DKK1 (dickkopf homolog 1 (Xenopus laevis))

2007-04-01   Oscar Aguilera , Alberto Munoz 

Instituto de Investigaciones Biomedicas Alberto Sols, C\\\/ Arturo Duperier n4, Madrid (Spain); oaguilera@iib.uam.es .

Identity

HGNC
LOCATION
10q21.1
LOCUSID
ALIAS
DKK-1,SK
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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 name
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 name
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 name
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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
174499052007The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells.Aguilera O et al
114333022001Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow.Bafico A et al
174374122007Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy.Busceti CL et al
152292492004Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain.Caricasole A et al
155924302005FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development.Chamorro MN et al
94507481998Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction.Glinka A et al
155925052005The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer.González-Sancho JM et al
118675242002The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death.Grotewold L et al
145556162004A functional genomics approach for the identification of putative tumor suppressor genes: Dickkopf-1 as suppressor of HeLa cell transformation.Mikheev AM et al
166460532006Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation.Politou MC et al
114487712001Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6.Semënov MV et al
146954082003The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma.Tian E et al

Other Information

Locus ID:

NCBI: 22943
MIM: 605189
HGNC: 2891
Ensembl: ENSG00000107984

Variants:

dbSNP: 22943
ClinVar: 22943
TCGA: ENSG00000107984
COSMIC: DKK1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000107984ENST00000373970O94907
ENSG00000107984ENST00000373970I1W660

Expression (GTEx)

0
100
200
300
400
500
600
700
800
900

Pathways

PathwaySourceExternal ID
Wnt signaling pathwayKEGGko04310
Wnt signaling pathwayKEGGhsa04310
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by WNT in cancerREACTOMER-HSA-4791275
Misspliced LRP5 mutants have enhanced beta-catenin-dependent signalingREACTOMER-HSA-5339717
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Negative regulation of TCF-dependent signaling by WNT ligand antagonistsREACTOMER-HSA-3772470

References

Pubmed IDYearTitleCitations
208234172011Medulloblastoma comprises four distinct molecular variants.407
146954082003The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma.380
172377932007Dickkopf-1 is a master regulator of joint remodeling.298
270153062016Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT.151
170681502007Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo.147
155925052005The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer.135
227387992012Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study.119
164911182006Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer.115
152292492004Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain.112
155924302005FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development.101

Citation

Oscar Aguilera ; Alberto Munoz

DKK1 (dickkopf homolog 1 (Xenopus laevis))

Atlas Genet Cytogenet Oncol Haematol. 2007-04-01

Online version: http://atlasgeneticsoncology.org/gene/44007/dkk1