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NDRG1 (N-myc downstream regulated 1)

Identity

Other namesCAP43
CMT4D
DRG-1
DRG1
GC4
HMSNL
NDR1
NMSL
PROXY1
RIT42
RTP
Rit42
TARG1
TDD5
HGNC (Hugo) NDRG1
LocusID (NCBI) 10397
Location 8q24.22
Location_base_pair Starts at 134249414 and ends at 134309547 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  DNA size: 60.05Kb; mRNA size: 2997 bp; 16 exons.
Description NDRG1 consists of 60,085 basepairs, starting at basepair 134,318,596 and ending at basepair 134,378,680 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.
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

 
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, the presence of hydrolytic catalytic activity is still questionable. NDRG1 has more than seven phosphorylation sites, among others a phosphopantetheine attachment site, protein kinase C, casein kinase II, tyrosine kinase, protein kinase A and calmodulin kinase II. NRDG1 is phosphorylated by Protein Kinase A and Calmodulin kinase II, and is a physiological substrate of SGK1 and GSK-3-beta kinase, a kinase involved in cancer growth and progression.
Expression NDRG1 is relatively ubiquitously expressed in normal human cells, and especially highly expressed in prostate, brain, kidney, placenta, ovarian, testicular and intestinal cells. NDRG1 is mostly found in epithelial cells.
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 NDRG1 is reported to be a metastasis suppressor gene which is downregulated in prostate, colon and breast cancers. 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.
The function of NDRG1 may be controlled at least in part by phosphorylation. It 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. There is evidence that NDRG1 is involved in the induction of differentiation. NDRG1 is downregulated under conditions of cell growth. NDRG1 expression peaks in the G1 and G2/M phases, and is lowest in the S phase. NDRG1 is also a microtubule-associated protein, which may play an important role in maintaining spindle structure during cell division. 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.
Certain transcription factors such as MYC, ERG1, HIF1-ALPHA bind to the NDRG1 promoter region and regulate its expression.
NDRG1 is upregulated during colon epithelial cell differentiation. It is regulated by hormones such as androgens and estradiol. 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.
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

Entity Various solid cancers
Disease Prostate, breast, colon, renal, bladder, pancreatic, hepatic cancer.
Prognosis 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.
Oncogenesis 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 Caused by the Gypsy founder mutation, homozygote R148X, also called homozygote C564t. 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.
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.
  

External links

Nomenclature
HGNC (Hugo)NDRG1   7679
Cards
AtlasNDRG1ID41512ch8q24
Entrez_Gene (NCBI)NDRG1  10397  N-myc downstream regulated 1
GeneCards (Weizmann)NDRG1
Ensembl (Hinxton)ENSG00000104419 [Gene_View]  chr8:134249414-134309547 [Contig_View]  NDRG1 [Vega]
AceView (NCBI)NDRG1
Genatlas (Paris)NDRG1
WikiGenes10397
SOURCE (Princeton)NM_001135242 NM_001258432 NM_001258433 NM_006096
Genomic and cartography
GoldenPath (UCSC)NDRG1  -  8q24.22   chr8:134249414-134309547 -  8q24   [Description]    (hg19-Feb_2009)
EnsemblNDRG1 - 8q24 [CytoView]
Mapping of homologs : NCBINDRG1 [Mapview]
OMIM601455   605262   
Gene and transcription
Genbank (Entrez)AF004162 AF039944 AF147402 AF230380 AK091147
RefSeq transcript (Entrez)NM_001135242 NM_001258432 NM_001258433 NM_006096
RefSeq genomic (Entrez)AC_000140 NC_000008 NC_018919 NG_007943 NT_008046 NW_001839138 NW_004929340
Consensus coding sequences : CCDS (NCBI)NDRG1
Cluster EST : UnigeneHs.618002 [ NCBI ]
CGAP (NCI)Hs.618002
Alternative Splicing : Fast-db (Paris)GSHG0029877
Alternative Splicing GalleryENSG00000104419
Gene ExpressionNDRG1 [ NCBI-GEO ]     NDRG1 [ SEEK ]   NDRG1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92597 (Uniprot)
NextProtQ92597  [Medical]
With graphics : InterProQ92597
Splice isoforms : SwissVarQ92597 (Swissvar)
Domains : Interpro (EBI)Ndr   
Related proteins : CluSTrQ92597
Domain families : Pfam (Sanger)Ndr (PF03096)   
Domain families : Pfam (NCBI)pfam03096   
DMDM Disease mutations10397
Blocks (Seattle)Q92597
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
InParanoidQ92597
Interologous Interaction database Q92597
IntegromeDBNDRG1
STRING (EMBL)NDRG1
Ontologies - Pathways
Ontology : AmiGOprotein binding  nucleus  cytoplasm  centrosome  cytosol  microtubule  plasma membrane  cell-cell adherens junction  microtubule binding  response to metal ion  microtubule cytoskeleton  Rab GTPase binding  DNA damage response, signal transduction by p53 class mediator  peripheral nervous system myelin maintenance  gamma-tubulin binding  cadherin binding  mast cell activation  perinuclear region of cytoplasm  recycling endosome membrane  cellular response to hypoxia  positive regulation of spindle checkpoint  
Ontology : EGO-EBIprotein binding  nucleus  cytoplasm  centrosome  cytosol  microtubule  plasma membrane  cell-cell adherens junction  microtubule binding  response to metal ion  microtubule cytoskeleton  Rab GTPase binding  DNA damage response, signal transduction by p53 class mediator  peripheral nervous system myelin maintenance  gamma-tubulin binding  cadherin binding  mast cell activation  perinuclear region of cytoplasm  recycling endosome membrane  cellular response to hypoxia  positive regulation of spindle checkpoint  
REACTOMENDRG1
Protein Interaction DatabaseNDRG1
Wikipedia pathwaysNDRG1
Gene fusion - rearrangments
Rearrangement : COSMICNDRG1 [8q24.22]  -  ERG [21q22.2]
Rearrangement : TICdbERG [21q22.2]  -  NDRG1 [8q24.22]
Rearrangement : TICdbNDRG1 [8q24.22]  -  ERG [21q22.2]
Rearrangement : TICdbNDRG1 [8q24.22]  -  NDRG1 [8q24.22]
Rearrangement : TICdbNDRG1 [8q24.22]  -  NDRG1 [8q24.22]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)NDRG1
SNP (GeneSNP Utah)NDRG1
SNP : HGBaseNDRG1
Genetic variants : HAPMAPNDRG1
1000_GenomesNDRG1 
ICGC programENSG00000104419 
Cancer Gene: CensusNDRG1 
Somatic Mutations in Cancer : COSMICNDRG1 
CONAN: Copy Number AnalysisNDRG1 
Mutations and Diseases : HGMDNDRG1
OMIM601455    605262   
GENETestsNDRG1
Disease Genetic AssociationNDRG1
Huge Navigator NDRG1 [HugePedia]  NDRG1 [HugeCancerGEM]
Genomic VariantsNDRG1  NDRG1 [DGVbeta]
Exome VariantNDRG1
dbVarNDRG1
ClinVarNDRG1
snp3D : Map Gene to Disease10397
General knowledge
Homologs : HomoloGeneNDRG1
Homology/Alignments : Family Browser (UCSC)NDRG1
Phylogenetic Trees/Animal Genes : TreeFamNDRG1
Chemical/Protein Interactions : CTD10397
Chemical/Pharm GKB GenePA31482
Clinical trialNDRG1
Cancer Resource (Charite)ENSG00000104419
Other databases
Probes
Litterature
PubMed123 Pubmed reference(s) in Entrez
CoreMineNDRG1
iHOPNDRG1

Bibliography

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The N-Myc down regulated Gene1 (NDRG1) Is a Rab4a effector involved in vesicular recycling of E-cadherin.
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REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written10-2009Michel 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

Citation

This paper should be referenced as such :
Wissing M, Rosmus N, Carducci M, Kachhap S . NDRG1 (N-myc downstream regulated 1). Atlas Genet Cytogenet Oncol Haematol. October 2009 .
URL : http://AtlasGeneticsOncology.org/Genes/NDRG1ID41512ch8q24.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44828/1/10-2009-NDRG1ID41512ch8q24.pdf   [ Bibliographic record ]

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Apr 16 11:39:08 CEST 2014

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