Affinage

CXXC5

CXXC-type zinc finger protein 5 · UniProt Q7LFL8

Length
322 aa
Mass
33.0 kDa
Annotated
2026-04-28
65 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CXXC5 is a dual-compartment regulatory protein that functions as a negative-feedback inhibitor of canonical Wnt/β-catenin signaling and as a context-dependent transcriptional regulator coupling CpG methylation status to gene expression. In the cytoplasm, CXXC5 binds Dishevelled (Dvl) via its Dvl-binding motif to suppress Wnt/β-catenin signaling, thereby restraining osteoblast differentiation, hair follicle cycling, cutaneous wound healing, and longitudinal bone growth, as demonstrated by accelerated phenotypes in Cxxc5-knockout mice and rescue by competitor peptides or small molecules that disrupt the CXXC5–Dvl interaction (PMID:25633194, PMID:26056233, PMID:28595998, PMID:30971423). In the nucleus, CXXC5 binds unmethylated CpG dinucleotides through its ZF-CXXC domain and recruits TET1/TET2 demethylases to CpG islands to maintain local hypomethylation, while also assembling repressive complexes including CRL4B–NuRD and interacting with HDAC1, SUV39H1, and MeCP2 to silence specific target genes such as TSC1 and CD40L (PMID:28416650, PMID:39585161, PMID:36539038, PMID:26896487). CXXC5 additionally acts as a direct transcriptional activator at promoters of lineage genes including Flk-1 (endothelial differentiation), MBP (myelination), and SMAD7 (erythropoiesis), and its protein levels are controlled by ubiquitin-dependent proteasomal degradation (PMID:24136587, PMID:26462610, PMID:33241676, PMID:40371716).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 High

    Establishing that CXXC5 is a cytoplasmic Wnt pathway inhibitor that directly binds Dvl answered the question of how BMP4 cross-talks with Wnt signaling in neural stem cells and identified CXXC5 as a negative regulator acting at the Dvl level.

    Evidence Co-IP, FRET, TOPflash reporter, and RNAi in neural stem cells

    PMID:19001364

    Open questions at the time
    • Structural basis of the CXXC5–Dvl interaction was unknown
    • In vivo physiological relevance of the CXXC5–Dvl axis was not yet tested
  2. 2009 Medium

    Identifying CXXC5 (RINF) as a retinoid-inducible nuclear factor required for myelopoiesis revealed its role in hematopoietic differentiation independent of its Wnt-inhibitory function.

    Evidence Microarray, shRNA knockdown, CD34+ progenitor differentiation assays

    PMID:19182210

    Open questions at the time
    • Direct transcriptional targets in myeloid cells were not identified
    • Whether the myelopoietic role involves CpG binding or Dvl interaction was unclear
  3. 2013 High

    Demonstrating that CXXC5 directly binds and activates the Flk-1 promoter through its CXXC motif established CXXC5 as a bona fide DNA-binding transcriptional activator, expanding its function beyond cytoplasmic Wnt inhibition to nuclear gene regulation.

    Evidence In vitro DNA binding with CXXC mutagenesis, reporter assays, CXXC5-KO mice, zebrafish morpholino

    PMID:23906331 PMID:24136587

    Open questions at the time
    • Genome-wide binding targets were not mapped
    • Mechanism of transcriptional activation (cofactor recruitment) was unknown
  4. 2015 High

    Cxxc5-knockout mice with elevated bone density and accelerated wound healing, together with rescue by a Dvl-binding motif competitor peptide (PTD-DBM), established the in vivo physiological significance of the CXXC5–Dvl negative-feedback loop in Wnt-dependent tissue homeostasis.

    Evidence Cxxc5-KO mouse phenotyping (bone, skin wound), PTD-DBM peptide competition, β-catenin reporter assays

    PMID:25633194 PMID:26056233

    Open questions at the time
    • Tissue-specific versus systemic contribution of CXXC5 was not delineated
    • Whether CXXC5's nuclear transcriptional functions also contribute to these phenotypes was untested
  5. 2016 High

    Multiple studies in 2016 broadened CXXC5's mechanistic repertoire: crystal structure of Dvl1 PDZ domain defined the CXXC5 binding interface; CXXC5 was shown to activate myelin gene (MBP) transcription and regulate myelination in vivo; CXXC5 was found to recruit SUV39H1 to induce H3K9 methylation and repress CD40L in T cells; and small-molecule Dvl–CXXC5 inhibitors rescued osteoporosis in vivo.

    Evidence X-ray crystallography/NMR (Dvl PDZ), CXXC5-KO mouse myelination/electrophysiology, ChIP for H3K9me with Co-IP (SUV39H1), NMR-validated small molecules in ovariectomized mice

    PMID:26462610 PMID:26896487 PMID:26941261 PMID:27932247

    Open questions at the time
    • Full-length CXXC5–Dvl co-crystal structure was not solved
    • Whether SUV39H1 recruitment depends on the CXXC domain or a distinct interface was unknown
    • How CXXC5 switches between activator and repressor modes at different loci was unresolved
  6. 2017 High

    Two advances established CXXC5 as an epigenetic gatekeeper: in pDCs, CXXC5 recruits TET2 to maintain CpG island hypomethylation at Irf7, linking CXXC5 to innate antiviral immunity; in skin, CXXC5 was shown to suppress hair regrowth via Dvl interaction, extending the Wnt-inhibitory axis to hair follicle neogenesis.

    Evidence CXXC5-KO mice with bisulfite sequencing and viral infection (pDCs); CXXC5-KO mice with PTD-DBM peptide in wound-induced hair neogenesis

    PMID:28416650 PMID:28595998

    Open questions at the time
    • Whether TET2 recruitment by CXXC5 is direct or mediated by bridging factors was not resolved
    • Genome-wide scope of CXXC5-dependent CpG island protection was not determined
  7. 2018 High

    Identifying that CXXC5 competes with Smad2/3 for HDAC1 binding to relieve TGF-β signaling repression established a mechanism by which CXXC5 acts as a positive regulator of TGF-β-mediated growth arrest and apoptosis in hepatocellular carcinoma.

    Evidence Co-IP of CXXC5–HDAC1–Smad ternary interactions, RNA-seq, CXXC5 knockdown with apoptosis assays

    PMID:29036306

    Open questions at the time
    • Stoichiometry and dynamics of the CXXC5–HDAC1–Smad competition were not quantified
    • Whether this mechanism operates in non-hepatic contexts was untested
  8. 2019 High

    ChIP-seq in ESCs revealed that CXXC5 (Rinf) occupies promoters and enhancers of Tet1/2 and pluripotency genes, forming a complex with Nanog, Oct4, Tet1, and Tet2, thereby linking CXXC5 to the core pluripotency/epigenetic network and explaining how its loss causes aberrant differentiation.

    Evidence ChIP-seq, reciprocal Co-IP, Rinf-deficient ESCs with RNA-seq

    PMID:31433977

    Open questions at the time
    • Whether CXXC5's DNA binding is instructive for recruiting the pluripotency complex or vice versa was unclear
    • Functional redundancy with CXXC4/Idax at these loci was not fully resolved
  9. 2020 High

    Recombinant CXXC5 was shown to directly bind unmethylated CpG dinucleotides in vitro, and CXXC5 was found to directly bind and repress the MYCL1 promoter in quiescent hepatic stellate cells, maintaining CpG methylation and preventing activating histone marks — establishing CXXC5 as a locus-specific transcriptional repressor whose loss triggers gene derepression.

    Evidence Recombinant protein CpG binding assay; ChIP at MYCL1 promoter with bisulfite sequencing and H3K9/K27ac ChIP in hepatic stellate cells

    PMID:32249801 PMID:34621736

    Open questions at the time
    • How CXXC5 binding at CpG islands maintains DNA methylation (preventing TET access or recruiting DNMTs) was unresolved
    • Whether CXXC5 represses MYCL1 through NuRD or other corepressors was not determined
  10. 2022 High

    Multiple 2022 studies resolved key aspects: CXXC5 colocalizes with TET1/2 genome-wide at CpG islands and its loss causes global DNA hypomethylation (via ectopic TET activity), CXXC5 assembles a CRL4B–NuRD repressor complex to silence TSC1 and activate mTOR in breast cancer, CXXC5 directly activates SMAD7 transcription to sustain erythroid expansion, and combined CXXC5/Idax loss phenocopies TET deficiency in neural differentiation.

    Evidence Whole-genome bisulfite sequencing in CXXC5-KO ESCs; Co-IP with CRL4B/NuRD and ChIP-seq; ChIP at SMAD7 promoter with KD rescue in human CD34+ cells; Idax/Rinf double-KO differentiation assays

    PMID:33241676 PMID:35390758 PMID:36539038 PMID:39585161

    Open questions at the time
    • Whether CXXC5 anchors TET at CpG islands to prevent spreading or actively recruits TET for local demethylation — i.e., the directionality of the CXXC5–TET interaction — remains debated
    • The mechanism of CRL4B–NuRD recruitment by CXXC5 (direct or bridged) was not mapped
    • Structural basis for CXXC5's ability to serve as both activator and repressor at different loci is unknown
  11. 2025 High

    Identification of specific ubiquitinated lysine residues controlling CXXC5 proteasomal degradation established post-translational turnover as a primary mechanism regulating CXXC5 protein levels and hence its functional output.

    Evidence BioUbiquitination–IP–MS with site-directed mutagenesis and proteasome inhibitor treatment in MCF-7 and HEK293FT cells

    PMID:40371716

    Open questions at the time
    • The E3 ubiquitin ligase(s) targeting CXXC5 for degradation were not identified
    • Whether ubiquitination of CXXC5 is signal-regulated (e.g., Wnt- or TGF-β-dependent) is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: what determines whether CXXC5 acts as transcriptional activator versus repressor at a given locus; the identity of E3 ligase(s) controlling CXXC5 turnover; a co-crystal structure of full-length CXXC5 with Dvl; and how the cytoplasmic (Dvl-binding) and nuclear (chromatin-regulatory) functions of CXXC5 are coordinated in individual cells.
  • No structural model of full-length CXXC5 exists
  • Signal-dependent partitioning between cytoplasm and nucleus is not characterized
  • The logic governing activator vs repressor function at specific loci is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 5 GO:0140110 transcription regulator activity 5
Localization
GO:0005634 nucleus 10 GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1266738 Developmental Biology 5 R-HSA-4839726 Chromatin organization 5 R-HSA-74160 Gene expression (Transcription) 5
Partners
DVL1HDAC1MECP2NANOGSMAD3SUV39H1TET1TET2
Complex memberships
CRL4B-NuRD repressor complexNanog-Oct4-Tet1/2 pluripotency complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 CXXC5 interacts with Dishevelled (Dvl) in the cytoplasm and acts as a BMP4-induced inhibitor of canonical Wnt signaling in neural stem cells; CXXC5 overexpression repressed Axin2 levels and attenuated Wnt3a-mediated TOPflash reporter activity, and CXXC5 co-localized and co-immunoprecipitated with Dvl, confirmed by FRET. Co-immunoprecipitation, FRET, TOPflash reporter assay, RNA interference, overexpression The Journal of biological chemistry High 19001364
2015 CXXC5 acts as a negative-feedback regulator of the Wnt/β-catenin pathway during osteoblast differentiation by Wnt-dependent binding to Dvl; CXXC5-deficient mice have elevated bone mineral density, and a competitor peptide (PTD-DBM) blocking CXXC5-Dvl interaction activated Wnt/β-catenin signaling and osteoblast differentiation. CXXC5-/- mouse model, competitor peptide disruption of protein-protein interaction, ex vivo calvaria cultures, β-catenin reporter assays Cell death and differentiation High 25633194
2015 CXXC5 negatively regulates cutaneous wound healing by interacting with Dvl and suppressing Wnt/β-catenin signaling; CXXC5-/- mice show accelerated wound healing with enhanced keratin 14 and collagen synthesis; disruption of CXXC5-Dvl interaction with PTD-DBM peptide activated β-catenin and collagen production, and combined PTD-DBM and valproic acid treatment synergistically accelerated wound healing. CXXC5-/- mouse model, peptide competitor (PTD-DBM), in vitro overexpression and siRNA knockdown of CXXC5 in keratinocytes/fibroblasts, β-catenin/α-SMA/collagen I western blotting The Journal of experimental medicine High 26056233
2017 CXXC5 epigenetically recruits the DNA demethylase Tet2 to maintain hypomethylation of CpG islands at the Irf7 locus and other CGI-containing genes in plasmacytoid dendritic cells (pDCs); genetic ablation of CXXC5 results in aberrant CpG methylation of the Irf7 gene, impaired IRF7 expression, and compromised TLR7/9-induced IFN response. CXXC5 genetic knockout in mice, bisulfite sequencing of CGIs, ChIP for histone modifications, viral infection model (HSV, VSV) The Journal of experimental medicine High 28416650
2013 CXXC5 is a transcriptional activator of Flk-1 (VEGFR2/KDR); it directly binds the Flk-1 promoter region in vitro (DNA binding assay), mutation of the CXXC DNA-binding motif abolished transcriptional activity, and BMP4 induces CXXC5 expression to drive Flk-1 transcription and subsequent endothelial cell differentiation, migration, and vessel formation. In vitro DNA binding assay, promoter-reporter assays, CXXC5 overexpression/knockdown in mESCs and HUVECs, CXXC5-/- mouse (Matrigel plug angiogenesis), cxxc5 morpholino in zebrafish FASEB journal High 24136587
2016 CXXC5 acts as a transcriptional activator for major myelin genes (including MBP) in oligodendrocytes; CXXC5 directly binds the MBP promoter through its CXXC DNA-binding motif, is induced by Wnt/β-catenin signaling, and CXXC5-/- mice exhibit reduced myelin gene expression in the corpus callosum, abnormal myelin structure, and impaired axonal electrical conduction. CXXC5-/- mouse model, chromatin binding assay (direct binding to MBP promoter), myelination assays, electrophysiology Glia High 26462610
2017 CXXC5 is upregulated in miniaturized hair follicles and arrector pili muscles in balding scalps; CXXC5 negatively regulates hair regrowth and wound-induced hair follicle neogenesis via interaction with Dvl; CXXC5-/- mice display accelerated hair regrowth, and disrupting the CXXC5-Dvl interaction with a competitor peptide activates Wnt/β-catenin and accelerates hair regrowth and hair follicle neogenesis. CXXC5-/- mouse model, competitor peptide (PTD-DBM), alkaline phosphatase activity assay, wound-induced hair neogenesis model, immunohistochemistry The Journal of investigative dermatology High 28595998
2016 Crystal structure of the Dvl1 PDZ domain at 1.76 Å resolution was determined; molecular modeling combining the crystal structure with NMR data revealed the detailed interaction interface between Dvl1 PDZ domain and the CXXC5 peptide. X-ray crystallography (1.76 Å), NMR solution structure comparison, molecular modeling Biochemical and biophysical research communications High 27932247
2016 Small-molecule inhibitors of the Dvl-CXXC5 interaction activate the Wnt/β-catenin pathway and enhance osteoblast differentiation; NMR titration confirmed direct binding of compound KY-02061 to the Dvl PDZ domain; oral administration of KY-02327 rescued bone loss in an ovariectomized mouse model. In vitro fluorescence polarization assay for Dvl-CXXC5 interaction, NMR titration, primary osteoblast differentiation assays, ovariectomized mouse model EMBO molecular medicine High 26941261
2018 CXXC5 is required for TGF-β-mediated growth inhibition and apoptosis in hepatocellular carcinoma cells; CXXC5 associates with HDAC1 and competes with Smad2/3 for HDAC1 binding, thereby relieving the inhibitory effect of HDAC1 on TGF-β signaling and forming a positive feedback loop. RNA-seq (TGF-β target gene identification), CXXC5 knockdown, co-immunoprecipitation (CXXC5-HDAC1-Smad2/3 interactions), cell viability/apoptosis assays Journal of molecular cell biology High 29036306
2013 CXXC5 co-localizes and co-immunoprecipitates with Smad proteins; CXXC5 facilitates Smad3 phosphorylation and Smad4 nuclear translocation, activates TNF-α reporter activity, and induces apoptosis through both extrinsic (caspase-8) and intrinsic (mitochondrial) pathways. Co-immunoprecipitation, co-localization (fluorescence), FRET, luciferase reporter assay, caspase activity assays, TUNEL/Hoechst staining, flow cytometry Current molecular medicine Medium 23906331
2016 CXXC5 induces histone H3 lysine 9 methylation at the Cd40lg promoter in CD8+ T cells partly through interaction with the histone methyltransferase SUV39H1, thereby repressing CD40L expression; ThPOK transcription factor suppresses CXXC5 expression to relieve this repression in CD4+ T cells. Retroviral Thpok transduction, ChIP for H3K9me and H3K27me, CXXC5 transgene overexpression, co-immunoprecipitation (CXXC5-SUV39H1) Journal of leukocyte biology Medium 26896487
2019 CXXC5 (Rinf) in mouse embryonic stem cells binds chromatin at promoters and enhancers of Tet1, Tet2, and pluripotency genes; CXXC5 forms a complex with Nanog, Oct4, Tet1, and Tet2 and facilitates their proper recruitment to regulatory regions; CXXC5 deficiency reduces Tet enzyme and pluripotency gene expression and causes aberrant differentiation. ChIP-seq (CXXC5 and pluripotency factor binding), co-immunoprecipitation (CXXC5 with Nanog/Oct4/Tet1/Tet2), Rinf-deficient ESCs, RNA-seq Cell reports High 31433977
2016 Zebrafish CXXC5 interacts with SMAD proteins through its ZF-CXXC domain and SMAD MH1 domain; overexpression of CXXC5 increases TGF-β signaling reporter activity; knockdown of cxxc5 causes cardiac looping defects, cardiac dysplasia, and pericardial edema with downregulation of Tgf-β downstream genes (nkx2.5, hand2, has2); co-injection of hand2 mRNA rescues the looping defect. Co-immunoprecipitation (CXXC5-SMAD interaction), domain mapping, luciferase reporter assay, zebrafish morpholino knockdown, mRNA rescue experiment International journal of cardiology Medium 27077543
2009 CXXC5 (RINF) is a retinoid-inducible nuclear factor whose expression is upregulated during retinoic acid-induced differentiation of acute promyelocytic leukemia blasts and during cytokine-induced myelopoiesis of normal CD34+ progenitors; shRNA knockdown of CXXC5 impairs normal and tumoral myelopoiesis. Microarray, shRNA knockdown, CD34+ progenitor differentiation assays, nuclear localization by immunofluorescence Blood Medium 19182210
2019 CXXC5 is a negative regulator of Wnt/β-catenin signaling involved in growth plate senescence; CXXC5 levels gradually increase during growth plate senescence; Cxxc5-/- mice show delayed growth plate senescence and tibial elongation; small molecules (indirubin analogs) disrupting the CXXC5-Dvl interaction elongate tibial length in adolescent mice. Cxxc5-/- mouse model, in vitro CXXC5-Dvl interaction assay, small molecule screening, tibial length measurement, histological analysis of growth plates Life science alliance High 30971423
2020 CXXC5 binds the proximal MYCL1 promoter to repress MYCL1 transcription in quiescent hepatic stellate cells (HSCs); loss of CXXC5 during HSC activation removes CpG methylation and promotes acquisition of acetylated H3K9/H3K27 at the MYCL1 promoter, leading to MYCL1 transactivation and HSC activation. ChIP (CXXC5 binding to MYCL1 promoter), bisulfite sequencing, H3K9/H3K27 acetylation ChIP, RNA-seq, CXXC5 overexpression/knockdown, MYCL1 knockdown/overexpression epistasis Frontiers in cell and developmental biology High 34621736
2020 CXXC5 binds unmethylated CpG dinucleotides in vitro (demonstrated with recombinant protein); CXXC5 modulates expression of E2-responsive genes and participates in estrogen-driven cellular proliferation, though it lacks an intrinsic transcription activation/repression function. Recombinant protein production, in vitro CpG binding assay, CXXC5 overexpression/knockdown, E2-stimulation, RNA-seq/microarray for target gene identification Scientific reports High 32249801
2016 CXXC5 expression is directly regulated by E2-ERα through an estrogen response element (ERE) located upstream of the CXXC5 translation start codon; E2-ERα binds this ERE to drive CXXC5 transcription. Luciferase reporter assays, ERE mutagenesis, ChIP (ERα binding to CXXC5 ERE), RT-PCR/western blot after E2 stimulation Scientific reports Medium 27886276
2022 CXXC5 is a nuclear protein that extensively colocalizes with TET1 and TET2 at CpG islands in mouse ES cells; CXXC5 interacts with TET proteins (5-methylcytosine oxidases); CXXC5 knockout leads to genome-scale reduction of DNA methylation affecting all genomic compartments, suggesting CXXC5 anchors TET proteins at CpG islands to prevent ectopic demethylation. CXXC5 gene knockout, whole-genome bisulfite sequencing, RNA-seq, co-immunoprecipitation (CXXC5-TET1/TET2), ChIP/genomic colocalization analysis Epigenomics High 39585161
2022 CXXC5 interacts with the CRL4B and NuRD complexes to form a transcriptional repressor complex; ChIP-seq revealed the CXXC5-CRL4B-NuRD complex represses TSC1, activating mTOR signaling and suppressing autophagic cell death in breast cancer cells. Co-immunoprecipitation (CXXC5 with CRL4B/NuRD components), ChIP-seq, RNA-seq, cell proliferation assays, xenograft tumor model The Journal of biological chemistry High 36539038
2022 CXXC5 (Rinf) and its paralog Idax facilitate expression of Tet enzymes (Tet1/2/3) to promote neural and suppress trophectodermal programs during ESC differentiation; Tet genes are direct targets of CXXC5/Rinf, and combined loss of Idax and Rinf leads to impaired neural differentiation and trophoblast deregulation resembling Tet-deficient phenotypes. Idax/Rinf double-KO mice, directed neural progenitor and trophoblast differentiation assays, Tet gene expression analysis, embryoid body differentiation, embryonic brain NPC assays Stem cell research Medium 35390758
2022 CXXC5 (RINF) in immature erythroid cells directly binds the SMAD7 promoter to upregulate SMAD7 expression, thereby inhibiting TGF-β signaling to sustain red blood cell expansion; RINF knockdown reduces SMAD7 expression, accelerates erythroid maturation, and reduces RBC numbers; ectopic SMAD7 rescues the RINF-KD phenotype. shRNA knockdown in human CD34+ progenitors, erythroid differentiation assays, ChIP (RINF at SMAD7 promoter), 5-hydroxymethylation analysis, SMAD7 ectopic expression rescue Haematologica High 33241676
2023 CXXC5 mediates DHT-induced androgenetic alopecia through the PGD2 axis; CXXC5 is required downstream of PGD2 for hair loss induction; Cxxc5-/- mice are resistant to PGD2-induced and DHT-induced hair loss, and disruption of the CXXC5-Dvl interaction with PTD-DBM rescues hair loss. Cxxc5-/- mouse model, PGD2 topical application, DHT treatment, wound-induced hair neogenesis model, PTD-DBM peptide competition Cells Medium 36831222
2023 CXXC5 is overexpressed in AD patient tissues and in 5xFAD transgenic mice, correlating with suppressed Wnt/β-catenin signaling; Cxxc5-/-/5xFAD mice show rescued cognitive deficits, reduced amyloid-β plaques, and attenuated neuroinflammation; small molecule KY19334 (targeting CXXC5-Dvl interaction) significantly improved AD pathogenic phenotypes in 5xFAD mice. Cxxc5-/- x 5xFAD double mutant mice, KY19334 pharmacological treatment, behavioral tests (cognition), amyloid-β plaque quantification, western blotting, immunostaining Pharmacological research Medium 37355147
2021 Proximity interaction mapping of CXXC5 revealed that CXXC5 through its CXXC domain interacts with EMD (emerin), MAZ, and MeCP2; an interplay between CXXC5 and MeCP2 was critical for a subset of CXXC5 target gene expressions, suggesting CXXC5 acts as a nucleation factor for chromatin-regulatory complexes. Proximity-dependent biotinylation (BioID), mass spectrometry, domain-specific interaction mapping (CXXC domain), siRNA knockdown of MeCP2 with gene expression analysis Scientific reports Medium 34475492
2025 CXXC5 protein levels are primarily regulated by ubiquitination and degradation through the ubiquitin-proteasome pathway; multiple ubiquitinated lysine residues of CXXC5 were identified by bioUbiquitination approach coupled to sequential immunoprecipitation-mass spectrometry, and these residues contribute to its proteasomal degradation in both MCF-7 and HEK293FT cells. BioUbiquitination approach, sequential IP-mass spectrometry (ubiquitinated lysine identification), site-directed mutagenesis, proteasome inhibitor treatment, synchronized cell cycle analysis Protein science High 40371716

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 CXXC5 is a novel BMP4-regulated modulator of Wnt signaling in neural stem cells. The Journal of biological chemistry 91 19001364
2018 NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression. Oncogene 88 29780166
2017 Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs. The Journal of experimental medicine 84 28416650
2015 CXXC5 is a negative-feedback regulator of the Wnt/β-catenin pathway involved in osteoblast differentiation. Cell death and differentiation 68 25633194
2015 The Dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing. The Journal of experimental medicine 56 26056233
2018 CXXC5: A novel regulator and coordinator of TGF-β, BMP and Wnt signaling. Journal of cellular and molecular medicine 48 30479059
2017 Targeting of CXXC5 by a Competing Peptide Stimulates Hair Regrowth and Wound-Induced Hair Neogenesis. The Journal of investigative dermatology 48 28595998
2009 Functional involvement of RINF, retinoid-inducible nuclear factor (CXXC5), in normal and tumoral human myelopoiesis. Blood 47 19182210
2016 Small molecule inhibitors of the Dishevelled-CXXC5 interaction are new drug candidates for bone anabolic osteoporosis therapy. EMBO molecular medicine 41 26941261
2018 CXXC5 suppresses hepatocellular carcinoma by promoting TGF-β-induced cell cycle arrest and apoptosis. Journal of molecular cell biology 40 29036306
2013 CXXC5 is a transcriptional activator of Flk-1 and mediates bone morphogenic protein-induced endothelial cell differentiation and vessel formation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 40 24136587
2016 ThPOK represses CXXC5, which induces methylation of histone H3 lysine 9 in Cd40lg promoter by association with SUV39H1: implications in repression of CD40L expression in CD8+ cytotoxic T cells. Journal of leukocyte biology 31 26896487
2017 KANK1 inhibits cell growth by inducing apoptosis through regulating CXXC5 in human malignant peripheral nerve sheath tumors. Scientific reports 29 28067315
2022 Context-dependent tumor-suppressive BMP signaling in diffuse intrinsic pontine glioma regulates stemness through epigenetic regulation of CXXC5. Nature cancer 27 35915262
2019 CXXC5 Mediates P. gingivalis-suppressed Cementoblast Functions Partially via MAPK Signaling Network. International journal of biological sciences 27 31360111
2015 CXXC5 plays a role as a transcription activator for myelin genes on oligodendrocyte differentiation. Glia 26 26462610
2019 CXXC5 mediates growth plate senescence and is a target for enhancement of longitudinal bone growth. Life science alliance 25 30971423
2016 Estradiol-Estrogen Receptor α Mediates the Expression of the CXXC5 Gene through the Estrogen Response Element-Dependent Signaling Pathway. Scientific reports 25 27886276
2023 Performance of the WID-qEC test versus sonography to detect uterine cancers in women with abnormal uterine bleeding (EPI-SURE): a prospective, consecutive observational cohort study in the UK. The Lancet. Oncology 23 37944542
2021 Down-Regulation of CXXC5 De-Represses MYCL1 to Promote Hepatic Stellate Cell Activation. Frontiers in cell and developmental biology 23 34621736
2013 CXXC5 Associates with Smads to Mediate TNF-α Induced Apoptosis. Current molecular medicine 21 23906331
2014 CXXC5 regulates differentiation of C2C12 myoblasts into myocytes. Journal of muscle research and cell motility 20 25433557
2019 Rinf Regulates Pluripotency Network Genes and Tet Enzymes in Embryonic Stem Cells. Cell reports 19 31433977
2016 CXXC5 is required for cardiac looping relating to TGFβ signaling pathway in zebrafish. International journal of cardiology 19 27077543
2023 Inhibiting the cytosolic function of CXXC5 accelerates diabetic wound healing by enhancing angiogenesis and skin repair. Experimental & molecular medicine 18 37524876
2020 CXXC5 as an unmethylated CpG dinucleotide binding protein contributes to estrogen-mediated cellular proliferation. Scientific reports 18 32249801
2018 miR-32 promotes esophageal squamous cell carcinoma metastasis by targeting CXXC5. Journal of cellular biochemistry 18 30362164
2013 CXXC5 (retinoid-inducible nuclear factor, RINF) is a potential therapeutic target in high-risk human acute myeloid leukemia. Oncotarget 18 23988457
2020 CXXC5 orchestrates Stat3/Erk/Akt signaling networks to modulate P. gingivalis-elicited autophagy in cementoblasts. Biochimica et biophysica acta. Molecular cell research 17 33285176
2018 Discovery of a small-molecule inhibitor of Dvl-CXXC5 interaction by computational approaches. Journal of computer-aided molecular design 17 29627878
2022 The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer. Genome medicine 16 36258199
2023 CXXC5 Mediates DHT-Induced Androgenetic Alopecia via PGD2. Cells 15 36831222
2023 The WID-EC test for the detection and risk prediction of endometrial cancer. International journal of cancer 14 36533702
2023 Inhibition of CXXC5 function rescues Alzheimer's disease phenotypes by restoring Wnt/β-catenin signaling pathway. Pharmacological research 14 37355147
2022 The WID-qEC test: Performance in a hospital-based cohort and feasibility to detect endometrial and cervical cancers. International journal of cancer 14 36056582
2022 Inhibition of CXXC5 function reverses obesity-related metabolic diseases. Clinical and translational medicine 12 35384342
2022 Metabolic improvement and liver regeneration by inhibiting CXXC5 function for non-alcoholic steatohepatitis treatment. Experimental & molecular medicine 12 36114279
2022 DNA methylation-based detection and prediction of cervical intraepithelial neoplasia grade 3 and invasive cervical cancer with the WID™-qCIN test. Clinical epigenetics 10 36414968
2017 The Negative Regulator CXXC5: Making WNT Look a Little Less Dishevelled. The Journal of investigative dermatology 10 28967390
2016 Crystal structure of the PDZ domain of mouse Dishevelled 1 and its interaction with CXXC5. Biochemical and biophysical research communications 10 27932247
2022 Zinc-finger protein CXXC5 promotes breast carcinogenesis by regulating the TSC1/mTOR signaling pathway. The Journal of biological chemistry 9 36539038
2020 Frontline Science: Cxxc5 expression alters cell cycle and myeloid differentiation of mouse hematopoietic stem and progenitor cells. Journal of leukocyte biology 9 32083332
2020 CXXC5 Attenuates Pulmonary Fibrosis in a Bleomycin-Induced Mouse Model and MLFs by Suppression of the CD40/CD40L Pathway. BioMed research international 8 32337277
2017 CXXC5 expression in prostate cancer: implications for cancer progression. International journal of experimental pathology 8 29027288
2021 A prelude to the proximity interaction mapping of CXXC5. Scientific reports 7 34475492
2024 CXXC5 drove inflammation and ovarian cancer proliferation via transcriptional activation of ZNF143 and EGR1. Cellular signalling 5 38642782
2024 High performance of the DNA methylation-based WID-qEC test for detecting uterine cancers independent of sampling modalities. International journal of cancer 5 38739012
2024 Performance of the WID-qEC test to detect uterine cancers in black women with abnormal uterine bleeding: A prospective observational cohort study in Ghana. International journal of cancer 5 39655721
2022 Blockade of CXXC5-dishevelled interaction inhibits adipogenic differentiation, obesity, and insulin resistance in mice. Scientific reports 5 36450849
2025 Signal integrator function of CXXC5 in Cancer. Cell communication and signaling : CCS 4 39806388
2024 CXXC5 mitigates P. gingivalis-inhibited cementogenesis by influencing mitochondrial biogenesis. Cell communication and signaling : CCS 4 38167023
2022 The epigenetic regulator RINF (CXXC5) maintains SMAD7 expression in human immature erythroid cells and sustains red blood cells expansion. Haematologica 4 33241676
2022 Indirubin-3'-alkoxime derivatives for upregulation of Wnt signaling through dual inhibition of GSK-3β and the CXXC5-Dvl interaction. Bioorganic chemistry 4 35176556
2022 Idax and Rinf facilitate expression of Tet enzymes to promote neural and suppress trophectodermal programs during differentiation of embryonic stem cells. Stem cell research 4 35390758
2023 Histone Deacetylase 6 Inhibitor CKD-WID Suppressed Monosodium Urate-Induced Osteoclast Formation by Blocking Calcineurin-NFAT Pathway in RAW 264.7 Cells. Pharmaceuticals (Basel, Switzerland) 3 36986544
2025 CXXC5 function blockade promotes diabetic wound healing through stimulating fibroblast and vascular endothelial cell activation. Cell communication and signaling : CCS 2 40001144
2024 CXXC5 stabilizes DNA methylation patterns in mouse embryonic stem cells. Epigenomics 2 39585161
2023 Undifferentially Expressed CXXC5 as a Transcriptionally Regulatory Biomarker of Breast Cancer. Advanced biology 2 37423953
2024 A novel study on CXXC5: unraveling its regulatory mechanisms in hematopoietic stem cell biology through proteomics and gene editing. Genes & genomics 1 39150611
2026 The cervico-vaginal DNA methylation WID-qEC test: An epigenetic marker associated with ovarian cancer in the absence of endometrial and cervical cancer. International journal of cancer 0 41609407
2026 Cost-minimisation analysis of the WID-qEC epigenetic biomarker compared to transvaginal ultrasound for triaging abnormal uterine bleeding. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research 0 41962837
2025 CXXC5 is a ubiquitinated protein and is degraded by the ubiquitin-proteasome pathway. Protein science : a publication of the Protein Society 0 40371716
2023 MiR-28-3p regulates high glucose-induced endothelial dysfunction by targeting CXXC5. Archives of medical science : AMS 0 40741256
2020 Author Correction: CXXC5 as an unmethylated CpG dinucleotide binding protein contributes to estrogen-mediated cellular proliferation. Scientific reports 0 32546710
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