Affinage

DKK3

Dickkopf-related protein 3 · UniProt Q9UBP4

Length
350 aa
Mass
38.4 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DKK3 (REIC) is a secreted, N-glycosylated Dickkopf-family glycoprotein that functions as a context-dependent regulator of cell survival, differentiation, and Wnt/TGF-β signaling, acting predominantly as a tumor suppressor whose expression is lost in immortalized and tumor-derived cells (PMID:10652205, PMID:15516983). In cancer cells, restoring DKK3 triggers endoplasmic reticulum stress and JNK-dependent apoptosis, with mitochondrial Bax translocation and Bcl-2 loss, selectively in malignant but not normal cells (PMID:16266978, PMID:18922905); an N-terminal region is sufficient to drive ER stress and apoptosis (PMID:18727918), while the chaperones Hsp70/72 and ER-resident BiP/GRP78 set the threshold for this killing, with low levels conferring sensitivity (PMID:17549386, PMID:19626590). Downstream, ER-stress-induced ATF3 cooperates with Smad to repress Id-1 and activate JNK (PMID:18922905). DKK3 restrains Wnt/β-catenin signaling through multiple routes: blocking β-catenin nuclear accumulation and TCF-4 target genes c-Myc and cyclin D1 (PMID:18048388), direct β-catenin binding (PMID:34326879), and an intracellular isoform Dkk3b that sequesters cytoplasmic β-catenin with β-TrCP (PMID:28738084). It also suppresses TGF-β/Smad signaling by reducing TGF-β receptor levels and Smad2/3 phosphorylation (PMID:29843383, PMID:28458155). Beyond cancer, DKK3 controls differentiation and tissue homeostasis: it drives monocyte-to-dendritic-cell differentiation and STAT/GSK-3β phosphorylation via its cysteine-rich C-terminal domain (PMID:19212670, PMID:25823913), binds and inhibits ASK1 to block P38/JNK signaling in hepatocytes and improve insulin sensitivity (PMID:27016281), promotes smooth-muscle differentiation of vascular progenitors via TGF-β/ATF6 and Wnt (PMID:29284609), and acts as a paracrine inhibitor of muscle stem cell differentiation by enhancing nuclear β-catenin–FoxO3 transcription of the atrogenes Fbxo32 and Trim63 (PMID:29717119). Its transcription is controlled by activators (Pax6, FoxO4) and repressors (PRMT5-mediated histone methylation, MYC-miR-92a, Baf60c-Six4) (PMID:25029272, PMID:36106640, PMID:33462997, PMID:34593610, PMID:37284884). In HNSCC, DKK3 paradoxically acts as an oncogene through PI3K/Akt signaling independent of Wnt/TCF (PMID:28470144).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 Medium

    Establishing DKK3 as a Dickkopf-family secreted protein lost in transformed cells framed it as a candidate tumor suppressor.

    Evidence cDNA cloning, sequence/structural analysis, and Northern expression profiling across normal vs immortalized/tumor cell lines

    PMID:10652205

    Open questions at the time
    • No mechanism for the growth/expression difference defined
    • Secretion and processing not yet biochemically resolved
  2. 2004 Medium

    Biochemical characterization showed DKK3 exists as cytosolic and secreted N-glycosylated isoforms and that ectopic expression suppresses tumor growth, linking the protein to growth control.

    Evidence Western blot, glycosylation analysis, colony formation, and xenograft assays

    PMID:15516983

    Open questions at the time
    • Apoptotic mechanism unresolved
    • Relationship between isoforms and function unclear
  3. 2005 High

    Defining that DKK3 re-expression kills cancer cells via JNK and mitochondrial apoptosis, selectively sparing normal cells, established its therapeutic tumor-suppressor mechanism.

    Evidence Adenoviral overexpression, JNK and apoptosis assays, Bax/Bcl-2 readouts, xenograft in prostate cancer

    PMID:16266978

    Open questions at the time
    • Upstream trigger of JNK not yet identified
    • Basis of cancer-cell selectivity unknown
  4. 2008 High

    Identifying ER stress as the upstream trigger and the ATF3/Smad-Id-1-JNK axis, plus N-terminal sufficiency, connected DKK3 expression to a defined pro-apoptotic cascade.

    Evidence Adenoviral overexpression, Id-1 promoter mutagenesis/reporter assays, truncation mutants, ER stress reporters, orthotopic and in vivo delivery models

    PMID:18654608 PMID:18727918 PMID:18922905

    Open questions at the time
    • How intracellular DKK3 initiates ER stress mechanistically unresolved
    • Receptor for the apoptotic signal not defined
  5. 2010 Medium

    Identifying Hsp70/72 and BiP/GRP78 as determinants of sensitivity explained the cancer-selective and resistance phenotypes of DKK3-induced apoptosis.

    Evidence Pharmacological induction/inhibition of Hsp70/72, isolation of resistant clones, BiP siRNA knockdown, xenograft validation

    PMID:17549386 PMID:19626590

    Open questions at the time
    • Direct molecular interaction of DKK3 with these chaperones not shown
    • Single-lab pharmacology
  6. 2008 High

    Showing DKK3 inhibits Wnt/β-catenin signaling via reciprocal gain/loss-of-function clarified a second, non-apoptotic tumor-suppressive arm.

    Evidence Ectopic expression and siRNA, TCF/LEF reporter, nuclear fractionation in lung cancer

    PMID:18048388

    Open questions at the time
    • Mechanism of β-catenin inhibition not yet defined in this context
    • Extracellular vs intracellular site of action unclear
  7. 2011 Medium

    Subcellular localization, Tctex-1 interaction, and demonstration that some cancers use JNK-only (not Wnt) apoptosis revealed context-dependence and a dynein-linked ER association.

    Evidence Confocal microscopy, yeast/mammalian two-hybrid with domain mapping, JNK inhibitors and cell-cycle/epigenetic analysis in RCC

    PMID:21042718 PMID:21268126 PMID:21835165

    Open questions at the time
    • Functional consequence of Tctex-1 interaction untested
    • Determinants of Wnt-dependent vs JNK-only response unknown
  8. 2015 Medium

    Mapping immune and angiogenic functions to specific DKK3 domains/partners established roles beyond cancer-cell-intrinsic apoptosis.

    Evidence C17-REIC recombinant domain protein with monocyte differentiation and STAT/GSK-3β readouts; Co-IP of DKK3-β2-microglobulin with VEGFR-2/Akt/mTOR readouts

    PMID:19212670 PMID:25823913 PMID:26278164

    Open questions at the time
    • Cell-surface receptor for DKK3 immune signaling not identified
    • β2M interaction not reciprocally validated structurally
  9. 2016 High

    Co-IP and ASK1 epistasis defined a direct DKK3-ASK1 interaction that inhibits P38/JNK in metabolic tissue, expanding DKK3 to a physiological signaling regulator.

    Evidence Co-immunoprecipitation, hepatocyte-specific KO/overexpression, dominant-negative and constitutively active ASK1 epistasis, metabolic phenotyping

    PMID:27016281

    Open questions at the time
    • Whether ASK1 binding underlies the cancer apoptosis JNK axis untested
    • Direct binding interface not mapped
  10. 2018 High

    Identifying nuclear β-catenin/FoxO3-driven atrogene transcription, endogenous CRISPR-activation suppressing TGF-β/Smad, and the Dkk3b/β-TrCP sequestering isoform resolved distinct mechanisms by which DKK3 acts on β-catenin and TGF-β.

    Evidence Co-IP (β-catenin/FoxO3, Dkk3b/β-catenin/β-TrCP), reporter assays, transgenic/KO mice, CRISPR-dCas9-VPR endogenous activation

    PMID:28738084 PMID:29717119 PMID:29843383

    Open questions at the time
    • How a secreted protein gains nuclear/cytoplasmic β-catenin access unresolved
    • Receptor mediating TGF-β suppression unknown
  11. 2017 High

    Genetic and pharmacological studies established DKK3 as a driver of vascular/cardiac differentiation and a tissue-protective TGF-β/Wnt regulator, and uncovered an oncogenic PI3K/Akt mode in HNSCC.

    Evidence DKK3-/- atherosclerosis and AngII cardiac models, keloid fibroblast TGF-βR inhibition, PI3K inhibitor in HNSCC xenografts

    PMID:28458155 PMID:28470144 PMID:29196099 PMID:29284609

    Open questions at the time
    • Why DKK3 switches between tumor-suppressor and oncogene contexts unknown
    • Receptor identity across these contexts undefined
  12. 2021 High

    Defining transcriptional regulators (Pax6, FoxO4 activators; PRMT5, MYC-miR-92a, Baf60c-Six4 repressors) and immune/regeneration outputs placed DKK3 in defined gene-regulatory and paracrine circuits.

    Evidence ChIP/ChIP-seq, EMSA, promoter mutagenesis, Co-IP, conditional KO mice, organoids, and rescue/infection models

    PMID:25029272 PMID:33462997 PMID:34306986 PMID:34593610 PMID:36106640 PMID:37284884

    Open questions at the time
    • How upstream regulation integrates to set context-specific DKK3 function unclear
    • Receptor-level mechanism for paracrine immune/muscle effects undefined
  13. 2024 Medium

    Showing DKK3 can also activate Wnt/β-catenin to drive MFF transcription and renal fibrosis demonstrated that DKK3 outputs on β-catenin are bidirectional and context-determined.

    Evidence ChIP, MeRIP/RIP, dual-luciferase, siRNA knockdown, UUO mouse model

    PMID:35659360 PMID:38682264

    Open questions at the time
    • Determinants of Wnt activation vs inhibition by DKK3 unresolved
    • Single-lab disease-model evidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • The cell-surface receptor(s) and unifying molecular logic governing whether DKK3 acts as a tumor suppressor, oncogene, or differentiation factor remain undefined.
  • No definitive signaling receptor identified for secreted DKK3
  • No structural model reconciling intracellular ER/ASK1 actions with secreted paracrine effects
  • Context determinants of opposing Wnt and apoptotic outputs unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 1
Localization
GO:0005576 extracellular region 4 GO:0005783 endoplasmic reticulum 3 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-5357801 Programmed Cell Death 2
Partners
ASK1B2MBTRCCTNNB1FOXO3TCTEX-1

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Adenovirus-mediated overexpression of REIC/Dkk-3 in human prostate cancer cells induces apoptosis through activation of c-Jun-NH2-kinase (JNK), mitochondrial translocation of Bax, and reduction of Bcl-2, selectively in cancer cells lacking endogenous REIC/Dkk-3 but not in normal prostate epithelial/stromal cells. Adenoviral overexpression, apoptosis assays, JNK activation assays, xenograft mouse model Cancer research High 16266978
2000 REIC/Dkk-3 encodes a 350 amino acid secreted protein with coiled-coil structures at N- and C-termini; it is a member of the Dickkopf family and its expression is down-regulated in immortalized and tumor-derived human cell lines compared to normal counterparts. cDNA cloning, sequence analysis, protein database search, expression profiling by Northern blot Biochemical and biophysical research communications Medium 10652205
2004 DKK3/REIC protein exists as two isoforms: a 55 kDa cytosolic form and a 50 kDa secreted form; it is N-glycosylated. Ectopic expression suppresses cell growth and induces apoptosis, and reduces tumor growth in nude mice. Western blot, glycosylation analysis, ectopic expression, colony formation, xenograft Oncogene Medium 15516983
2007 Downregulation of Dkk3 activates the Wnt/β-catenin pathway in lung cancer: ectopic Dkk3 expression inhibits TCF-4 activity, prevents nuclear accumulation of β-catenin, and reduces expression of TCF-4 targets c-Myc and cyclin D1; siRNA knockdown of Dkk3 is sufficient to promote β-catenin nuclear translocation and c-Myc expression. Ectopic expression, siRNA knockdown, TCF/LEF reporter assay, Western blot, nuclear fractionation Carcinogenesis High 18048388
2008 REIC/Dkk-3-induced apoptosis in malignant mesothelioma proceeds through JNK activation, which is regulated by transcriptional downregulation of Id-1 via cooperative binding of ATF3 and Smad to the Id-1 promoter; ATF3 activation is induced by endoplasmic reticulum (ER) stress triggered by REIC/Dkk-3 overexpression. Adenoviral overexpression, mutagenesis of Id-1 promoter, reporter assays, co-transfection, orthotopic mouse model Cancer research High 18922905
2008 Adenovirus-mediated REIC/Dkk-3 overexpression induces apoptosis in breast cancer cells in a JNK phosphorylation-dependent manner and downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells through JNK activation, thereby sensitizing cells to doxorubicin. Adenoviral overexpression, JNK inhibitor, Western blot, drug resistance assays, xenograft Cancer gene therapy Medium 18654608
2009 REIC/Dkk-3 overexpression in normal human fibroblasts (NHF) triggers ER stress and induces production of interleukin-7 (IL-7) via a signaling cascade involving IRE1α, ASK1, p38, and IRF-1. Ad-REIC-infected NHF transplanted with cancer cells suppresses tumor growth, partly abrogated by IL-7 antibody. Adenoviral overexpression, siRNA knockdown of pathway components, cytokine measurement, co-transplantation tumor model, antibody neutralization The Journal of biological chemistry High 19279003
2009 Recombinant REIC/Dkk-3 protein induces differentiation of human CD14+ monocytes into a novel dendritic cell-like cell type (REIC/Dkk-3Mo) and induces phosphorylation of STAT1 and STAT3; intratumoral administration suppresses tumor growth with DC and CD8+ T cell accumulation. Recombinant protein treatment, flow cytometry, STAT phosphorylation assay, in vivo intratumoral injection International journal of oncology Medium 19212670
2010 REIC/Dkk-3 protein is localized to secretory vesicles in a punctate pattern around the nucleus in normal cells, and predominantly in the endoplasmic reticulum (ER) in cancer cells stably transfected with REIC/Dkk-3. Soluble recombinant REIC/Dkk-3 promotes prostatic acinar morphogenesis of RWPE-1 cells. Immunohistochemistry, confocal microscopy, recombinant protein treatment, 3D acinar morphogenesis assay International journal of oncology Medium 21042718
2011 REIC/Dkk-3 physically interacts with dynein light chain Tctex-1 via its 136–157 amino acid region (containing a [-E-X-G-R-R-X-H-] motif); both proteins co-localize around the ER in human fibroblasts. Yeast two-hybrid screening, mammalian two-hybrid system with deletion mutants, immunocytochemistry Biochemical and biophysical research communications Medium 21835165
2011 In renal cell carcinoma cells, Dkk-3 does not inhibit the canonical Wnt/β-catenin pathway but induces apoptosis via the non-canonical JNK pathway; Dkk-3 overexpression also increases p21, MDM-2, and Puma expression and induces G0/G1 arrest. Dkk-3 expression is regulated by histone modification rather than CpG methylation in RCC. Plasmid transfection, JNK pathway inhibitors, flow cytometry, Western blot, nude mouse xenograft, chromatin modification analysis Molecular carcinogenesis Medium 21268126
2007 Heat shock protein Hsp70/72 is a key determinant of tumor cell-specific apoptosis induced by REIC/Dkk-3: cancer cells with low Hsp70/72 expression are sensitive to Ad-REIC-induced JNK-dependent apoptosis, while Hsp70/72 induction protects cancer cells and its inhibition sensitizes normal cells. Adenoviral overexpression, Hsp70/72 inducer/inhibitor pharmacological experiments, apoptosis assays International journal of molecular medicines Medium 17549386
2010 BiP/GRP78 (an ER-resident chaperone) is a major determinant of resistance to Ad-REIC-induced apoptosis: BiP expression levels are inversely correlated with apoptosis rates, and siRNA-mediated downregulation of BiP sensitizes resistant prostate cancer cells to Ad-REIC in vitro and in vivo. Repeated Ad-REIC exposure to isolate resistant clones, Western blot screening, siRNA knockdown, xenograft model International journal of cancer Medium 19626590
2008 An N-terminal 78 amino acid truncation of REIC/Dkk-3 is sufficient to induce ER stress and apoptosis in prostate cancer cells, identifying the N-terminal region as critical for ER stress induction. Truncation mutant construction, ER stress reporter, apoptosis assays, in vivo polymer-plasmid delivery Biochemical and biophysical research communications Medium 18727918
2016 DKK3 in hepatocytes physically interacts with ASK1 under palmitate stimulation and inhibits activation of the downstream P38/JNK pathway. Hepatocyte-specific DKK3 overexpression improves insulin sensitivity and reduces hepatic steatosis, while DKK3 deficiency worsens these; dominant-negative ASK1 blocks DKK3-deficiency effects and constitutively active ASK1 overcomes DKK3 overexpression effects. Co-immunoprecipitation, hepatocyte-specific KO and overexpression mouse models, dominant-negative/constitutively active ASK1 epistasis, Western blot, metabolic phenotyping Journal of hepatology High 27016281
2017 DKK3 induces differentiation of Sca1+ vascular progenitors and fibroblasts into smooth muscle cells via activation of TGF-β/ATF6 and Wnt signaling pathways. Absence of DKK3 (DKK3-/- ApoE-/- mice) leads to vulnerable atherosclerotic plaques with reduced SMC numbers and matrix deposition. DKK3-/- mouse model, ApoE-/- atherosclerosis model, in vitro differentiation assays, Western blot for TGF-β/ATF6 and Wnt pathways, carotid stenosis model Arteriosclerosis, thrombosis, and vascular biology High 29284609
2018 Dkk3 induces nuclear import of β-catenin and enhances its interaction with FoxO3, which activates transcription of E3 ubiquitin ligases Fbxo32 and Trim63 (atrogin-1 and MuRF1), driving muscle atrophy. Forced Dkk3 expression in young mice causes muscle atrophy; reducing expression in old muscles restores muscle size and function. Transgenic/KO mouse models, co-immunoprecipitation (β-catenin/FoxO3), luciferase reporter for Fbxo32/Trim63 promoters, protein fractionation for nuclear β-catenin Nature communications High 29717119
2017 DKK3 overexpression in cardiac fibroblasts inhibits ADAM17 phosphorylation, thereby increasing ACE2 expression and promoting AngII degradation; DKK3 also inhibits GSK-3β and β-catenin and decreases nuclear β-catenin translocation. These mechanisms reduce AngII-induced cardiac hypertrophy and fibrosis. Adenoviral overexpression, siRNA knockdown, Western blot, EdU proliferation assay, immunofluorescence, mouse AngII infusion model Journal of molecular and cellular cardiology Medium 29196099
2017 DKK3 overexpression in HNSCC cells increases phosphorylation of Akt (S473) and c-Jun (Ser63) and promotes cancer cell proliferation, migration, and invasion via PI3K-Akt signaling, not through the canonical Wnt/β-catenin/TCF pathway (TCF/LEF reporter assay was negative). Plasmid transfection, Western blot, reporter assays (TCF/LEF), PI3K inhibitor (LY294002), migration/invasion assays, xenograft Oncology research Medium 28470144
2015 The cysteine-rich C-terminal core domain of REIC/Dkk-3 (C17-REIC, ~17 kDa) is sufficient to induce DC-like cell differentiation from monocytes and induces phosphorylation of GSK-3β and STAT proteins at levels comparable to GM-CSF. Full-length and C17-REIC proteins exert anticancer effects in vivo via immune cell activation. Recombinant truncated protein generation, monocyte differentiation assay, flow cytometry, Western blot (GSK-3β/STAT phosphorylation), in vivo mouse renal adenocarcinoma model Oncology reports Medium 25823913
2018 CRISPR-dCas9-VPR-mediated induction of endogenous DKK3 expression in PC3 prostate cancer cells inhibits TGF-β/Smad-dependent transcriptional activity and attenuates cell migration and proliferation, confirming a physiological role for endogenous Dkk-3 in limiting TGF-β/Smad signaling. CRISPR-dCas9-VPR transcriptional activation, TGF-β/Smad reporter assay, migration/proliferation assays, DNMT inhibitor (decitabine) Cancers Medium 29843383
2017 DKK3 overexpression in keloid fibroblasts inhibits TGF-β receptor I, TGF-β receptor II expression, and reduces phosphorylation of Smad2 and Smad3, thereby suppressing cell proliferation, inducing apoptosis, and inhibiting collagen I, collagen III, and α-SMA synthesis. Plasmid transfection (pcDNA3.1-DKK3), Western blot, TGF-β receptor inhibitor (LY2109761), proliferation/apoptosis assays Biomedicine & pharmacotherapy Medium 28458155
2015 Dkk3 in cardiac tissue activates Dvl1 and key proteins of the canonical Wnt pathway (cytoplasmic/nuclear β-catenin, c-Myc, Axin2) while downregulating non-canonical Wnt pathway proteins (JNK, CaMKII, HDAC4). Dkk3 transgenic expression improves cardiac function in DCM mice; Dkk3 knockout worsens it. Dkk3 transgenic and KO mice crossed with cTnT(R141W) DCM model mice, Western blot of canonical/non-canonical Wnt pathway components, survival analysis, cardiac morphology Laboratory investigation Medium 26641069
2019 DKK3 overexpression in human fibroblasts under defined conditions triggers mesenchymal-to-epithelial transition, upregulates KDR (VEGFR2), and transdifferentiates fibroblasts into functional endothelial cells capable of angiogenesis, regulated by the VEGF/miR-125a-5p/STAT3 axis. Plasmid overexpression, morphology assays, gene expression profiling, in vitro/in vivo angiogenesis assays, tissue-engineered vascular graft, pathway analysis Arteriosclerosis, thrombosis, and vascular biology Medium 30816803
2020 DKK3 attenuates JNK/AP-1-mediated neuroinflammation after intracerebral hemorrhage via Kremen-1 and DVL-1 (Dishevelled-1) pathways: rDKK3 administration reduces brain edema and JNK/AP-1 activation, effects abrogated by Kremen-1 siRNA or DVL-1 siRNA knockdown. Recombinant protein administration, Kremen-1 and DVL-1 siRNA knockdown, Western blot, immunofluorescence, ICH mouse model Journal of neuroinflammation Medium 32331523
2022 DKK3 ameliorates neuropathic pain by inhibiting ASK1/JNK/p38-mediated microglia M1 polarization and neuroinflammation via Kremen-1 and DVL-1 pathways: intrathecal rDKK3 reduces p-ASK1, p-JNK, p-p38 and shifts microglia from M1 to M2; effects reversed by Kremen-1 siRNA or DVL-1 siRNA. Intrathecal rDKK3 injection, Kremen-1/DVL-1 siRNA, Western blot, immunofluorescence, ELISA, SNI rat model Journal of neuroinflammation Medium 35658977
2021 PRMT5 epigenetically silences DKK3 by binding to its promoter and inducing symmetric methylation of H3R8 and H4R3 histones, leading to DKK3 repression and consequent WNT/β-catenin pathway activation in breast cancer cells. ChIP assay (PRMT5 binding to DKK3 promoter, H3R8/H4R3 methylation), PRMT5 inhibitor (CMP5), demethylating agents Journal of cellular and molecular medicine Medium 33462997
2021 FoxO4 directly transcriptionally activates Dkk3 (identified by genome-wide occupancy and transcriptomic analyses); recombinant DKK3 protein restores normal IFN-γ production in FoxO4-deficient Th1 cells through downregulation of Lef1 expression. Genome-wide ChIP-seq occupancy, transcriptomic analysis, conditional T cell FoxO4 KO mice, recombinant DKK3 protein rescue, Listeria infection model The Journal of clinical investigation High 36106640
2021 Loss of Dkk3 in mice reduces liver damage upon acute/chronic injury via increased proliferation of hepatocytes and LGR5+ liver progenitor cells; mechanistically, Dkk3 loss abolishes canonical Wnt signaling and reduces Gli3 expression, resulting in increased Hedgehog-signaling activity. Dkk3-null mouse model, acute/chronic liver injury models, organoid assays, Wnt and Hedgehog pathway Western blot/reporter analysis, iPSC reprogramming screen Advanced science Medium 34306986
2023 Baf60c in skeletal myofibers interacts with Six4 to synergistically suppress Dkk3 expression; myofiber-specific Baf60c ablation upregulates Dkk3, which acts as a secreted paracrine inhibitor of muscle stem cell differentiation and impairs muscle regeneration in vivo. Dkk3 knockdown in obese mice improves muscle regeneration. Myofiber-specific Baf60c KO and transgenic mice, co-IP (Baf60c-Six4), luciferase reporter for Dkk3 promoter, in vivo Dkk3 siRNA knockdown, muscle regeneration assays The Journal of experimental medicine High 37284884
2015 DKK-3 physically interacts with β2-microglobulin (β2M) and suppresses β2M-mediated activation of VEGFR-2/Akt/mTOR signaling and tumor angiogenesis in ovarian carcinoma cells; DKK-3 overexpression reduces VEGFR-2/Akt/mTOR phosphorylation and luciferase reporter activity. Co-immunoprecipitation, luciferase assay, Western blot, overexpression/siRNA knockdown of β2M Cellular signalling Medium 26278164
2017 The Dkk3 locus encodes an additional intracellular isoform, Dkk3b, originating from a transcriptional start site in intron 2. Dkk3b protein sequesters cytoplasmic unphosphorylated β-catenin in an extra-nuclear complex with β-TrCP, preventing β-catenin nuclear translocation and thereby arresting β-catenin-driven cell proliferation. Identification of novel transcript/protein, co-immunoprecipitation (Dkk3b-β-catenin-β-TrCP complex), subcellular fractionation, proliferation assays PloS one Medium 28738084
2014 Pax6 and Pax6(5a) directly bind a conserved binding site in the Dkk3 promoter (within a 200 bp region upstream of the TSS) and transcriptionally activate Dkk3 expression; mutation of this binding site abolishes transcriptional activation. Pax6-expressing fibroblasts show reduced responsiveness to canonical Wnt pathway stimulation. EMSA, promoter deletion/mutagenesis, luciferase reporter assay, RT-qPCR, Western blot, PAX6 siRNA knockdown in human cell lines PloS one Medium 25029272
2021 MYC suppresses DKK3 transcription through the miR-17-92 cluster member miR-92a; DKK3 overexpression suppresses Wnt signaling in Apc-null murine colonic organoids and human colon cancer cells despite downstream activating mutations in the Wnt pathway. miR-92a overexpression/knockdown, DKK3 overexpression/knockdown, Wnt reporter assay, organoid assay, syngeneic orthotopic metastasis model Molecular cancer research Medium 34593610
2006 DKK3 delivered by adenovirus to human adrenocortical cells inhibits aldosterone and cortisol biosynthesis (alone or with cAMP) and decreases cAMP-stimulated CYP17 mRNA, indicating a direct functional role for DKK3 in adrenocortical steroidogenesis. Adenoviral DKK3 delivery to primary adrenocortical cells, steroid biosynthesis measurement, real-time PCR for steroidogenic enzymes Hormone and metabolic research Medium 16981135
2024 DKK3 upregulation (driven by METTL3-mediated m6A modification) activates the Wnt/β-catenin pathway by binding to the MFF promoter via TCF4/β-catenin, increasing MFF transcription, causing mitochondrial fission, oxidative stress, and renal fibrosis; DKK3 knockdown alleviates these effects. ChIP (DKK3 binding to MFF promoter), MeRIP (m6A), RIP, dual-luciferase assay, siRNA knockdown, UUO mouse model, Western blot Renal failure Medium 38682264
2022 DKK3 secreted by human amniotic mesenchymal stem cells inhibits hepatic stellate cell activation and liver fibrosis by blocking the canonical Wnt/β-catenin signaling pathway, as demonstrated by siRNA knockdown of DKK3 in hAMSCs reversing the anti-fibrotic effect. hAMSC transplantation, antibody array, siRNA knockdown of DKK3 in hAMSCs, Western blot for Wnt/β-catenin pathway, CCl4-induced fibrosis model Stem cell research & therapy Medium 35659360
2021 Dkk3 directly interacts with β-catenin (shown by co-immunoprecipitation and immunofluorescence co-localization); overexpression of Dkk3 promotes osteogenic differentiation of BMSCs by inhibiting this interaction and activating downstream osteogenic gene transcription. Co-immunoprecipitation, immunofluorescence co-localization, luciferase reporter (miR-129-5p/Dkk3), Western blot, osteogenic differentiation assays, in vivo calvaria defect model Stem cells international Medium 34326879

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Adenovirus-mediated overexpression of REIC/Dkk-3 selectively induces apoptosis in human prostate cancer cells through activation of c-Jun-NH2-kinase. Cancer research 169 16266978
2000 A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines. Biochemical and biophysical research communications 168 10652205
2004 Dickkopf-3/REIC functions as a suppressor gene of tumor growth. Oncogene 154 15516983
2007 Downregulation of Dkk3 activates beta-catenin/TCF-4 signaling in lung cancer. Carcinogenesis 142 18048388
2001 Antiproliferative activity of REIC/Dkk-3 and its significant down-regulation in non-small-cell lung carcinomas. Biochemical and biophysical research communications 112 11708809
2013 microRNA-183 is an oncogene targeting Dkk-3 and SMAD4 in prostate cancer. British journal of cancer 109 23538390
2002 Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells. Gene 109 11814687
2022 DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation. Journal of neuroinflammation 104 35658977
2004 Decreased expression of REIC/Dkk-3 in human renal clear cell carcinoma. The Journal of urology 104 14767340
2001 Reduced expression of REIC/Dkk-3 gene in non-small cell lung cancer. International journal of oncology 94 11408931
2008 REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer. Cancer gene therapy 74 18654608
2008 Wnt signalling in human breast cancer: expression of the putative Wnt inhibitor Dickkopf-3 (DKK3) is frequently suppressed by promoter hypermethylation in mammary tumours. Breast cancer research : BCR 74 18826564
2008 Down-regulation of inhibition of differentiation-1 via activation of activating transcription factor 3 and Smad regulates REIC/Dickkopf-3-induced apoptosis. Cancer research 74 18922905
2016 DKK3 expression in hepatocytes defines susceptibility to liver steatosis and obesity. Journal of hepatology 63 27016281
2008 REIC/Dkk-3 induces cell death in human malignant glioma. Neuro-oncology 62 18443132
2017 DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells. Arteriosclerosis, thrombosis, and vascular biology 61 29284609
2009 Promoter methylation and mRNA expression of DKK-3 and WIF-1 in hepatocellular carcinoma. World journal of gastroenterology 61 19496188
2018 Loss of long non-coding RNA CRRL promotes cardiomyocyte regeneration and improves cardiac repair by functioning as a competing endogenous RNA. Journal of molecular and cellular cardiology 60 30125571
2007 REIC/Dkk-3 as a potential gene therapeutic agent against human testicular cancer. International journal of molecular medicine 59 17273781
2007 Adenovirus-mediated REIC/Dkk-3 gene transfer inhibits tumor growth and metastasis in an orthotopic prostate cancer model. Cancer gene therapy 59 17599093
2009 Overexpression of REIC/Dkk-3 in normal fibroblasts suppresses tumor growth via induction of interleukin-7. The Journal of biological chemistry 58 19279003
2011 Wnt antagonist DICKKOPF-3 (Dkk-3) induces apoptosis in human renal cell carcinoma. Molecular carcinogenesis 57 21268126
2022 Human amniotic mesenchymal stem cells-derived IGFBP-3, DKK-3, and DKK-1 attenuate liver fibrosis through inhibiting hepatic stellate cell activation by blocking Wnt/β-catenin signaling pathway in mice. Stem cell research & therapy 54 35659360
2018 Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy. Nature communications 54 29717119
2017 DKK3 regulates cell proliferation, apoptosis and collagen synthesis in keloid fibroblasts via TGF-β1/Smad signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 52 28458155
2017 DKK3 overexpression attenuates cardiac hypertrophy and fibrosis in an angiotensin-perfused animal model by regulating the ADAM17/ACE2 and GSK-3β/β-catenin pathways. Journal of molecular and cellular cardiology 49 29196099
2009 Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression. International journal of oncology 48 19212670
2013 MiR-92b inhibitor promoted glioma cell apoptosis via targeting DKK3 and blocking the Wnt/beta-catenin signaling pathway. Journal of translational medicine 46 24325785
2018 CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer. Cancers 42 29843383
2015 Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway. Laboratory investigation; a journal of technical methods and pathology 39 26641069
2018 miR-214 ameliorates acute kidney injury via targeting DKK3 and activating of Wnt/β-catenin signaling pathway. Biological research 38 30180910
2021 Protein arginine methyltransferase 5 (PRMT5) activates WNT/β-catenin signalling in breast cancer cells via epigenetic silencing of DKK1 and DKK3. Journal of cellular and molecular medicine 37 33462997
2009 MSX1 induces the Wnt pathway antagonist genes DKK1, DKK2, DKK3, and SFRP1 in neuroblastoma cells, but does not block Wnt3 and Wnt5A signalling to DVL3. Cancer letters 37 19815336
2015 DKK3 blocked translocation of β-catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc-3 cell. Journal of cellular and molecular medicine 36 26395974
2021 Cantharidin inhibits osteosarcoma proliferation and metastasis by directly targeting miR-214-3p/DKK3 axis to inactivate β-catenin nuclear translocation and LEF1 translation. International journal of biological sciences 34 34326690
2010 Expression pattern of REIC/Dkk-3 in various cell types and the implications of the soluble form in prostatic acinar development. International journal of oncology 34 21042718
2019 miR-25-3p promotes glioma cell proliferation and migration by targeting FBXW7 and DKK3. Experimental and therapeutic medicine 33 31258712
2020 Circular RNA Hsa_circ_0004018 Inhibits Wnt/β-Catenin Signaling Pathway by Targeting microRNA-626/DKK3 in Hepatocellular Carcinoma. OncoTargets and therapy 32 33061423
2018 Dickkopf homolog 3 (DKK3): A candidate for detection and treatment of cancers? Journal of cellular physiology 31 29206297
2021 miR-129-5p Promotes Osteogenic Differentiation of BMSCs and Bone Regeneration via Repressing Dkk3. Stem cells international 30 34326879
2016 Key role of Dkk3 protein in inhibition of cancer cell proliferation: An in silico identification. Journal of theoretical biology 30 26780644
2013 DKK3 is a potential tumor suppressor gene in papillary thyroid carcinoma. Endocrine-related cancer 30 23702469
2006 Adenovirus-delivered DKK3/WNT4 and steroidogenesis in primary cultures of adrenocortical cells. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 30 16981135
2021 lnc‑MICAL2‑1 sponges miR‑25 to regulate DKK3 expression and inhibits activation of the Wnt/β‑catenin signaling pathway in breast cancer. International journal of molecular medicine 29 34970696
2014 Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/β-catenin pathway. Oncology reports 28 25573172
2013 Adenovirus-mediated REIC/Dkk-3 gene therapy: Development of an autologous cancer vaccination therapy (Review). Oncology letters 28 24527065
2010 The embryonic genes Dkk3, Hoxd8, Hoxd9 and Tbx1 identify muscle types in a diet-independent and fiber-type unrelated way. BMC genomics 28 20230627
2021 The emerging plasma biomarker Dickkopf-3 (DKK3) and its association with renal and cardiovascular disease in the general population. Scientific reports 27 33883651
2014 Decreased expression of Dkk1 and Dkk3 in human clear cell renal cell carcinoma. Molecular medicine reports 27 24676838
2020 DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage. Journal of neuroinflammation 26 32331523
2017 DKK3 Overexpression Increases the Malignant Properties of Head and Neck Squamous Cell Carcinoma Cells. Oncology research 26 28470144
2023 Myofiber Baf60c controls muscle regeneration by modulating Dkk3-mediated paracrine signaling. The Journal of experimental medicine 25 37284884
2023 The Multifaceted Role of Human Dickkopf-3 (DKK-3) in Development, Immune Modulation and Cancer. Cells 25 38201279
2020 DKK3 expression and function in head and neck squamous cell carcinoma and other cancers. Journal of oral biosciences 25 32032750
2016 Adenovirus vector carrying REIC/DKK-3 gene: neoadjuvant intraprostatic injection for high-risk localized prostate cancer undergoing radical prostatectomy. Cancer gene therapy 25 27767086
2015 Ad-REIC Gene Therapy: Promising Results in a Patient with Metastatic CRPC Following Chemotherapy. Clinical Medicine Insights. Oncology 25 25861236
2011 Tumor suppressor REIC/Dkk-3 interacts with the dynein light chain, Tctex-1. Biochemical and biophysical research communications 25 21835165
2007 Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3. International journal of molecular medicine 25 17549386
2019 MicroRNA-95-3p promoted the development of prostatic cancer via regulating DKK3 and activating Wnt/β-catenin pathway. European review for medical and pharmacological sciences 24 30779066
2019 DKK3 (Dikkopf-3) Transdifferentiates Fibroblasts Into Functional Endothelial Cells-Brief Report. Arteriosclerosis, thrombosis, and vascular biology 24 30816803
2019 The E2F3/miR-125a/DKK3 regulatory axis promotes the development and progression of gastric cancer. Cancer cell international 24 31423109
2017 The Dkk3 gene encodes a vital intracellular regulator of cell proliferation. PloS one 24 28738084
2014 Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer. Journal of gastroenterology and hepatology 24 24372695
2012 DNA methylation status of REIC/Dkk-3 gene in human malignancies. Journal of cancer research and clinical oncology 24 22274868
2012 The roles of REIC gene and its encoding product in gastric carcinoma. Cell cycle (Georgetown, Tex.) 24 22421143
2014 Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer. PloS one 23 24498395
2011 Intraperitoneal administration of an adenovirus vector carrying REIC/Dkk-3 suppresses peritoneal dissemination of scirrhous gastric carcinoma. Oncology reports 23 21249317
2020 Long noncoding RNA LINC00261 suppresses prostate cancer tumorigenesis through upregulation of GATA6-mediated DKK3. Cancer cell international 22 33013201
2015 DNA methylation of DKK3 modulates docetaxel chemoresistance in human nonsmall cell lung cancer cell. Cancer biotherapy & radiopharmaceuticals 22 25760729
2020 miR-942-5p promotes the proliferation and invasion of human melanoma cells by targeting DKK3. Journal of receptor and signal transduction research 21 32772782
2019 Upregulation of DKK3 by miR-483-3p plays an important role in the chemoprevention of colorectal cancer mediated by black raspberry anthocyanins. Molecular carcinogenesis 21 31763724
2015 The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression. Oncology reports 21 25823913
2014 Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma. Gene therapy 21 25394252
2023 Urinary DKK3 as a biomarker for short-term kidney function decline in children with chronic kidney disease: an observational cohort study. The Lancet. Child & adolescent health 20 37119829
2018 DKK3 knockdown confers negative effects on the malignant potency of head and neck squamous cell carcinoma cells via the PI3K/Akt and MAPK signaling pathways. International journal of oncology 20 30569110
2012 REIC/Dkk-3-encoding adenoviral vector as a potentially effective therapeutic agent for bladder cancer. International journal of oncology 20 22665039
2010 Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk-3. International journal of cancer 20 19626590
2020 A combined bioinformatics, experimental and clinical approach to identify novel cardiac-specific heart failure biomarkers: is Dickkopf-3 (DKK3) a possible candidate? European journal of heart failure 19 32809235
2011 Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1. Oncology reports 19 22076283
2008 An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis. Biochemical and biophysical research communications 19 18727918
2009 REIC/Dkk-3 stable transfection reduces the malignant phenotype of mouse prostate cancer RM9 cells. International journal of molecular medicine 18 19885619
2020 The Suppressing Effects of Dkk3 Expression on Aggressiveness and Tumorigenesis of Colorectal Cancer. Frontiers in oncology 17 33425757
2019 Dickkopf Homolog 3 (DKK3) Acts as a Potential Tumor Suppressor in Gallbladder Cancer. Frontiers in oncology 17 31737564
2016 GATA4 promotes hepatoblastoma cell proliferation by altering expression of miR125b and DKK3. Oncotarget 17 27788486
2016 Expression pattern of DKK3, dickkopf WNT signaling pathway inhibitor 3, in the malignant progression of oral submucous fibrosis. Oncology reports 17 27959428
2022 The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity. The Journal of clinical investigation 16 36106640
2016 Hypermethylation of CDH13, DKK3 and FOXL2 promoters and the expression of EZH2 in ovary granulosa cell tumors. Molecular medicine reports 16 27431680
2014 Pax6 regulates the expression of Dkk3 in murine and human cell lines, and altered responses to Wnt signaling are shown in FlpIn-3T3 cells stably expressing either the Pax6 or the Pax6(5a) isoform. PloS one 16 25029272
2024 DKK3 promotes renal fibrosis by increasing MFF-mediated mitochondrial dysfunction in Wnt/β-catenin pathway-dependent manner. Renal failure 15 38682264
2013 Epigenetic Silencing of DKK3 in medulloblastoma. International journal of molecular sciences 15 23567267
2011 Expression of REIC/Dkk-3 in normal and hyperproliferative epidermis. Experimental dermatology 15 21323747
2021 Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 34306986
2019 LINC00459 sponging miR-218 to elevate DKK3 inhibits proliferation and invasion in melanoma. Scientific reports 14 31844121
2015 Dickkopf-3 (DKK-3) obstructs VEGFR-2/Akt/mTOR signaling cascade by interacting of β2-microglobulin (β2M) in ovarian tumorigenesis. Cellular signalling 14 26278164
2023 RETRACTED: Molecular Investigation of DKK3 in Cerebral Ischemic/Reperfusion Injury. Biomedicines 13 36979794
2021 MYC Hyperactivates Wnt Signaling in APC/CTNNB1-Mutated Colorectal Cancer Cells through miR-92a-Dependent Repression of DKK3. Molecular cancer research : MCR 13 34593610
2013 Reduced expression of DKK3 is associated with adverse clinical outcomes of uterine cervical squamous cell carcinoma. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 13 23154266
2016 Aberrant DKK3 expression in the oral leukoplakia and oral submucous fibrosis: a comparative immunohistochemical study. European journal of histochemistry : EJH 12 27349317
2016 Novel REIC/Dkk-3-encoding adenoviral vector as a promising therapeutic agent for pancreatic cancer. Cancer gene therapy 12 27468808
2012 The clinicopathological significance of REIC expression in colorectal carcinomas. Histology and histopathology 12 22473694

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