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Gene Review

DKK1  -  dickkopf WNT signaling pathway inhibitor 1

Homo sapiens

Synonyms: DKK-1, Dickkopf-1, Dickkopf-related protein 1, Dkk-1, SK, ...
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Disease relevance of DKK1

  • These data support in vivo function of DKK1, independent of p53, in human gliomas with no major impact on their pathogenesis [1].
  • To analyze DKK1 for its role in initiation or progression, we screened a series of 73 brain tumors for structural alterations in the entire coding sequence by single-strand conformation polymorphism and direct sequencing [1].
  • The genomic structure, chromosome location, and analysis of the human DKK1 head inducer gene as a candidate for holoprosencephaly [2].
  • The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma [3].
  • In primary colorectal tumors, DKK-1 was found hypermethylated in 17% (nine of 54) of cases [4].
  • DKK-1 is expressed at high level in colon cancer cell lines with a differentiated phenotype such as Caco-2 or HT-29 [5].

Psychiatry related information on DKK1


High impact information on DKK1


Chemical compound and disease context of DKK1


Biological context of DKK1


Anatomical context of DKK1


Associations of DKK1 with chemical compounds


Physical interactions of DKK1

  • The G171V mutation prevents Dkk from binding to LRP5, thereby increasing LRP5 function; the result is high bone mass due to uncoupling of bone formation and resorption [21].

Regulatory relationships of DKK1

  • Our data indicate that the Wnt/beta-catenin pathway is downregulated by the induction of DKK-1 expression, a mechanism that is lost in colon cancer [22].
  • DKK1 translation can be induced by p53, thereby linking TP53 and Wnt/beta1-catenin signaling pathways [1].
  • In vitro, TCF-Lef activity in presence of Wnt3a was significantly reduced in cells expressing LRP5 haplotypes carrying the T allele of exon 10 and 18 compared to the wild-type allele, whereas co-expression of Dkk1 completely inhibited Wnt3a response through all LRP5 haplotypes [23].
  • Early Wnt-3A signaling as measured by beta-catenin accumulation was not affected by the BMP antagonists but was blocked by Dkk-1 [24].
  • The regulatory action of DKK1 antisense oligonucleotide treatment on bone tissue appeared to suppress the promoting effect of estrogen deficiency on osteoclastogenesis-stimulatory factor RANKL expression and osteoclast differentiation [18].

Other interactions of DKK1


Analytical, diagnostic and therapeutic context of DKK1

  • A combined ELISA assays for both DKK1 and carcinoembryonic antigen increased sensitivity and classified 82.2% of the NSCLC patients as positive whereas only 7.7% of healthy volunteers were falsely diagnosed to be positive [28].
  • We found that DKK1 antisense oligonucleotide significantly abrogated the suppressing effect of ovariectomy on weight, mineral content, mineral density and peak load of femurs [18].
  • Quantitative RT-PCR confirmed the expression of Dkk3 in the implants [29].
  • Overexpression of Dkk-1 and Dkk-4 was further confirmed by real-time PCR [30].
  • We examined the hDkk-1 expression levels in 32 HB biopsy specimens and in the corresponding liver samples, in 4 HB cell lines, and in a panel of other tumors and normal tissues using a differential PCR approach and Northern blotting [31].


  1. Mutation analysis of DKK1 and in vivo evidence of predominant p53-independent DKK1 function in gliomas. Mueller, W., Lass, U., Wellmann, S., Kunitz, F., von Deimling, A. Acta Neuropathol. (2005) [Pubmed]
  2. The genomic structure, chromosome location, and analysis of the human DKK1 head inducer gene as a candidate for holoprosencephaly. Roessler, E., Du, Y., Glinka, A., Dutra, A., Niehrs, C., Muenke, M. Cytogenet. Cell Genet. (2000) [Pubmed]
  3. 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, J.D. N. Engl. J. Med. (2003) [Pubmed]
  4. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Aguilera, O., Fraga, M.F., Ballestar, E., Paz, M.F., Herranz, M., Espada, J., García, J.M., Muñoz, A., Esteller, M., González-Sancho, J.M. Oncogene (2006) [Pubmed]
  5. The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells. Aguilera, O., Peña, C., García, J.M., Larriba, M.J., Ordóñez-Morán, P., Navarro, D., Barbáchano, A., López de Silanes, I., Ballestar, E., Fraga, M.F., Esteller, M., Gamallo, C., Bonilla, F., González-Sancho, J.M., Muñoz, A. Carcinogenesis (2007) [Pubmed]
  6. Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1. Scali, C., Caraci, F., Gianfriddo, M., Diodato, E., Roncarati, R., Pollio, G., Gaviraghi, G., Copani, A., Nicoletti, F., Terstappen, G.C., Caricasole, A. Neurobiol. Dis. (2006) [Pubmed]
  7. Wnt-beta-catenin signaling initiates taste papilla development. Liu, F., Thirumangalathu, S., Gallant, N.M., Yang, S.H., Stoick-Cooper, C.L., Reddy, S.T., Andl, T., Taketo, M.M., Dlugosz, A.A., Moon, R.T., Barlow, L.A., Millar, S.E. Nat. Genet. (2007) [Pubmed]
  8. Developmental biology. Making head or tail of Dickkopf. Nusse, R. Nature (2001) [Pubmed]
  9. Inhibition of Wnt activity induces heart formation from posterior mesoderm. Marvin, M.J., Di Rocco, G., Gardiner, A., Bush, S.M., Lassar, A.B. Genes Dev. (2001) [Pubmed]
  10. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Bafico, A., Liu, G., Yaniv, A., Gazit, A., Aaronson, S.A. Nat. Cell Biol. (2001) [Pubmed]
  11. FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development. Chamorro, M.N., Schwartz, D.R., Vonica, A., Brivanlou, A.H., Cho, K.R., Varmus, H.E. EMBO J. (2005) [Pubmed]
  12. Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53. Wang, J., Shou, J., Chen, X. Oncogene (2000) [Pubmed]
  13. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma. Terpos, E., Heath, D.J., Rahemtulla, A., Zervas, K., Chantry, A., Anagnostopoulos, A., Pouli, A., Katodritou, E., Verrou, E., Vervessou, E.C., Dimopoulos, M.A., Croucher, P.I. Br. J. Haematol. (2006) [Pubmed]
  14. Mesenchymal-epithelial interactions in the skin: increased expression of dickkopf1 by palmoplantar fibroblasts inhibits melanocyte growth and differentiation. Yamaguchi, Y., Itami, S., Watabe, H., Yasumoto, K., Abdel-Malek, Z.A., Kubo, T., Rouzaud, F., Tanemura, A., Yoshikawa, K., Hearing, V.J. J. Cell Biol. (2004) [Pubmed]
  15. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Ai, M., Holmen, S.L., Van Hul, W., Williams, B.O., Warman, M.L. Mol. Cell. Biol. (2005) [Pubmed]
  16. The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis. Christodoulides, C., Laudes, M., Cawthorn, W.P., Schinner, S., Soos, M., O'Rahilly, S., Sethi, J.K., Vidal-Puig, A. J. Cell. Sci. (2006) [Pubmed]
  17. 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, A.J., Caruso, A., Storto, M., Gaviraghi, G., Terstappen, G.C., Nicoletti, F. J. Neurosci. (2004) [Pubmed]
  18. Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss. A histomorphological study in ovariectomized rats. Wang, F.S., Ko, J.Y., Lin, C.L., Wu, H.L., Ke, H.J., Tai, P.J. Bone (2007) [Pubmed]
  19. Dkk-1-derived synthetic peptides and lithium chloride for the control and recovery of adult stem cells from bone marrow. Gregory, C.A., Perry, A.S., Reyes, E., Conley, A., Gunn, W.G., Prockop, D.J. J. Biol. Chem. (2005) [Pubmed]
  20. Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA. Shou, J., Ali-Osman, F., Multani, A.S., Pathak, S., Fedi, P., Srivenugopal, K.S. Oncogene (2002) [Pubmed]
  21. LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders. Levasseur, R., Lacombe, D., de Vernejoul, M.C. Joint, bone, spine : revue du rhumatisme. (2005) [Pubmed]
  22. The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. González-Sancho, J.M., Aguilera, O., García, J.M., Pendás-Franco, N., Peña, C., Cal, S., García de Herreros, A., Bonilla, F., Muñoz, A. Oncogene (2005) [Pubmed]
  23. Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men. Kiel, D.P., Ferrari, S.L., Cupples, L.A., Karasik, D., Manen, D., Imamovic, A., Herbert, A.G., Dupuis, J. Bone (2007) [Pubmed]
  24. Sclerostin inhibition of Wnt-3a-induced C3H10T1/2 cell differentiation is indirect and mediated by bone morphogenetic proteins. Winkler, D.G., Sutherland, M.S., Ojala, E., Turcott, E., Geoghegan, J.C., Shpektor, D., Skonier, J.E., Yu, C., Latham, J.A. J. Biol. Chem. (2005) [Pubmed]
  25. Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis. Byun, T., Karimi, M., Marsh, J.L., Milovanovic, T., Lin, F., Holcombe, R.F. J. Clin. Pathol. (2005) [Pubmed]
  26. Growth promoting signaling by tenascin-C [corrected]. Ruiz, C., Huang, W., Hegi, M.E., Lange, K., Hamou, M.F., Fluri, E., Oakeley, E.J., Chiquet-Ehrismann, R., Orend, G. Cancer Res. (2004) [Pubmed]
  27. Elevated expression of DKK1 is associated with cytoplasmic/nuclear beta-catenin accumulation and poor prognosis in hepatocellular carcinomas. Yu, B., Yang, X., Xu, Y., Yao, G., Shu, H., Lin, B., Hood, L., Wang, H., Yang, S., Gu, J., Fan, J., Qin, W. J. Hepatol. (2009) [Pubmed]
  28. Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas. Yamabuki, T., Takano, A., Hayama, S., Ishikawa, N., Kato, T., Miyamoto, M., Ito, T., Ito, H., Miyagi, Y., Nakayama, H., Fujita, M., Hosokawa, M., Tsuchiya, E., Kohno, N., Kondo, S., Nakamura, Y., Daigo, Y. Cancer Res. (2007) [Pubmed]
  29. Advanced molecular profiling in vivo detects novel function of dickkopf-3 in the regulation of bone formation. Aslan, H., Ravid-Amir, O., Clancy, B.M., Rezvankhah, S., Pittman, D., Pelled, G., Turgeman, G., Zilberman, Y., Gazit, Z., Hoffmann, A., Gross, G., Domany, E., Gazit, D. J. Bone Miner. Res. (2006) [Pubmed]
  30. Dickkopf homologs in squamous mucosa of esophagitis patients are overexpressed compared with Barrett's patients and healthy controls. Ali, I., Rafiee, P., Hogan, W.J., Jacob, H.J., Komorowski, R.A., Haasler, G.B., Shaker, R. Am. J. Gastroenterol. (2006) [Pubmed]
  31. Overexpression of human Dickkopf-1, an antagonist of wingless/WNT signaling, in human hepatoblastomas and Wilms' tumors. Wirths, O., Waha, A., Weggen, S., Schirmacher, P., Kühne, T., Goodyer, C.G., Albrecht, S., Von Schweinitz, D., Pietsch, T. Lab. Invest. (2003) [Pubmed]
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