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DKK3 (dickkopf 3 homolog (Xenopus laevis))

Written2013-04Naoki Katase, Tsutomu Nohno
Department of Molecular, Developmental Biology, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan

(Note : for Links provided by Atlas : click)

Identity

Alias_namesdickkopf (Xenopus laevis) homolog 3
dickkopf 3 homolog (Xenopus laevis)
Alias_symbol (synonym)REIC
RIG
Other alias
HGNC (Hugo) DKK3
LocusID (NCBI) 27122
Atlas_Id 40327
Location 11p15.3  [Link to chromosome band 11p15]
Location_base_pair Starts at 11962996 and ends at 12008639 bp from pter ( according to hg19-Feb_2009)  [Mapping DKK3.png]
Local_order USP47-LOC100996608-DKK3-MICAL2-MICALCL.
Fusion genes
(updated 2016)
CHST13 (3q21.3) / DKK3 (11p15.3)DKK3 (11p15.3) / DKK3 (11p15.3)FARP1 (13q32.2) / DKK3 (11p15.3)
HIST1H2AH (6p22.1) / DKK3 (11p15.3)TIAL1 (10q26.11) / DKK3 (11p15.3)

DNA/RNA

 
  DKK3 gene location at chromosome 11p15.2, and its annotated transcripts. Exons are indicated as boxes, Blue boxes present untranscripted region (UTR). The start codon (ATG) in exon 2, and stop codon (TAG) in exon 8 are indicated as arrows.
Description DKK3 gene is 46367 bp long, containing nine exons that span over 50 kbp of genomic DNA (Kobayashi et al., 2002). There are two exons in exon 1, which are alternatively used in two different transcripts. Totally, three transcript variants are known.
Transcription DKK3 gene is transcribed into three different isoforms (NM_015881, 2650 bp, NM_013253, 2635 bp, and NM_001018057, 2587 bp). Two of them result from alternative use of first exon (i.e. exon 1a and exon 1b, although they are both non-coding). One more variant lacks exon 1. All the variants share exons 2 to 8, and code for a 350 aa functioning protein.
Pseudogene None sited.

Protein

 
  All the DKK3 gene transcripts encode a 350 aa, 38.3 kDa glycoprotein (NM_015881→NP_056965, NM_013253→NP_037385,and NM_001018057→NP_001018067, respectively). DKK3 protein contains N-terminal signal peptide, two cysteine rich domains (i.e. DKK-type Cys-1 and DKK-type Cys-2). DKK-type Cys-1 is located within the DKK_N (Dickkopf N-terminal cysteine rich region, pfam04706) region. DKK-type Cys-2 include prokineticin region (pfam06607, white dashed lines). Two coiled-coil regions are present in N-terminal side and C-terminal side. Putative N-glycosylation sites are indicated.
Description DKK3 protein possesses several defined regions, which may confer multiple functions to the protein. Amino acid (aa) 1-21 is a signal peptide (SP) that characterizes this protein as a secreted protein. Four putative N-glycosylated sites and O-glycosylated at one site region (aa 26-46) suggest that the protein may undergo posttranslational modification before its secretion.
Two cysteine-rich domains are conserved over species. N-terminal one is DKK_N (formerly called Cys-1) and C-terminal one is called Colipase fold (formerly called Cys-2). Both two domains contain 10 cysteine residues and are separated by a 12 aa linker region. Colipase fold features lipid hydrolysis and may contribute to lipid binding (interact with cell surface LRP5/LRP6, for instance.) Colipase fold is solved to form interactive surface with finger-like structure. The presence of coiled-coil domain suggests possible protein-protein interaction. All these structural features facilitate Wnt/DKK interactions (as will be apparent below). Moreover, DKK3 possesses potential proteolytic cleavage sites by furin-type proteases, suggesting that the protein is subject to posttranslational processing.
Expression Human DKK3 DNA/RNA expression is widely observed in human normal tissues. Northern blotting analyses reveal that DKK3 mRNA is expressed in brain, heart, lung, liver, pancreas, spleen, kidney, small intestine, colon, skeletal muscle and placenta. Amongst them, DKK3 expression is particularly high in heart and brain.
Reflecting the alias of this gene, RIG (Regulated in glioma) or REIC (Reduced expression in cancer), DKK3 mRNA and protein expression is deregulated in a wide range of tumors, including glioma, gastric carcinoma, colorectal carcinoma, hepatocellular carcinoma, pancreatic cancer, leukemia, renal cell carcinoma, bladder carcinoma, prostate cancer, testicular carcinoma, ovarian carcinoma, cervical cancer, breast cancers, non-small cell lung cancer, mesothelioma and skin cancers. This downregulation in mRNA expression is caused by promoter hypermethylation. Thus, DKK3 is thought to be a potential tumor suppressor, and is focussed as a therapeutic target. However, in DKK3 protein expression level, some reports show that DKK3 protein expression is up-regulated, suggesting cancer specific expression pattern and potential alternative role in cancer invasion.
Localisation DKK3 protein is an extracellular secreted protein. Its intracellular localization is observed in cytoplasm, organelle and endoplasmic reticulum.
 
  DKK family is known as a negative regulator of Wnt signaling. There are three pathways in Wnt signaling, Wnt/beta-catenin pathway, planar cell polarity pathway and Wnt/Ca2+ cascade. Wnt/beta-catenin pathway is called canonical pathway and latter two are called non-canonical pathway.
In Wnt/beta-catenin pathway, cytoplasmic beta-catenin is ubiquitinated and degraded without Wnt ligand binding. When Wnt ligands bind to the receptor complex, Frizzled and Lrp5/6, cytoplasmic beta-catenin is stabilized and translocated into the nucleus, inducing TCF/LEF mediated transcription. DKK family members antagonize this pathway by binding Lrp5/6 and Kremen. Among DKK family member, DKK1, 2 and 4 can bind to LRP5/6, but DKK3 cannot. DKK2 can also activate beta-catenin accumulation.
Binding of DKKs with LRP5/6 and Kremen complex resulted in endocytosis of Kremen.
Function DKK is firstly identified in Xenopus embryogenesis (Glinka et al., 1998), and named after its role as head inducer, Dickkopf (dick=thick, kopf=head). DKK binds to the Wnt co-receptor, lipoprotein receptor-related protein5/6 class (LRP5/6), and exert antagonistic function for Wnt induced beta-catenin stabilization (Fedi et al., 1999; He et al., 2004). DKKs play an important role in vertebrate antero-posterior axial patterning, limb formation, eye formation and bone formation (Niehrs, 2006).
The Wnt signaling inhibitory ability differs between the DKK members; DKK1 and DKK4 can inhibit Wnt/beta-catenin pathway, and DKK2 can both inhibit and activate beta-catenin signaling (Wu et al., 2000), and co-receptor class of Kremen protein facilitates DKK1, 2, and 4 binding to block Wnt signaling (Bafico et al., 2001). However, DKK3 neither bind to LRP5/6 nor does Kremen (Mao et al., 2003; Brott et al., 2001).
The receptor for DKK3 is yet to be investigated and its Wnt/beta-catenin inhibitory function is still elusive (Veeck et al., 2012). However, Wnt modulating function of DKK3 are reported in several kinds of malignancies including glioma (Mizobuchi et al., 2008), breast cancer (Wang et al., 2008), prostate cancer (Abarzua et al., 2005 and Kawano et al., 2006) and lung cancer (Yue et al., 2008). And because of its obvious tumor suppressor function, DKK3 is regarded as tumor suppressor.
Recently, intracellular function of DKK3 was noted. Cytoplasmic DKK3 may bind to beta TrCP, and facilitate beta-catenin degradation (Lee et al., 2009).
In cancers, DKK3 mRNA expression is down-regulated by promoter methylation (see below), but there is a discrepancy between mRNA expression and protein expression in tissue samples, which may reflect tumor heterogeneity.
Homology DKK3 homolog is conserved over species, in vertebrates including zebrafish, murine, rat, chicken, dog, cow, Rhesus monkey and chimpanzee and invertebrate, such as Dictyostelium, cnidarian, tunicate and ascidian.
In vertebrates, DKK proteins consist from 4 members (i.e. DKK1, 2, 3 and 4). Although all these proteins possess two cysteine-rich domains, the homology among DKK1, 2 and 4 is 41-50%, whereas that between DKK3 and other members it is 37-40%.

Mutations

Note Neither germinal nor somatic mutation is reported. 5 single nucleotide polymorphisms (SNP) are known (rs3206824, rs11022095, rs1472189, rs7396187, and rs2291599). Please refer to the link below.

Implicated in

Note
  
Entity Brain tumors (neuroblastoma, glioma and ganglioneuroma)
Note DKK3 protein expression is down-regulated in brain tumors.
In neuroblastoma, DKK3 mRNA expression is low. DKK3 functions as tumor suppressor, and its expression is negatively regulated via miR92, which is up-regulated by MYCN (De Brouwer et al., 2012; Haug et al., 2011).
In ganglioneuroma, DKK3 expression is high (Koppen et al., 2008).
In glioma and malignant glioma, DNA hypermethylation in DKK3 and consequent reduced expression of DKK3 protein are observed. Forced expression of DKK3 in glioma cell lines induces JUN phosphorylation-mediated apoptosis (Götze et al., 2010; Mizobuchi et al., 2008).
Prognosis Low DKK3 expression in neuroblastoma correlates with poor prognosis.
Oncogenesis DKK3 methylation status may indicate neuroblastic tumor maturation.
  
  
Entity Alzheimer's disease
Note DKK3 level in the cerebrospinal fluid in Alzheimer's disease patients is higher than plasma DKK3 level (Zenzmaier et al., 2009).
  
  
Entity Gastrointestinal cancers, head and neck, oral cancer
Note Some reports indicate that loss of DKK3 function may be involved in oral, and head and neck squamous cell carcinomas (SCC). Frequent LOH in DKK3 locus (11p15.2) is reported (Katase et al., 2008). DKK3 mRNA expression is decreased in oral SCC tissue sample and cell lines (Pannone et al., 2010). However, protein expression status is different. DKK3 protein is dominantly expressed in oral SCC tissue sample and cell line (Katase et al., 2012). Moreover, DKK3 knockdown in oral SCC derived cells resulted in reduced cell migration and invasion (Katase et al., 2013). DKK3 expression increases from epithelial dysplasia, carcinoma in situ to invasive cancer, and is though to be independent with Wnt/beta-catenin pathway (Fujii et al., 2011).
Prognosis LOH in DKK3 locus inversely correlates with lymph nodal metastasis and overall survival. DKK3 protein expression correlates with shorter disease free survival, metastasis free survival.
Oncogenesis DKK3 is suggested to be involved in SCC carcinogenesis in head and neck, and oral region. However, its detailed function is yet to be investigated.
  
  
Entity Gastrointestinal cancers, esophageal cancer
Note DKK3 DNA is hypermethylated in esophageal cancer patient samples and cell lines (Liu et al., 2011; Maehata et al., 2008). However, one report indicates that DKK3 protein is overexpressed (Zhang et al., 2010).
Prognosis Methylation of DKK3 predicts risk of recurrence. DKK3 protein expression correlates with invasive depth, lymph nodal metastasis and advanced TNM stage.
Oncogenesis DKK3 methylation may be involved in esophageal cancer development.
  
  
Entity Gastrointestinal cancers, gastric cancer
Note In gastric adenocarcinoma cell lines, DKK3 mRNA expression is down-regulated (Yu et al., 2009; Maehata et al., 2008; Sato et al., 2007). However, in tissue samples, DKK3 protein expression was observed. DKK3 protein expression is also observed in tumor endothelium adjacent to cancer tissue (Mühlmann et al., 2010). In mice gastric scirrhous carcinoma model, intraperitoneal administration of adenovirus vector carrying DKK3 significantly decreases tumor dissemination and increased recruitment of killer T cells (Than et al., 2011).
Prognosis Methylation of DKK3 is a prognostic predictor for shorter survival. DKK3 protein expression in cancer cells is associated with pT-stage and UICC stage. DKK3 protein expression correlates with favorable prognosis.
Oncogenesis Reduced DKK3 mRNA expression by CpG methylation is thought to be involved in gastric cancer development, and might be a potential clinical target.
  
  
Entity Gastrointestinal cancers, colorectal cancer
Note In colorectal adenocarcinoma cell lines, DKK3 expression is down-regulated both in mRNA and protein level. Forced overexpression of DKK3 mRNA results in G0/G1 cell cycle arrest, induction of apoptosis and reduced cell proliferation. Increased cytoplasmic beta-catenin is also noted (Yang et al., 2012). In clinical tissue samples, DKK3 protein expression is decreased compared to corresponding normal tissues, and DKK3 expression correlates with invasion depth, TNM stage and dedifferentiation (Wang et al., 2012).
DKK3 protein expression in tumor vessels is noted. Immunohistochemical analysis revealed that vessels in/adjacent to the cancer tissue shows DKK3 protein expression, whereas normal vessels do not. This implies pro-angiogenic function of DKK3 protein (Zitt et al., 2008; Untergasser et al., 2008).
Oncogenesis DKK3 might be involved in carcinogenesis of colorectal cancer via Wnt/beta-catenin pathway.
  
  
Entity Liver tumors, hepatocellular carcinoma and hepatoblastoma
Note In hepatocellular carcinoma (HCC) and cirrhosis-related HCC tissue samples, DKK3 mRNA expression is low because of promoter hypermethylation (Yang et al., 2010; Ding et al., 2009). However, in HCC and hepatoblastomas tissue sample, DKK3 protein expression is up-regulated (Pei et al., 2009).
Prognosis Hypermethylation of DKK3 may correlate to shorter progression free survival in cirrhosis-related HCC. Hypermethylation is more frequent in high-grade tumor.
Oncogenesis DKK3 may be involved in tumorigenesis of HCC and associated with dedifferentiated nature.
  
  
Entity Pancreatic cancer
Note DKK3 expression is low in pancreatic cancer cell lines (MIA PaCa-2 and AsPC-1), due to DNA methylation. DKK3 expression in transfection of expressing plasmids decreased cell proliferation and beta-catenin expression (Gu et al., 2011). However, another report indicates that DKK3 expression is overexpressed in PANC-1 cell line (derived from human pancreatic ductal carcinoma), and that its down-regulation results in reduction in cellular proliferation (Zenzmaier et al., 2012).
DKK3 protein expression in tissue samples revealed that DKK3 protein expression is observed both in cancer cells and tumor endothelium (Fong et al., 2009).
Prognosis DKK3 expressing endothelium is sensitive to anticancer drug. Low DKK3 protein expression in tumor endothelium correlates with worse clinical outcome.
Oncogenesis DKK3 may be involved in carcinogenesis in pancreatic carcinoma via Wnt/beta-catenin signaling.
  
  
Entity Hematopoietic neoplasm, leukemias
Note The possible function of DKK3 as immune modulator and involvement in hematopoietic neoplasms are reported. As for chronic lymphatic leukemia (CLL), CLL-derived cell line demonstrated DKK3 methylation ranging 23-37%. DKK3 methylation is also observed in CLL patients, ranging 18.7-61% (Moskalev et al., 2012).
A small population of acute myeloid leukemia (AML) patient shows DKK3 methylation (Griffiths et al., 2010; Valencia et al., 2009).
DKK3 methylation is also reported in acute lymphatic leukemia (ALL) derived cell lines and patients (Roman-Gomez et al., 2004).
Recombinant DKK3 may alter CD14+ monocyte into novel phenotype, which demonstrates dendritic cell like appearance and IL-4, GM-CSF. Administration of recombinant DKK3 results in tumor regression with CD11c+, CD8+ T-cell infiltration (Watanabe et al., 2009).
Prognosis DKK3 methylation is a prognostic predictor of disease free survival in ALL.
  
  
Entity Gynecological cancers, cervical cancer
Note In cervical squamous cell carcinoma (SCC) tissue samples and cell lines, DNA methylation of DKK3 is reported (Kang et al., 2012). Overexpression in cervical SCC cell line results in reduction of cellular beta-catenin level (Lee et al., 2009). DKK3 methylation is reported also in cervical adenocarcinoma (van der Meide et al., 2011).
Prognosis DKK3 DNA methylation status may correlate with larger tumor size and shorter disease free survival.
Oncogenesis DKK3 methylation and aberrant Wnt/beta-catenin signaling may be involved in cervical SCC.
  
  
Entity Gynecological cancers, ovarian cancer and endometrial cancer
Note DKK3 mRNA expression is decreased in ovarian cancer tissue (You et al., 2011), and serum DKK3 protein level is low in ovarian cancer patients compared to non-cancerous subject (Jiang et al., 2010).
In endometrial cancer tissue samples, DKK3 mRNA expression is down-regulated, and overexpression in endometrial cancer cell lines results in reduced cell proliferation and beta-catenin mediated TCF activity (Dellinger et al., 2012).
Prognosis Low serum DKK3 level correlate with high frequency of lymph nodal metastasis. Low DKK3 mRNA level correlates with high stage and high incidence of lymph nodal metastasis.
Oncogenesis DKK3 may be involved in carcinogenesis of ovarian and endometrial cancer.
  
  
Entity Breast cancer
Note DNA hypermethylation of DKK3 is reported both in breast cancer tissue samples and cell lines (Veeck et al., 2008; Veeck et al., 2009; Fujikane et al., 2010). Forced expression in cancer cell lines results in induction of JNK-mediated apoptosis and reduction of anticancer drug resistance (Kawasaki et al.,2009). Another report demonstrated that knockdown of DKK3 by shRNA transfection revealed the possible function of DKK3 as modulator of Wnt/beta-catenin signaling modulator in breast cancer (Wang et al., 2008).
Prognosis DKK3 DNA methylation status may be a prognostic factor for disease free survival and overall survival.
Oncogenesis DKK3 may be involved in carcinogenesis of breast cancer, and may modulate Wnt/beta-catenin signaling.
  
  
Entity Urologic cancers, renal cancer and bladder cancer
Note In renal cell carcinoma (RCC), DKK3 mRNA expression is down-regulated because of promoter CpG island methylation. Stable transfection of DKK3 in RCC cell lines does not affect in Wnt/beta-catenin pathway, but induce apoptosis via JNK pathway (Ueno et al., 2011). Methylation of DKK3 is also observed in renal clear cell carcinoma (RCCC) (Kurose et al., 2004).
SNP in DKK3 gene is reported in RCC (Hirata et al., 2009).
DKK3 methylation is observed in bladder cancer, and forced expression in bladder cancer cell lines induces JNK mediated apoptosis (Urakami et al., 2006; Hirata et al., 2012; Jin et al., 2012).
Prognosis rs1472189 SNP correlates with distant metastasis.
Oncogenesis DKK3 methylation may be involved in carcinogenesis in RCC and bladder carcinoma.
  
  
Entity Prostate cancer and testicular cancer
Note In prostate cancer, mRNA and protein expression are down-regulated. DKK3 protein expression in prostate cancer decreases gradually in prostate carcinogenesis (Kawano et al., 2006; Zenzmaier et al., 2008). High DKK3 protein level is reported in seminal plasma of prostate cancer patients (Zenzmaier et al., 2011).
Overexpression in prostate cancer cell line induces JNK-mediated apoptosis (Abarzua et al., 2005) and decreases lymph nodal metastasis in prostate cancer mice model (Edamura et al., 2007; Chen et al., 2009).
In testicular cancer, DKK3 expression is down-regulated, and forced expression in cancer cell lines induce JNK-mediated apoptosis (Tanimoto et al., 2007).
Prognosis DKK3 protein expression loss may correlate to tumor grade. Overexpression of DKK3 in prostate cancer model may ameliorate tumor progression.
Oncogenesis DKK3 methylation may be involved in carcinogenesis in prostate and testicular cancers.
  
  
Entity Lung cancer and mesothelioma
Note Reduced DKK3 mRNA level is firstly reported in human non-small cell lung cancer (NSCLC) tissue sample (Nozaki et al., 2001). Decreased expression of DKK3 mRNA is due to DNA methylation, and DKK3 may regulate cancer cell growth via Wnt/beta-catenin pathway (Yue et al., 2008). DKK3 methylation is observed also in precarcinomatous lesion, atypical adenomatous hyperplasia (Licchesi et al., 2008). In mesothelioma cell line, DKK3 expression is down-regulated, and overexpression of DKK3 induce JNK-mediated apoptosis (Kashiwakura et al., 2008).
Oncogenesis DKK3 may be involved in NSCLC via Wnt/beta-catenin signaling regulation.
  
  
Entity Skin cancer and malignant melanoma
Note DKK3 protein expression is down-regulated in skin cancers (Du et al., 2011). In malignant melanoma tissue sample and cell lines, DKK3 mRNA expression is strongly reduced. Stable expression of DKK3 in malignant melanoma reduces cellular migration (Kuphal et al., 2006).
Oncogenesis DKK3 may function as a tumor suppressor in skin tumors and malignant melanoma.
  
  
Entity Osteosarcoma
Note Osteosarcoma-derived cell line, Saos2 shows decreased expression of DKK3, which may modulate Wnt/beta-catenin signaling (Hoang et al., 2004).
Oncogenesis DKK3 may be involved in osteosarcoma carcinogenesis.
  

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PMID 19192722
 
Knockdown of Dkk-3 decreases cancer cell migration and invasion independently of the Wnt pathways in oral squamous cell carcinoma-derived cells.
Katase N, Lefeuvre M, Tsujigiwa H, Fujii M, Ito S, Tamamura R, Buery RR, Gunduz M, Nagatsuka H.
Oncol Rep. 2013 Apr;29(4):1349-55. doi: 10.3892/or.2013.2251. Epub 2013 Jan 24.
PMID 23354949
 
Regulation of prostate cell growth and morphogenesis by Dickkopf-3.
Kawano Y, Kitaoka M, Hamada Y, Walker MM, Waxman J, Kypta RM.
Oncogene. 2006 Oct 19;25(49):6528-37. Epub 2006 Jun 5.
PMID 16751809
 
REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer.
Kawasaki K, Watanabe M, Sakaguchi M, Ogasawara Y, Ochiai K, Nasu Y, Doihara H, Kashiwakura Y, Huh NH, Kumon H, Date H.
Cancer Gene Ther. 2009 Jan;16(1):65-72. doi: 10.1038/cgt.2008.58. Epub 2008 Jul 25.
PMID 18654608
 
Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells.
Kobayashi K, Ouchida M, Tsuji T, Hanafusa H, Miyazaki M, Namba M, Shimizu N, Shimizu K.
Gene. 2002 Jan 9;282(1-2):151-8.
PMID 11814687
 
Dickkopf-3 expression is a marker for neuroblastic tumor maturation and is down-regulated by MYCN.
Koppen A, Ait-Aissa R, Koster J, Ora I, Bras J, van Sluis PG, Caron H, Versteeg R, Valentijn LJ.
Int J Cancer. 2008 Apr 1;122(7):1455-64.
PMID 18059033
 
Functional and structural diversity of the human Dickkopf gene family.
Krupnik VE, Sharp JD, Jiang C, Robison K, Chickering TW, Amaravadi L, Brown DE, Guyot D, Mays G, Leiby K, Chang B, Duong T, Goodearl AD, Gearing DP, Sokol SY, McCarthy SA.
Gene. 1999 Oct 1;238(2):301-13.
PMID 10570958
 
Expression of Dickkopf genes is strongly reduced in malignant melanoma.
Kuphal S, Lodermeyer S, Bataille F, Schuierer M, Hoang BH, Bosserhoff AK.
Oncogene. 2006 Aug 17;25(36):5027-36. Epub 2006 Mar 27.
PMID 16568085
 
Decreased expression of REIC/Dkk-3 in human renal clear cell carcinoma.
Kurose K, Sakaguchi M, Nasu Y, Ebara S, Kaku H, Kariyama R, Arao Y, Miyazaki M, Tsushima T, Namba M, Kumon H, Huh NH.
J Urol. 2004 Mar;171(3):1314-8.
PMID 14767340
 
Dkk3, downregulated in cervical cancer, functions as a negative regulator of beta-catenin.
Lee EJ, Jo M, Rho SB, Park K, Yoo YN, Park J, Chae M, Zhang W, Lee JH.
Int J Cancer. 2009 Jan 15;124(2):287-97. doi: 10.1002/ijc.23913.
PMID 19003969
 
Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung.
Licchesi JD, Westra WH, Hooker CM, Machida EO, Baylin SB, Herman JG.
Carcinogenesis. 2008 May;29(5):895-904. doi: 10.1093/carcin/bgn017. Epub 2008 Feb 28.
PMID 18308762
 
Plasma DNA methylation of Wnt antagonists predicts recurrence of esophageal squamous cell carcinoma.
Liu JB, Qiang FL, Dong J, Cai J, Zhou SH, Shi MX, Chen KP, Hu ZB.
World J Gastroenterol. 2011 Nov 28;17(44):4917-21. doi: 10.3748/wjg.v17.i44.4917.
PMID 22171134
 
Functional epigenomics identifies genes frequently silenced in prostate cancer.
Lodygin D, Epanchintsev A, Menssen A, Diebold J, Hermeking H.
Cancer Res. 2005 May 15;65(10):4218-27.
PMID 15899813
 
Transcriptional silencing of Dickkopf gene family by CpG island hypermethylation in human gastrointestinal cancer.
Maehata T, Taniguchi H, Yamamoto H, Nosho K, Adachi Y, Miyamoto N, Miyamoto C, Akutsu N, Yamaoka S, Itoh F.
World J Gastroenterol. 2008 May 7;14(17):2702-14.
PMID 18461655
 
Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling.
Mao B, Niehrs C.
Gene. 2003 Jan 2;302(1-2):179-83.
PMID 12527209
 
REIC/Dkk-3 induces cell death in human malignant glioma.
Mizobuchi Y, Matsuzaki K, Kuwayama K, Kitazato K, Mure H, Kageji T, Nagahiro S.
Neuro Oncol. 2008 Jun;10(3):244-53. doi: 10.1215/15228517-2008-016. Epub 2008 Apr 28.
PMID 18443132
 
Concurrent epigenetic silencing of wnt/β-catenin pathway inhibitor genes in B cell chronic lymphocytic leukaemia.
Moskalev EA, Luckert K, Vorobjev IA, Mastitsky SE, Gladkikh AA, Stephan A, Schrenk M, Kaplanov KD, Kalashnikova OB, Potz O, Joos TO, Hoheisel JD.
BMC Cancer. 2012 Jun 6;12:213. doi: 10.1186/1471-2407-12-213.
PMID 22672427
 
Immunohistochemically detectable dickkopf-3 expression in tumor vessels predicts survival in gastric cancer.
Muhlmann G, Untergasser G, Zitt M, Zitt M, Maier H, Mikuz G, Kronberger IE, Haffner MC, Gunsilius E, Ofner D.
Virchows Arch. 2010 Jun;456(6):635-46. doi: 10.1007/s00428-010-0926-4. Epub 2010 May 15.
PMID 20473620
 
Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins.
Nakayama K.
Biochem J. 1997 Nov 1;327 ( Pt 3):625-35. (REVIEW)
PMID 9599222
 
Function and biological roles of the Dickkopf family of Wnt modulators.
Niehrs C.
Oncogene. 2006 Dec 4;25(57):7469-81. (REVIEW)
PMID 17143291
 
Reduced expression of REIC/Dkk-3 gene in non-small cell lung cancer.
Nozaki I, Tsuji T, Iijima O, Ohmura Y, Andou A, Miyazaki M, Shimizu N, Namba M.
Int J Oncol. 2001 Jul;19(1):117-21.
PMID 11408931
 
WNT pathway in oral cancer: epigenetic inactivation of WNT-inhibitors.
Pannone G, Bufo P, Santoro A, Franco R, Aquino G, Longo F, Botti G, Serpico R, Cafarelli B, Abbruzzese A, Caraglia M, Papagerakis S, Lo Muzio L.
Oncol Rep. 2010 Oct;24(4):1035-41.
PMID 20811686
 
Overexpression of Dickkopf 3 in hepatoblastomas and hepatocellular carcinomas.
Pei Y, Kano J, Iijima T, Morishita Y, Inadome Y, Noguchi M.
Virchows Arch. 2009 Jun;454(6):639-46. doi: 10.1007/s00428-009-0772-4. Epub 2009 May 13.
PMID 19437037
 
Transcriptional silencing of the Dickkopfs-3 (Dkk-3) gene by CpG hypermethylation in acute lymphoblastic leukaemia.
Roman-Gomez J, Jimenez-Velasco A, Agirre X, Castillejo JA, Navarro G, Barrios M, Andreu EJ, Prosper F, Heiniger A, Torres A.
Br J Cancer. 2004 Aug 16;91(4):707-13.
PMID 15226763
 
Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors.
Sato H, Suzuki H, Toyota M, Nojima M, Maruyama R, Sasaki S, Takagi H, Sogabe Y, Sasaki Y, Idogawa M, Sonoda T, Mori M, Imai K, Tokino T, Shinomura Y.
Carcinogenesis. 2007 Dec;28(12):2459-66. Epub 2007 Aug 3.
 
REIC/Dkk-3 as a potential gene therapeutic agent against human testicular cancer.
Tanimoto R, Abarzua F, Sakaguchi M, Takaishi M, Nasu Y, Kumon H, Huh NH.
Int J Mol Med. 2007 Mar;19(3):363-8.
PMID 17273781
 
Intraperitoneal administration of an adenovirus vector carrying REIC/Dkk-3 suppresses peritoneal dissemination of scirrhous gastric carcinoma.
Than SS, Kataoka K, Sakaguchi M, Murata H, Abarzua F, Taketa C, Du G, Yashiro M, Yanagihara K, Nasu Y, Kumon H, Huh NH.
Oncol Rep. 2011 Apr;25(4):989-95. doi: 10.3892/or.2011.1149. Epub 2011 Jan 18.
PMID 21249317
 
A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines.
Tsuji T, Miyazaki M, Sakaguchi M, Inoue Y, Namba M.
Biochem Biophys Res Commun. 2000 Feb 5;268(1):20-4.
PMID 10652205
 
Antiproliferative activity of REIC/Dkk-3 and its significant down-regulation in non-small-cell lung carcinomas.
Tsuji T, Nozaki I, Miyazaki M, Sakaguchi M, Pu H, Hamazaki Y, Iijima O, Namba M.
Biochem Biophys Res Commun. 2001 Nov 23;289(1):257-63.
PMID 11708809
 
Wnt antagonist DICKKOPF-3 (Dkk-3) induces apoptosis in human renal cell carcinoma.
Ueno K, Hirata H, Majid S, Chen Y, Zaman MS, Tabatabai ZL, Hinoda Y, Dahiya R.
Mol Carcinog. 2011 Jun;50(6):449-57. doi: 10.1002/mc.20729. Epub 2011 Jan 25.
PMID 21268126
 
The Dickkopf-homolog 3 is expressed in tumor endothelial cells and supports capillary formation.
Untergasser G, Steurer M, Zimmermann M, Hermann M, Kern J, Amberger A, Gastl G, Gunsilius E.
Int J Cancer. 2008 Apr 1;122(7):1539-47.
PMID 18033687
 
Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection.
Urakami S, Shiina H, Enokida H, Kawakami T, Kawamoto K, Hirata H, Tanaka Y, Kikuno N, Nakagawa M, Igawa M, Dahiya R.
Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2109-16.
PMID 16609023
 
Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia.
Valencia A, Roman-Gomez J, Cervera J, Such E, Barragan E, Bolufer P, Moscardo F, Sanz GF, Sanz MA.
Leukemia. 2009 Sep;23(9):1658-66. doi: 10.1038/leu.2009.86. Epub 2009 Apr 23.
PMID 19387464
 
Wnt signalling in human breast cancer: expression of the putative Wnt inhibitor Dickkopf-3 (DKK3) is frequently suppressed by promoter hypermethylation in mammary tumours.
Veeck J, Bektas N, Hartmann A, Kristiansen G, Heindrichs U, Knuchel R, Dahl E.
Breast Cancer Res. 2008;10(5):R82. doi: 10.1186/bcr2151. Epub 2008 Sep 30.
PMID 18826564
 
Targeting the Wnt pathway in cancer: the emerging role of Dickkopf-3.
Veeck J, Dahl E.
Biochim Biophys Acta. 2012 Jan;1825(1):18-28. doi: 10.1016/j.bbcan.2011.09.003. Epub 2011 Sep 22. (REVIEW)
PMID 21982838
 
Prognostic relevance of Wnt-inhibitory factor-1 (WIF1) and Dickkopf-3 (DKK3) promoter methylation in human breast cancer.
Veeck J, Wild PJ, Fuchs T, Schuffler PJ, Hartmann A, Knuchel R, Dahl E.
BMC Cancer. 2009 Jul 1;9:217. doi: 10.1186/1471-2407-9-217.
PMID 19570204
 
The clinicopathological significance of REIC expression in colorectal carcinomas.
Wang W, Zhu W, Xu XY, Nie XC, Yang X, Xing YN, Yu M, Liu YP, Takano Y, Zheng HC.
Histol Histopathol. 2012 Jun;27(6):735-43.
PMID 22473694
 
Musashi1 modulates mammary progenitor cell expansion through proliferin-mediated activation of the Wnt and Notch pathways.
Wang XY, Yin Y, Yuan H, Sakamaki T, Okano H, Glazer RI.
Mol Cell Biol. 2008 Jun;28(11):3589-99. doi: 10.1128/MCB.00040-08. Epub 2008 Mar 24.
PMID 18362162
 
Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression.
Watanabe M, Kashiwakura Y, Huang P, Ochiai K, Futami J, Li SA, Takaoka M, Nasu Y, Sakaguchi M, Huh NH, Kumon H.
Int J Oncol. 2009 Mar;34(3):657-63.
PMID 19212670
 
Mutual antagonism between dickkopf1 and dickkopf2 regulates Wnt/beta-catenin signalling.
Wu W, Glinka A, Delius H, Niehrs C.
Curr Biol. 2000 Dec 14-28;10(24):1611-4.
PMID 11137016
 
Methylation of Dickkopf-3 as a prognostic factor in cirrhosis-related hepatocellular carcinoma.
Yang B, Du Z, Gao YT, Lou C, Zhang SG, Bai T, Wang YJ, Song WQ.
World J Gastroenterol. 2010 Feb 14;16(6):755-63.
PMID 20135726
 
Overexpression of Dickkopf-3 induces apoptosis through mitochondrial pathway in human colon cancer.
Yang ZR, Dong WG, Lei XF, Liu M, Liu QS.
World J Gastroenterol. 2012 Apr 14;18(14):1590-601. doi: 10.3748/wjg.v18.i14.1590.
PMID 22529687
 
Expression of the Wnt antagonist DKK3 is frequently suppressed in sporadic epithelial ovarian cancer.
You A, Fokas E, Wang LF, He H, Kleb B, Niederacher D, Engenhart-Cabillic R, An HX.
J Cancer Res Clin Oncol. 2011 Apr;137(4):621-7. doi: 10.1007/s00432-010-0916-6. Epub 2010 Jun 9.
PMID 20532910
 
Promoter methylation of the Wnt/beta-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer.
Yu J, Tao Q, Cheng YY, Lee KY, Ng SS, Cheung KF, Tian L, Rha SY, Neumann U, Rocken C, Ebert MP, Chan FK, Sung JJ.
Cancer. 2009 Jan 1;115(1):49-60. doi: 10.1002/cncr.23989.
PMID 19051296
 
Downregulation of Dkk3 activates beta-catenin/TCF-4 signaling in lung cancer.
Yue W, Sun Q, Dacic S, Landreneau RJ, Siegfried JM, Yu J, Zhang L.
Carcinogenesis. 2008 Jan;29(1):84-92. Epub 2007 Nov 28.
PMID 18048388
 
Dickkopf-3 maintains the PANC-1 human pancreatic tumor cells in a dedifferentiated state.
Zenzmaier C, Hermann M, Hengster P, Berger P.
Int J Oncol. 2012 Jan;40(1):40-6. doi: 10.3892/ijo.2011.1180. Epub 2011 Aug 29.
PMID 21879258
 
[Expression of Dickkopf-3 in esophageal squamous cell carcinoma].
Zhang Y, Dong WG, Yang ZR, Lei XF, Luo HS.
Zhonghua Nei Ke Za Zhi. 2010 Apr;49(4):325-7.
PMID 20627041
 
Dickkopf-3 as a new potential marker for neoangiogenesis in colorectal cancer: expression in cancer tissue and adjacent non-cancerous tissue.
Zitt M, Untergasser G, Amberger A, Moser P, Stadlmann S, Zitt M, Muller HM, Muhlmann G, Perathoner A, Margreiter R, Gunsilius E, Ofner D.
Dis Markers. 2008;24(2):101-9.
PMID 18219095
 
Colipase: structure and interaction with pancreatic lipase.
van Tilbeurgh H, Bezzine S, Cambillau C, Verger R, Carriere F.
Biochim Biophys Acta. 1999 Nov 23;1441(2-3):173-84. (REVIEW)
PMID 10570245
 
Promoter methylation analysis of WNT/β-catenin signaling pathway regulators to detect adenocarcinoma or its precursor lesion of the cervix.
van der Meide WF, Snellenberg S, Meijer CJ, Baalbergen A, Helmerhorst TJ, van der Sluis WB, Snijders PJ, Steenbergen RD.
Gynecol Oncol. 2011 Oct;123(1):116-22. doi: 10.1016/j.ygyno.2011.06.015. Epub 2011 Jul 2.
PMID 21726894
 

Citation

This paper should be referenced as such :
Katase, N ; Nohno, T
DKK3 (dickkopf 3 homolog (Xenopus laevis))
Atlas Genet Cytogenet Oncol Haematol. 2013;17(10):678-686.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/DKK3ID40327ch11p15.html


External links

Nomenclature
HGNC (Hugo)DKK3   2893
Cards
AtlasDKK3ID40327ch11p15
Entrez_Gene (NCBI)DKK3  27122  dickkopf WNT signaling pathway inhibitor 3
AliasesREIC; RIG
GeneCards (Weizmann)DKK3
Ensembl hg19 (Hinxton)ENSG00000050165 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000050165 [Gene_View]  chr11:11962996-12008639 [Contig_View]  DKK3 [Vega]
ICGC DataPortalENSG00000050165
TCGA cBioPortalDKK3
AceView (NCBI)DKK3
Genatlas (Paris)DKK3
WikiGenes27122
SOURCE (Princeton)DKK3
Genetics Home Reference (NIH)DKK3
Genomic and cartography
GoldenPath hg38 (UCSC)DKK3  -     chr11:11962996-12008639 -  11p15.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)DKK3  -     11p15.3   [Description]    (hg19-Feb_2009)
EnsemblDKK3 - 11p15.3 [CytoView hg19]  DKK3 - 11p15.3 [CytoView hg38]
Mapping of homologs : NCBIDKK3 [Mapview hg19]  DKK3 [Mapview hg38]
OMIM605416   
Gene and transcription
Genbank (Entrez)AB033421 AB034203 AB057591 AF052161 AF177396
RefSeq transcript (Entrez)NM_001018057 NM_001330220 NM_013253 NM_015881
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)DKK3
Cluster EST : UnigeneHs.731954 [ NCBI ]
CGAP (NCI)Hs.731954
Alternative Splicing GalleryENSG00000050165
Gene ExpressionDKK3 [ NCBI-GEO ]   DKK3 [ EBI - ARRAY_EXPRESS ]   DKK3 [ SEEK ]   DKK3 [ MEM ]
Gene Expression Viewer (FireBrowse)DKK3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)27122
GTEX Portal (Tissue expression)DKK3
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UBP4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UBP4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UBP4
Splice isoforms : SwissVarQ9UBP4
PhosPhoSitePlusQ9UBP4
Domains : Interpro (EBI)Dickkopf_N   
Domain families : Pfam (Sanger)Dickkopf_N (PF04706)   
Domain families : Pfam (NCBI)pfam04706   
Conserved Domain (NCBI)DKK3
DMDM Disease mutations27122
Blocks (Seattle)DKK3
SuperfamilyQ9UBP4
Human Protein AtlasENSG00000050165
Peptide AtlasQ9UBP4
HPRD05659
IPIIPI00007403   IPI00910436   IPI00002714   IPI00386812   IPI01015225   IPI00971192   IPI00975563   IPI00977198   
Protein Interaction databases
DIP (DOE-UCLA)Q9UBP4
IntAct (EBI)Q9UBP4
FunCoupENSG00000050165
BioGRIDDKK3
STRING (EMBL)DKK3
ZODIACDKK3
Ontologies - Pathways
QuickGOQ9UBP4
Ontology : AmiGOextracellular space  anatomical structure morphogenesis  Wnt signaling pathway  regulation of transforming growth factor beta receptor signaling pathway  adrenal gland development  negative regulation of aldosterone biosynthetic process  negative regulation of transcription, DNA-templated  negative regulation of canonical Wnt signaling pathway  negative regulation of anti-Mullerian hormone signaling pathway  negative regulation of cortisol biosynthetic process  
Ontology : EGO-EBIextracellular space  anatomical structure morphogenesis  Wnt signaling pathway  regulation of transforming growth factor beta receptor signaling pathway  adrenal gland development  negative regulation of aldosterone biosynthetic process  negative regulation of transcription, DNA-templated  negative regulation of canonical Wnt signaling pathway  negative regulation of anti-Mullerian hormone signaling pathway  negative regulation of cortisol biosynthetic process  
NDEx NetworkDKK3
Atlas of Cancer Signalling NetworkDKK3
Wikipedia pathwaysDKK3
Orthology - Evolution
OrthoDB27122
GeneTree (enSembl)ENSG00000050165
Phylogenetic Trees/Animal Genes : TreeFamDKK3
HOVERGENQ9UBP4
HOGENOMQ9UBP4
Homologs : HomoloGeneDKK3
Homology/Alignments : Family Browser (UCSC)DKK3
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerDKK3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)DKK3
dbVarDKK3
ClinVarDKK3
1000_GenomesDKK3 
Exome Variant ServerDKK3
ExAC (Exome Aggregation Consortium)DKK3 (select the gene name)
Genetic variants : HAPMAP27122
Genomic Variants (DGV)DKK3 [DGVbeta]
DECIPHERDKK3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisDKK3 
Mutations
ICGC Data PortalDKK3 
TCGA Data PortalDKK3 
Broad Tumor PortalDKK3
OASIS PortalDKK3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICDKK3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDDKK3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch DKK3
DgiDB (Drug Gene Interaction Database)DKK3
DoCM (Curated mutations)DKK3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)DKK3 (select a term)
intoGenDKK3
NCG5 (London)DKK3
Cancer3DDKK3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605416   
Orphanet
MedgenDKK3
Genetic Testing Registry DKK3
NextProtQ9UBP4 [Medical]
TSGene27122
GENETestsDKK3
Target ValidationDKK3
Huge Navigator DKK3 [HugePedia]
snp3D : Map Gene to Disease27122
BioCentury BCIQDKK3
ClinGenDKK3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD27122
Chemical/Pharm GKB GenePA27347
Clinical trialDKK3
Miscellaneous
canSAR (ICR)DKK3 (select the gene name)
Probes
Litterature
PubMed117 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineDKK3
EVEXDKK3
GoPubMedDKK3
iHOPDKK3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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