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DKK1 (dickkopf homolog 1 (Xenopus laevis))

Identity

Other namesDickkkopf-1
DKK-1
mdkk1
hDkk1
dickkopf (Xenopus laevis) homolog 1
SK
HGNC (Hugo) DKK1
LocusID (NCBI) 22943
Location 10q21.1
Location_base_pair Starts at 54074041 and ends at 54077417 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  hDKK1 contains 3 introns and 4 exons (depictured in red).
Description Position: 53744064 - 53747595 ; Strand: ( + ). DKK1 is present in the contig NT008583 of Genebank; 4 Exon(s) all coding; DNA size 3.07 Kb.
Transcription 1 detected transcript; open reading frame: 1494 bp.

Protein

 
  Boxes in red:
1) Signal peptide (1 to 24 aa) 2) Low complexity region (45 to 57 aa) 3) Dickkopf domain (84 to 140 aa)
Description This gene encodes a protein that is a member of the dickkopf family. HDKK1 encode for a 266 amino acids (aa) protein. The calculated molecular weight is 28.7 KDa. Isoelectric point: 8.74. It possesses two clusters of ten cysteine residues separated by a linker region.
Expression Highly expressed in thyroid, small intestine, stomach, liver, placenta, pancreas, uterus, abdominal cavity, bladder and skin. Weaker expression has been detected in colon and spleen. It is involved in embryonic development through its inhibition of the WNT signaling pathway.
Localisation Extracellular region; secreted protein.
Function Inhibitor of the Wnt signaling pathway.

Implicated in

Entity Myeloma bone disease
Disease Patients with multiple myeloma frequently show painful bone lesions and in a recent analysis an increase in Dkk1 in the serum of those patients was noted, whose levels correlated with lesion occurrence. Bone marrow serum containing an elevated level of Dkk1 inhibited the differentiation of osteoblast precursor cells in vitro. Authors propose that Dkk1 produced by myeloma cells blocks osteoblast differentiation, thereby causing the lytic bone lesions. Supporting this idea, treatment of myeloma patients by autologous stem cell transplantation induces a decrease in Dkk1 levels, which is accompanied with elevation of bone formation markers. This raises again interesting therapeutic approaches for interference with the Lrp5/Lrp6-Dkk1 interaction.
  
Entity Cancer
Disease Different studies displayed changes of Dkk expression in tumor cell lines or tissues. In colon cancer, DKK-1 is a downstream target gene of beta-catenin, as it is in human ovarian endometrioid adenocarcinomas. DKK-1 is silenced in colon cancer by DNA hypermethylation and this correlates with advanced Dukes' stages of colorectal tumorigenesis. DKK-1 overexpression in colon cancer cells or Hela cells reduces colony formation and tumor growth in xenografts, pointing out to a tumor-suppressor function for DKK-1.
  
Entity Alzheimer
Disease DKK-1 has been also related to neurodegenerative disease. DKK-1 has been shown to be induced in degenerating neurons from Alzheimer patients as well as in cultured neurons challenged with beta-amyloid peptide. Hence, DKK-1 may promote apoptosis in Alzheimer neurons by enhancing Gsk3-mediated phosphorylation of the Tau protein in beta-amyloid-treated neurons.
  
Entity Epilepsia
Disease Recently, it has been shown that induction of the wnt inhibitor, dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy. Strong DKK-1 expression was found in six bioptic samples and in one autoptic sample from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Furthermore, DKK-1 expression was undetectable or very low in autoptic samples from nonepileptic patients or in bioptic samples from patients with complex partial seizures without neuronal loss and/or reactive gliosis in the hippocampus.
  

External links

Nomenclature
HGNC (Hugo)DKK1   2891
Cards
AtlasDKK1ID44007ch10q11
Entrez_Gene (NCBI)DKK1  22943  dickkopf WNT signaling pathway inhibitor 1
GeneCards (Weizmann)DKK1
Ensembl (Hinxton)ENSG00000107984 [Gene_View]  chr10:54074041-54077417 [Contig_View]  DKK1 [Vega]
ICGC DataPortalENSG00000107984
cBioPortalDKK1
AceView (NCBI)DKK1
Genatlas (Paris)DKK1
WikiGenes22943
SOURCE (Princeton)NM_012242
Genomic and cartography
GoldenPath (UCSC)DKK1  -  10q21.1   chr10:54074041-54077417 +  10q11.2   [Description]    (hg19-Feb_2009)
EnsemblDKK1 - 10q11.2 [CytoView]
Mapping of homologs : NCBIDKK1 [Mapview]
OMIM605189   
Gene and transcription
Genbank (Entrez)AF127563 AF177394 AK314902 AY359005 BC001539
RefSeq transcript (Entrez)NM_012242
RefSeq genomic (Entrez)AC_000142 NC_000010 NC_018921 NT_030059 NW_001837985 NW_004929376
Consensus coding sequences : CCDS (NCBI)DKK1
Cluster EST : UnigeneHs.40499 [ NCBI ]
CGAP (NCI)Hs.40499
Alternative Splicing : Fast-db (Paris)GSHG0003375
Alternative Splicing GalleryENSG00000107984
Gene ExpressionDKK1 [ NCBI-GEO ]     DKK1 [ SEEK ]   DKK1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO94907 (Uniprot)
NextProtO94907  [Medical]
With graphics : InterProO94907
Splice isoforms : SwissVarO94907 (Swissvar)
Domains : Interpro (EBI)Dickkopf_N [organisation]  
Related proteins : CluSTrO94907
Domain families : Pfam (Sanger)Dickkopf_N (PF04706)   
Domain families : Pfam (NCBI)pfam04706   
DMDM Disease mutations22943
Blocks (Seattle)O94907
PDB (SRS)3S2K    3S8V   
PDB (PDBSum)3S2K    3S8V   
PDB (IMB)3S2K    3S8V   
PDB (RSDB)3S2K    3S8V   
Human Protein AtlasENSG00000107984 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasO94907
HPRD05544
IPIIPI00016353   
Protein Interaction databases
DIP (DOE-UCLA)O94907
IntAct (EBI)O94907
FunCoupENSG00000107984
BioGRIDDKK1
InParanoidO94907
Interologous Interaction database O94907
IntegromeDBDKK1
STRING (EMBL)DKK1
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  negative regulation of transcription from RNA polymerase II promoter  cell morphogenesis involved in differentiation  endoderm formation  mesoderm formation  hair follicle development  regulation of receptor internalization  signal transducer activity  protein binding  extracellular space  plasma membrane  growth factor activity  negative regulation of Wnt signaling pathway  embryonic limb morphogenesis  negative regulation of BMP signaling pathway  forebrain development  negative regulation of protein complex assembly  response to retinoic acid  negative regulation of peptidyl-serine phosphorylation  negative regulation of mesodermal cell fate specification  regulation of endodermal cell fate specification  receptor antagonist activity  negative regulation of skeletal muscle tissue development  low-density lipoprotein particle receptor binding  face morphogenesis  negative regulation of pathway-restricted SMAD protein phosphorylation  positive regulation of heart induction by negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  Wnt signaling pathway involved in somitogenesis  extracellular negative regulation of signal transduction  negative regulation of canonical Wnt signaling pathway involved in cardiac muscle cell fate commitment  negative regulation of cardiac muscle cell differentiation  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  negative regulation of transcription from RNA polymerase II promoter  cell morphogenesis involved in differentiation  endoderm formation  mesoderm formation  hair follicle development  regulation of receptor internalization  signal transducer activity  protein binding  extracellular space  plasma membrane  growth factor activity  negative regulation of Wnt signaling pathway  embryonic limb morphogenesis  negative regulation of BMP signaling pathway  forebrain development  negative regulation of protein complex assembly  response to retinoic acid  negative regulation of peptidyl-serine phosphorylation  negative regulation of mesodermal cell fate specification  regulation of endodermal cell fate specification  receptor antagonist activity  negative regulation of skeletal muscle tissue development  low-density lipoprotein particle receptor binding  face morphogenesis  negative regulation of pathway-restricted SMAD protein phosphorylation  positive regulation of heart induction by negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  Wnt signaling pathway involved in somitogenesis  extracellular negative regulation of signal transduction  negative regulation of canonical Wnt signaling pathway involved in cardiac muscle cell fate commitment  negative regulation of cardiac muscle cell differentiation  
Pathways : BIOCARTAWnt/LRP6 Signalling [Genes]   
Pathways : KEGGWnt signaling pathway   
Protein Interaction DatabaseDKK1
Wikipedia pathwaysDKK1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)DKK1
snp3D : Map Gene to Disease22943
SNP (GeneSNP Utah)DKK1
SNP : HGBaseDKK1
Genetic variants : HAPMAPDKK1
Exome VariantDKK1
1000_GenomesDKK1 
ICGC programENSG00000107984 
Somatic Mutations in Cancer : COSMICDKK1 
CONAN: Copy Number AnalysisDKK1 
Mutations and Diseases : HGMDDKK1
Mutations and Diseases : intOGenDKK1
Genomic VariantsDKK1  DKK1 [DGVbeta]
dbVarDKK1
ClinVarDKK1
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM605189   
MedgenDKK1
GENETestsDKK1
Disease Genetic AssociationDKK1
Huge Navigator DKK1 [HugePedia]  DKK1 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneDKK1
Homology/Alignments : Family Browser (UCSC)DKK1
Phylogenetic Trees/Animal Genes : TreeFamDKK1
Chemical/Protein Interactions : CTD22943
Chemical/Pharm GKB GenePA27345
Clinical trialDKK1
Cancer Resource (Charite)ENSG00000107984
Other databases
Probes
Litterature
PubMed237 Pubmed reference(s) in Entrez
CoreMineDKK1
iHOPDKK1
OncoSearchDKK1

Bibliography

Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction.
Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C
Nature. 1998 ; 391 (6665) : 357-362.
PMID 9450748
 
Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow.
Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA
Nature cell biology. 2001 ; 3 (7) : 683-686.
PMID 11433302
 
Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6.
Semˆ´nov MV, Tamai K, Brott BK, Kˆºhl M, Sokol S, He X
Current biology : CB. 2001 ; 11 (12) : 951-961.
PMID 11448771
 
The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death.
Grotewold L, Rˆºther U
The EMBO journal. 2002 ; 21 (5) : 966-975.
PMID 11867524
 
The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma.
Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD Jr
The New England journal of medicine. 2003 ; 349 (26) : 2483-2494.
PMID 14695408
 
Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain.
Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, Storto M, Gaviraghi G, Terstappen GC, Nicoletti F
The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004 ; 24 (26) : 6021-6027.
PMID 15229249
 
A functional genomics approach for the identification of putative tumor suppressor genes: Dickkopf-1 as suppressor of HeLa cell transformation.
Mikheev AM, Mikheeva SA, Liu B, Cohen P, Zarbl H
Carcinogenesis. 2004 ; 25 (1) : 47-59.
PMID 14555616
 
FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development.
Chamorro MN, Schwartz DR, Vonica A, Brivanlou AH, Cho KR, Varmus HE
The EMBO journal. 2005 ; 24 (1) : 73-84.
PMID 15592430
 
The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer.
Gonzˆ°lez-Sancho JM, Aguilera O, Garcˆ‚a JM, Pendˆ°s-Franco N, Peˆ±a C, Cal S, Garcˆ‚a de Herreros A, Bonilla F, Muˆ±oz A
Oncogene. 2005 ; 24 (6) : 1098-1103.
PMID 15592505
 
Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer.
Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J, Garcˆ‚a JM, Muˆ±oz A, Esteller M, Gonzˆ°lez-Sancho JM
Oncogene. 2006 ; 25 (29) : 4116-4121.
PMID 16491118
 
Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation.
Politou MC, Heath DJ, Rahemtulla A, Szydlo R, Anagnostopoulos A, Dimopoulos MA, Croucher PI, Terpos E
International journal of cancer. Journal international du cancer. 2006 ; 119 (7) : 1728-1731.
PMID 16646053
 
The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells.
Aguilera O, Peˆ±a C, Garcˆ‚a JM, Larriba MJ, Ordˆ„ˆ±ez-Morˆ°n P, Navarro D, Barbˆ°chano A, Lˆ„pez de Silanes I, Ballestar E, Fraga MF, Esteller M, Gamallo C, Bonilla F, Gonzˆ°lez-Sancho JM, Muˆ±oz A
Carcinogenesis. 2007 ; 28 (9) : 1877-1884.
PMID 17449905
 
Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy.
Busceti CL, Biagioni F, Aronica E, Riozzi B, Storto M, Battaglia G, Giorgi FS, Gradini R, Fornai F, Caricasole A, Nicoletti F, Bruno V
Epilepsia. 2007 ; 48 (4) : 694-705.
PMID 17437412
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written04-2007Oscar Aguilera, Alberto Munoz
Instituto de Investigaciones Biomedicas "Alberto Sols", C/ Arturo Duperier n4, Madrid (Spain); oaguilera@iib.uam.es .

Citation

This paper should be referenced as such :
Aguilera O, Munoz A
DKK1 (dickkopf homolog 1 (Xenopus laevis));
Atlas Genet Cytogenet Oncol Haematol. April 2007
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/DKK1ID44007ch10q11.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Oct 4 12:54:56 CEST 2014

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