
Downregulation of Cap43 gene by von Hippel-Lindau tumor suppressor protein in human renal cancer cells.
Masuda K, Ono M, Okamoto M, Morikawa W, Otsubo M, Migita T, Tsuneyoshi M, Okuda H, Shuin T, Naito S, Kuwano M.
Int J Cancer. 2003 Jul 20;105(6):803-10.
PMID 12767066
 
Identification of sites subjected to serine/threonine phosphorylation by SGK1 affecting N-myc downstream-regulated gene 1 (NDRG1)/Cap43-dependent suppression of angiogenic CXC chemokine expression in human pancreatic cancer cells
Murakami Y, Hosoi F, Izumi H, Maruyama Y, Ureshino H, Watari K, Kohno K, Kuwano M, Ono M
Biochem Biophys Res Commun 2010 May 28;396(2):376-81
PMID 20416281
 
Prognostic value of NDRG1 and SPARC protein expression in breast cancer patients
Nagai MA, Gerhard R, Fregnani JH, Nonogaki S, Rierger RB, Netto MM, Soares FA
Breast Cancer Res Treat 2011 Feb;126(1):1-14
PMID 20369286
 
High expression of the Cap43 gene in infiltrating macrophages of human renal cell carcinomas
Nishie A, Masuda K, Otsubo M, Migita T, Tsuneyoshi M, Kohno K, Shuin T, Naito S, Ono M, Kuwano M
Clin Cancer Res 2001 Jul;7(7):2145-51
PMID 11448934
 
Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D
Okamoto Y, Goksungur MT, Pehlivan D, Beck CR, Gonzaga-Jauregui C, Muzny DM, Atik MM, Carvalho CM, Matur Z, Bayraktar S, Boone PM, Akyuz K, Gibbs RA, Battaloglu E, Parman Y, Lupski JR
Genet Med 2014 May;16(5):386-94
PMID 24136616
 
Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheral nerves.
Okuda T, Higashi Y, Kokame K, Tanaka C, Kondoh H, Miyata T.
Mol Cell Biol. 2004 May;24(9):3949-56.
PMID 15082788
 
Differential expression of the RTP/Drg1/Ndr1 gene product in proliferating and growth arrested cells.
Piquemal D, Joulia D, Balaguer P, Basset A, Marti J, Commes T.
Biochim Biophys Acta. 1999 Jul 8;1450(3):364-73.
PMID 10395947
 
Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family.
Qu X, Zhai Y, Wei H, Zhang C, Xing G, Yu Y, He F.
Mol Cell Biochem. 2002 Jan;229(1-2):35-44.
PMID 11936845
 
The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia.
Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV.
Mol Cell Biol. 2002 Mar;22(6):1734-41.
PMID 11865053
 
Drg1 expression in 131 colorectal liver metastases: correlation with clinical variables and patient outcomes.
Shah MA, Kemeny N, Hummer A, Drobnjak M, Motwani M, Cordon-Cardo C, Gonen M, Schwartz GK.
Clin Cancer Res. 2005 May 1;11(9):3296-302.
PMID 15867226
 
N-myc-dependent repression of ndr1, a gene identified by direct subtraction of whole mouse embryo cDNAs between wild type and N-myc mutant.
Shimono A, Okuda T, Kondoh H.
Mech Dev. 1999 May;83(1-2):39-52.
PMID 10381566
 
NDRG1 is necessary for p53-dependent apoptosis.
Stein S, Thomas EK, Herzog B, Westfall MD, Rocheleau JV, Jackson RS 2nd, Wang M, Liang P.
J Biol Chem. 2004 Nov 19;279(47):48930-40. Epub 2004 Sep 17.
PMID 15377670
 
Identification of high-risk stage II colorectal tumors by combined analysis of the NDRG1 gene expression and the depth of tumor invasion
Strzelczyk B, Szulc A, Rzepko R, Kitowska A, Skokowski J, Szutowicz A, Pawelczyk T
Ann Surg Oncol 2009 May;16(5):1287-94
PMID 19259744
 
N-myc downregulated gene 1 is a phosphorylated protein in mast cells.
Sugiki T, Murakami M, Taketomi Y, Kikuchi-Yanoshita R, Kudo I.
Biol Pharm Bull. 2004 May;27(5):624-7.
PMID 15133234
 
Metastasis suppressor, NDRG1, mediates its activity through signaling pathways and molecular motors
Sun J, Zhang D, Bae DH, Sahni S, Jansson P, Zheng Y, Zhao Q, Yue F, Zheng M, Kovacevic Z, Richardson DR
Carcinogenesis 2013 Sep;34(9):1943-54
PMID 23671130
 
Identification of NDRG1 as an early inducible gene during in vitro maturation of cultured mast cells.
Taketomi Y, Sugiki T, Saito T, Ishii S, Hisada M, Suzuki-Nishimura T, Uchida MK, Moon TC, Chang HW, Natori Y, Miyazawa S, Kikuchi-Yanoshita R, Murakami M, Kudo I.
Biochem Biophys Res Commun. 2003 Jun 27;306(2):339-46.
PMID 12804568
 
The differentiation-related gene 1, Drg1, is markedly upregulated by androgens in LNCaP prostatic adenocarcinoma cells
Ulrix W, Swinnen JV, Heyns W, Verhoeven G
FEBS Lett 1999 Jul 16;455(1-2):23-6
PMID 10428464
 
Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway.
Unoki M, Nakamura Y.
Oncogene. 2001 Jul 27;20(33):4457-65.
PMID 11494141
 
Cap43, a novel gene specifically induced by Ni2+ compounds.
Zhou D, Salnikow K, Costa M.
Cancer Res. 1998 May 15;58(10):2182-9.
PMID 9605764
 
Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart
Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H, Miyata T
Genomics 2001 Apr 1;73(1):86-97
PMID 11352569
 
Ni(II) and Cu(II) binding with a 14-aminoacid sequence of Cap43 protein, TRSRSHTSEGTRSR
Zoroddu MA, Kowalik-Jankowska T, Kozlowski H, Salnikow K, Costa M
J Inorg Biochem 2001 Mar;84(1-2):47-54
PMID 11330481
 
A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms.
van Belzen N, Dinjens WN, Diesveld MP, Groen NA, van der Made AC, Nozawa Y, Vlietstra R, Trapman J, Bosman FT.
Lab Invest. 1997 Jul;77(1):85-92.
PMID 9251681
 

Citation

This paper should be referenced as such :
Nagai MA, Mangone FR
NDRG1 (N-myc downstream regulated 1);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/NDRG1ID41512ch8q24.html
History of this paper:
Wissing, M ; Rosmus, N ; Carducci, M ; Kachhap, S. NDRG1 (N-myc downstream regulated 1). Atlas Genet Cytogenet Oncol Haematol. 2010;14(8):776-780.
http://documents.irevues.inist.fr/bitstream/handle/2042/44828/10-2009-NDRG1ID41512ch8q24.pdf


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Prostate tumors: an overview
Prostate: Carcinoma with t(8;21)(q24;q22) NDRG1/ERG


External links

Nomenclature
HGNC (Hugo)NDRG1   7679
LRG (Locus Reference Genomic)LRG_258
Cards
AtlasNDRG1ID41512ch8q24
Entrez_Gene (NCBI)NDRG1  10397  N-myc downstream regulated 1
AliasesCAP43; CMT4D; DRG-1; DRG1; 
GC4; HMSNL; NDR1; NMSL; PROXY1; RIT42; RTP; TARG1; TDD5
GeneCards (Weizmann)NDRG1
Ensembl hg19 (Hinxton)ENSG00000104419 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000104419 [Gene_View]  chr8:133237171-133297304 [Contig_View]  NDRG1 [Vega]
ICGC DataPortalENSG00000104419
TCGA cBioPortalNDRG1
AceView (NCBI)NDRG1
Genatlas (Paris)NDRG1
WikiGenes10397
SOURCE (Princeton)NDRG1
Genetics Home Reference (NIH)NDRG1
Genomic and cartography
GoldenPath hg38 (UCSC)NDRG1  -     chr8:133237171-133297304 -  8q24.22   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NDRG1  -     8q24.22   [Description]    (hg19-Feb_2009)
EnsemblNDRG1 - 8q24.22 [CytoView hg19]  NDRG1 - 8q24.22 [CytoView hg38]
Mapping of homologs : NCBINDRG1 [Mapview hg19]  NDRG1 [Mapview hg38]
OMIM601455   605262   
Gene and transcription
Genbank (Entrez)###############################################################################################################################################################################################################################################################
RefSeq transcript (Entrez)NM_001135242 NM_001258432 NM_001258433 NM_006096
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)NDRG1
Cluster EST : UnigeneHs.618002 [ NCBI ]
CGAP (NCI)Hs.618002
Alternative Splicing GalleryENSG00000104419
Gene ExpressionNDRG1 [ NCBI-GEO ]   NDRG1 [ EBI - ARRAY_EXPRESS ]   NDRG1 [ SEEK ]   NDRG1 [ MEM ]
Gene Expression Viewer (FireBrowse)NDRG1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)10397
GTEX Portal (Tissue expression)NDRG1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92597   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ92597  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ92597
Splice isoforms : SwissVarQ92597
PhosPhoSitePlusQ92597
Domains : Interpro (EBI)AB_hydrolase    NDRG    NDRG1   
Domain families : Pfam (Sanger)Ndr (PF03096)   
Domain families : Pfam (NCBI)pfam03096   
Conserved Domain (NCBI)NDRG1
DMDM Disease mutations10397
Blocks (Seattle)NDRG1
SuperfamilyQ92597
Human Protein AtlasENSG00000104419
Peptide AtlasQ92597
HPRD05586
IPIIPI00022078   IPI00982468   IPI01019118   IPI01012905   IPI00923597   IPI00922016   IPI01012373   IPI01015403   IPI01011666   IPI00973989   IPI00974351   IPI00978066   IPI00977187   IPI00981993   IPI00979312   IPI00984595   IPI01011887   IPI00796530   IPI00983423   
Protein Interaction databases
DIP (DOE-UCLA)Q92597
IntAct (EBI)Q92597
FunCoupENSG00000104419
BioGRIDNDRG1
STRING (EMBL)NDRG1
ZODIACNDRG1
Ontologies - Pathways
QuickGOQ92597
Ontology : AmiGOprotein binding  nucleus  cytoplasm  centrosome  cytosol  cytosol  microtubule  plasma membrane  cell-cell adherens junction  microtubule binding  negative regulation of cell proliferation  response to metal ion  microtubule cytoskeleton  Rab GTPase binding  DNA damage response, signal transduction by p53 class mediator  peripheral nervous system myelin maintenance  regulation of apoptotic process  gamma-tubulin binding  myelin sheath  cadherin binding  mast cell activation  perinuclear region of cytoplasm  recycling endosome membrane  extracellular exosome  cellular response to hypoxia  positive regulation of spindle checkpoint  
Ontology : EGO-EBIprotein binding  nucleus  cytoplasm  centrosome  cytosol  cytosol  microtubule  plasma membrane  cell-cell adherens junction  microtubule binding  negative regulation of cell proliferation  response to metal ion  microtubule cytoskeleton  Rab GTPase binding  DNA damage response, signal transduction by p53 class mediator  peripheral nervous system myelin maintenance  regulation of apoptotic process  gamma-tubulin binding  myelin sheath  cadherin binding  mast cell activation  perinuclear region of cytoplasm  recycling endosome membrane  extracellular exosome  cellular response to hypoxia  positive regulation of spindle checkpoint  
REACTOMEQ92597 [protein]
REACTOME PathwaysR-HSA-6803205 [pathway]   
NDEx NetworkNDRG1
Atlas of Cancer Signalling NetworkNDRG1
Wikipedia pathwaysNDRG1
Orthology - Evolution
OrthoDB10397
GeneTree (enSembl)ENSG00000104419
Phylogenetic Trees/Animal Genes : TreeFamNDRG1
HOVERGENQ92597
HOGENOMQ92597
Homologs : HomoloGeneNDRG1
Homology/Alignments : Family Browser (UCSC)NDRG1
Gene fusions - Rearrangements
Fusion : MitelmanNDRG1/ERG [8q24.22/21q22.2]  
Fusion : MitelmanNDRG1/FOXP1 [8q24.22/3p13]  [t(3;8)(p13;q24)]  
Fusion : MitelmanNDRG1/PLEKHA5 [8q24.22/12p12.3]  [t(8;12)(q24;p12)]  
Fusion : MitelmanNDRG1/SNW1 [8q24.22/14q24.3]  [t(8;14)(q24;q24)]  
Fusion : MitelmanNDRG1/ST3GAL1 [8q24.22/8q24.22]  [t(8;8)(q24;q24)]  
Fusion : MitelmanPVT1/NDRG1 [8q24.21/8q24.22]  [t(8;8)(q24;q24)]  
Fusion : COSMICNDRG1 [8q24.22]  -  ERG [21q22.2]  [fusion_1133]  [fusion_1134]  [fusion_1135]  [fusion_1136]  [fusion_1146]  
Fusion: TCGANDRG1 8q24.22 ERG 21q22.2 PRAD
Fusion: TCGANDRG1 8q24.22 FOXP1 3p13 LUAD
Fusion: TCGANDRG1 8q24.22 PLEKHA5 12p12.3 KIRC
Fusion: TCGANDRG1 8q24.22 SNW1 14q24.3 BLCA
Fusion: TCGANDRG1 8q24.22 ST3GAL1 8q24.22 KIRC
Fusion : TICdbNDRG1 [8q24.22]  -  ERG [21q22.2]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNDRG1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NDRG1
dbVarNDRG1
ClinVarNDRG1
1000_GenomesNDRG1 
Exome Variant ServerNDRG1
ExAC (Exome Aggregation Consortium)NDRG1 (select the gene name)
Genetic variants : HAPMAP10397
Genomic Variants (DGV)NDRG1 [DGVbeta]
DECIPHERNDRG1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisNDRG1 
Mutations
ICGC Data PortalNDRG1 
TCGA Data PortalNDRG1 
Broad Tumor PortalNDRG1
OASIS PortalNDRG1 [ Somatic mutations - Copy number]
Cancer Gene: CensusNDRG1 
Somatic Mutations in Cancer : COSMICNDRG1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDNDRG1
intOGen PortalNDRG1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)Leiden Muscular Dystrophy pages
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch NDRG1
DgiDB (Drug Gene Interaction Database)NDRG1
DoCM (Curated mutations)NDRG1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NDRG1 (select a term)
intoGenNDRG1
NCG5 (London)NDRG1
Cancer3DNDRG1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601455    605262   
Orphanet14523   
MedgenNDRG1
Genetic Testing Registry NDRG1
NextProtQ92597 [Medical]
TSGene10397
GENETestsNDRG1
Target ValidationNDRG1
Huge Navigator NDRG1 [HugePedia]
snp3D : Map Gene to Disease10397
BioCentury BCIQNDRG1
ClinGenNDRG1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD10397
Chemical/Pharm GKB GenePA31482
Clinical trialNDRG1
Miscellaneous
canSAR (ICR)NDRG1 (select the gene name)
Probes
Litterature
PubMed181 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNDRG1
EVEXNDRG1
GoPubMedNDRG1
iHOPNDRG1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Jun 30 11:13:06 CEST 2017

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