Affinage

CCDC6

Coiled-coil domain-containing protein 6 · UniProt Q16204

Round 2 corrected
Length
474 aa
Mass
53.3 kDa
Annotated
2026-04-28
130 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCDC6 is a tumor-suppressor phosphoprotein that integrates DNA damage checkpoint signaling with transcriptional repression, and whose disruption through chromosomal rearrangements produces oncogenic fusion kinases in thyroid and lung cancers. CCDC6 sustains the intra-S-phase DNA damage checkpoint by regulating CDC25C cytoplasmic sequestration and 14-3-3σ expression, and promotes homologous recombination repair through Rad51 foci formation; its loss impairs these processes, conferring cisplatin resistance and creating a synthetic lethal vulnerability to PARP inhibition (PMID:22363533, PMID:25302833). CCDC6 also functions as a transcriptional corepressor that binds CREB1 and recruits HDAC1 and PP1 to CRE-containing promoters, suppressing CREB1 target gene expression (PMID:20498639). Protein stability of CCDC6 is positively regulated by ATM-dependent phosphorylation at Thr434, which prevents FBXW7-mediated ubiquitin-proteasomal degradation, and by USP7-mediated deubiquitination (PMID:23108047, PMID:27372520).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1987 High

    Identification of a novel transforming rearrangement in papillary thyroid carcinoma established CCDC6 (then called H4) as an unknown gene contributing to a fusion oncogene, opening the question of what its normal cellular function might be.

    Evidence DNA transfection/oncogene detection assay in NIH 3T3 cells from human PTC samples

    PMID:3600795

    Open questions at the time
    • Normal function of the H4/CCDC6 gene entirely unknown
    • Fusion partner (RET) not yet identified
  2. 1990 High

    Molecular cloning of RET/PTC1 revealed that the first 101 amino acids of CCDC6 are fused to the RET tyrosine kinase domain, establishing the precise molecular architecture of the oncogenic rearrangement and confirming it as a somatic event in thyroid tumors.

    Evidence cDNA cloning, sequencing, Southern blot, and RT-PCR comparing tumor and matched normal DNA

    PMID:2406025

    Open questions at the time
    • Function of full-length CCDC6 protein still unknown
    • Whether loss of the normal CCDC6 allele contributes to tumorigenesis not addressed
  3. 2010 High

    Discovery that CCDC6 represses CREB1 transcription by recruiting HDAC1 and PP1 to CRE-containing promoters provided the first defined molecular activity for the wild-type protein, explaining how its loss in RET/PTC1-positive tumors derepresses oncogenic CREB1 targets such as AREG and cyclin A.

    Evidence Reciprocal co-immunoprecipitation, ChIP, luciferase reporter assays in cell lines and primary PTC tissue

    PMID:20498639

    Open questions at the time
    • Whether CCDC6 represses CREB1 in tissues beyond thyroid not tested
    • Structural basis of CCDC6-CREB1 interaction unknown
  4. 2012 High

    Three concurrent advances linked CCDC6 to DNA damage response: (1) CCDC6 loss impairs the intra-S-phase checkpoint via failure of CDC25C sequestration and 14-3-3σ downregulation; (2) ATM phosphorylation of CCDC6 at Thr434 blocks FBXW7-mediated proteasomal degradation, stabilizing the protein during genotoxic stress; and (3) CCDC6-RET fusions were identified in lung adenocarcinoma, extending its relevance beyond thyroid cancer.

    Evidence shRNA knockdown with cell cycle/γH2AX analysis; Co-IP with site-directed mutagenesis and cycloheximide chase; RT-PCR/FISH screening of 1,529 lung cancers

    PMID:22327623 PMID:22363533 PMID:23108047

    Open questions at the time
    • Direct ATM kinase assay on Thr434 not shown in vitro
    • Mechanism by which CCDC6 regulates 14-3-3σ expression not defined
    • Structural basis of FBXW7-CCDC6 phosphodegron interaction not resolved
  5. 2014 High

    Demonstration that CCDC6-deficient NSCLC cells have impaired homologous recombination (reduced Rad51 foci), resist cisplatin, and are sensitized to PARP inhibition established a BRCAness-like synthetic lethal framework for CCDC6-low tumors.

    Evidence siRNA knockdown, Rad51 foci immunofluorescence, cell viability assays, drug combination index analysis in NSCLC cells

    PMID:25302833

    Open questions at the time
    • Whether CCDC6 directly participates in the HR machinery or acts upstream through checkpoint control unclear
    • In vivo validation of PARP inhibitor sensitivity in CCDC6-deficient tumors lacking
  6. 2016 Medium

    Identification of USP7 as the deubiquitinase that stabilizes CCDC6 revealed a second regulatory axis controlling its turnover; pharmacological USP7 inhibition (P5091) destabilized CCDC6 and phenocopied PARP-inhibitor sensitization, linking protein stability control to therapeutic vulnerability.

    Evidence Cycloheximide chase with USP7 inhibitor P5091, cell viability assays in lung neuroendocrine cancer cells

    PMID:27372520

    Open questions at the time
    • Direct deubiquitination of CCDC6 by USP7 not demonstrated with purified proteins
    • Whether USP7 and FBXW7 act on the same ubiquitin chains not examined
  7. 2018 High

    Validation that miR-146b-5p directly targets CCDC6 mRNA and that CCDC6 re-expression reverses miR-146b-5p-driven proliferation, migration, and xenograft growth confirmed CCDC6 as a functionally relevant tumor suppressor in papillary thyroid cancer, adding post-transcriptional downregulation as a mechanism of CCDC6 inactivation.

    Evidence 3′-UTR luciferase reporter assay, gain/loss-of-function studies, in vitro proliferation/invasion assays, subcutaneous xenograft mouse model

    PMID:30503553

    Open questions at the time
    • Whether miR-146b-5p regulation of CCDC6 operates in non-thyroid tissues not tested
    • Quantitative contribution of CCDC6 loss versus other miR-146b-5p targets not delineated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: (1) the structural basis of CCDC6's coiled-coil-mediated interactions with CREB1, HDAC1, and PP1; (2) whether CCDC6 directly participates in the homologous recombination machinery or acts exclusively through checkpoint signaling; and (3) in vivo therapeutic validation of PARP inhibitor efficacy in CCDC6-deficient solid tumors.
  • No crystal or cryo-EM structure of CCDC6 or its complexes
  • No in vivo genetic rescue demonstrating HR-specific versus checkpoint-specific contribution
  • Clinical trial data correlating CCDC6 status with PARP inhibitor response absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-73894 DNA Repair 3 R-HSA-1640170 Cell Cycle 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
CREB1FBXW7HDAC1PP1RETUSP7

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 A novel transforming oncogene (PTC) was isolated from human papillary thyroid carcinomas by DNA transfection into NIH 3T3 cells, later shown to result from rearrangement of an unknown 5' sequence (subsequently identified as H4/CCDC6) fused to the RET tyrosine kinase domain, establishing CCDC6 as the founding fusion partner in thyroid cancer. DNA transfection / oncogene detection assay in NIH 3T3 cells Nature High 3600795
1990 Molecular cloning and sequencing of the PTC (RET/PTC1) oncogene revealed that the unknown amino-terminal sequence fused to RET's tyrosine kinase domain is the H4 gene (later renamed CCDC6); the first 101 amino acids of CCDC6 are retained in the chimeric oncoprotein, and this rearrangement was shown to occur in vivo in somatic thyroid tumors but not in normal DNA from the same patients. Molecular cloning, cDNA sequencing, Southern blot, RT-PCR of tumor DNA/mRNA Cell High 2406025
1996 Transgenic mice expressing RET/PTC1 under control of the CCDC6 (H4) promoter developed mammary adenocarcinomas and skin tumors, demonstrating that the CCDC6 promoter drives ubiquitous expression of the fusion gene and that RET/PTC1 oncogenicity is not thyroid-restricted in vivo. Transgenic mouse model with tissue-specific promoter; RNA and protein expression analysis; tumor histopathology Oncogene Medium 8934550
2008 miR-146a was shown to target CCDC6 (also known as PTC1/H4) mRNA; a common SNP in pre-miR-146a reduces mature miR-146a levels and consequently leads to reduced suppression of CCDC6, implicating post-transcriptional regulation of CCDC6 expression as a contributor to papillary thyroid carcinoma predisposition. Luciferase reporter assay, in vitro miRNA processing assay, association genetics study Proceedings of the National Academy of Sciences of the United States of America Medium 18474871
2010 CCDC6 protein directly interacts with CREB1 and represses CREB1 transcriptional activity by recruiting histone deacetylase 1 (HDAC1) and protein phosphatase 1 (PP1) to the CRE site of CREB1 target gene promoters; loss of CCDC6 (via RET/PTC1 rearrangement) results in increased CREB1 phosphorylation and elevated expression of CREB1 targets AREG and cyclin A in papillary thyroid carcinomas. Co-immunoprecipitation, reporter assay, ChIP, Western blot in cell lines and primary PTC tissue Oncogene High 20498639
2012 Loss of CCDC6 expression (via lentiviral shRNA) impairs the intra-S-phase checkpoint: cells lacking CCDC6 show shortened S-phase, failure to accumulate in S-phase upon etoposide treatment, increased DNA damage markers (γH2AX), downregulation of the checkpoint regulator 14-3-3σ, and failure of CDC25C phosphatase to undergo genotoxic-stress-induced cytoplasmic sequestration, identifying CCDC6 as required for proper intra-S-phase checkpoint control and genomic stability. Lentiviral shRNA knockdown, flow cytometry cell cycle analysis, Western blot, immunofluorescence for γH2AX and CDC25C localization PloS one High 22363533
2012 FBXW7 E3 ubiquitin ligase physically interacts with CCDC6 and targets it for ubiquitin-mediated proteasomal degradation; ATM-mediated phosphorylation of CCDC6 at Thr434 in response to DNA damage blocks FBXW7-CCDC6 interaction, thereby preventing CCDC6 degradation and stabilizing CCDC6 during the DNA damage response. Co-immunoprecipitation, cycloheximide chase assay, ubiquitination assay, site-directed mutagenesis (Thr434), Western blot in lung cancer cells FEBS letters High 23108047
2012 CCDC6 was identified as a recurrent fusion partner of the RET kinase in lung adenocarcinoma (CCDC6-RET fusion), alongside KIF5B-RET, establishing CCDC6 as an oncogenic fusion driver beyond thyroid cancer. Integrated molecular screening (RT-PCR, FISH, sequencing) of 1,529 lung cancer samples Nature medicine High 22327623
2013 CCDC6 is expressed in Sertoli cells and spermatogonial cells of the testis and is lost in testicular germ cell tumors; CCDC6 silencing in GC1 germ cells reduces oxidative stress-induced apoptosis (decreased cytochrome c oxidation, lower Bad/PARP-1/Caspase 3 levels), impairs γH2AX activation, and decreases ROS release, demonstrating a pro-apoptotic, DNA-damage-checkpoint role for CCDC6 in germ cell biology. Immunohistochemistry, Western blot, siRNA knockdown, H2O2 treatment, flow cytometry for ROS and cell viability, apoptosis markers BMC cancer Medium 24059746
2014 CCDC6 deficiency in non-small cell lung cancer (NSCLC) cells impairs DNA repair via homologous recombination (reduced Rad51 foci), confers resistance to cisplatin, and sensitizes cells to PARP1/2 inhibitor olaparib; the combination of cisplatin and olaparib is synergistic (combination index <1) in CCDC6-deficient NSCLC cells, establishing a synthetic lethal relationship between CCDC6 loss and PARP inhibition. siRNA knockdown, Rad51 foci assay, cell viability assays, drug combination index analysis, tissue microarray International journal of cancer High 25302833
2016 The deubiquitinating enzyme USP7 stabilizes CCDC6 protein by preventing its proteasomal degradation; inhibition of USP7 with P5091 accelerates CCDC6 turnover (shown by cycloheximide chase) and sensitizes lung neuroendocrine cancer cells to PARP inhibitors alone and in combination with cisplatin, confirming that CCDC6 protein stability is regulated by the USP7-mediated deubiquitination axis. Cycloheximide chase assay, USP7 inhibitor (P5091) treatment, cell viability assays, tissue microarray (TMA) immunostaining Lung cancer (Amsterdam, Netherlands) Medium 27372520
2017 CCDC6 is a recurrent partner in ROS1 and RET gene fusions in lung cancer; the impaired function of CCDC6 arising from these chromosomal rearrangements (loss of the normal allele product) may alter cell signaling and promote oncogene addiction, and CCDC6's role in DNA damage response influences therapeutic response to TKIs in fusion-positive lung cancers. Review integrating molecular data from fusion gene screening studies; preclinical cell-line experiments with TKIs Molecular cancer Low 29455670
2017 EGF/EGFR signaling triggers resistance to RET kinase inhibitors (sunitinib, E7080, vandetanib, sorafenib) in CCDC6-RET fusion-positive lung cancer cells by activating bypass survival signals through ERK and AKT; EGFR inhibition (gefitinib, cetuximab, or EGFR siRNA) restores sensitivity to RET inhibitors in these CCDC6-RET cells. Cell viability assays, Western blot for signaling pathway activation, siRNA knockdown of EGFR, antibody blockade, pharmacological inhibition in CCDC6-RET lung cancer cell line (LC-2/ad) Yonsei medical journal Medium 27873490
2018 miR-146b-5p directly targets CCDC6 mRNA (validated by luciferase reporter assay) and promotes papillary thyroid cancer cell proliferation, migration, invasion and cell cycle progression in vitro; overexpression of CCDC6 reverses these effects, and miR-146b-5p promotes tumor growth in a subcutaneous mouse model while CCDC6 overexpression suppresses it, establishing CCDC6 as a functionally relevant tumor suppressor target of miR-146b-5p in PTC. Luciferase reporter assay (3'UTR), gain- and loss-of-function studies (overexpression/siRNA), proliferation/invasion/migration assays, flow cytometry cell cycle analysis, xenograft mouse model Cancer letters High 30503553

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2012 RET, ROS1 and ALK fusions in lung cancer. Nature medicine 1065 22327623
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1990 PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 868 2406025
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2008 Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proceedings of the National Academy of Sciences of the United States of America 724 18474871
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2003 BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 532 12881714
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2013 Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Science signaling 383 24255178
1996 Generation and analysis of 280,000 human expressed sequence tags. Genome research 376 8889549
2015 Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. Nature methods 370 26414014
2019 PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASS components. Nature 367 30944473
1987 A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 367 3600795
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2005 Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. Proceedings of the National Academy of Sciences of the United States of America 263 16203990
2009 The role of histamine H4 receptor in immune and inflammatory disorders. British journal of pharmacology 231 19309354
2009 An integrated workflow for charting the human interaction proteome: insights into the PP2A system. Molecular systems biology 223 19156129
1996 X-Inactivation and histone H4 acetylation in embryonic stem cells. Developmental biology 210 8954732
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
1988 Depletion of histone H4 and nucleosomes activates the PHO5 gene in Saccharomyces cerevisiae. The EMBO journal 185 3046934
2004 Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry. Analytical chemistry 174 15144186
2019 UFL1 promotes histone H4 ufmylation and ATM activation. Nature communications 149 30886146
2015 Expression of Ca²⁺-permeable two-pore channels rescues NAADP signalling in TPC-deficient cells. The EMBO journal 139 25872774
2019 Glutarylation of Histone H4 Lysine 91 Regulates Chromatin Dynamics. Molecular cell 133 31542297
2005 Gli1 is important for medulloblastoma formation in Ptc1+/- mice. Oncogene 130 15806168
2009 Histamine H3 and H4 receptors as novel drug targets. Expert opinion on investigational drugs 120 19758107
2014 Design criteria for stable Pt/C fuel cell catalysts. Beilstein journal of nanotechnology 110 24605273
2014 The Two-pore channel (TPC) interactome unmasks isoform-specific roles for TPCs in endolysosomal morphology and cell pigmentation. Proceedings of the National Academy of Sciences of the United States of America 108 25157141
2009 Molecular and biochemical pharmacology of the histamine H4 receptor. British journal of pharmacology 108 19413568
2014 Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma. Thyroid : official journal of the American Thyroid Association 102 24798740
2015 The histamine H4 receptor: from orphan to the clinic. Frontiers in pharmacology 91 25873897
2010 Cutting the nonsense: the degradation of PTC-containing mRNAs. Biochemical Society transactions 91 21118136
2002 High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice. Oncogene 85 12386820
2000 Loss of p53 promotes anaplasia and local invasion in ret/PTC1-induced thyroid carcinomas. The American journal of pathology 80 10934169
2019 B7-H4, a promising target for immunotherapy. Cellular immunology 79 31733822
2000 A C. elegans patched gene, ptc-1, functions in germ-line cytokinesis. Genes & development 79 10921907
2018 H3-H4 Histone Chaperone Pathways. Annual review of genetics 75 30183406
2019 HAT1 Coordinates Histone Production and Acetylation via H4 Promoter Binding. Molecular cell 74 31278053
2010 Role of H2O2 in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells. Cancer research 71 20424115
2014 EGFR modulates DNA synthesis and repair through Tyr phosphorylation of histone H4. Developmental cell 67 25073158
1984 Tetrahymena H4 genes: structure, evolution and organization in macro- and micronuclei. Nucleic acids research 67 6322129
1979 H3.H4 tetramer directs DNA and core histone octamer assembly in the nucleosome core particle. Biochemistry 67 217424
1999 Overexpression of ptc1 inhibits induction of Shh target genes and prevents normal patterning in the neural tube. Developmental biology 62 10395791
1994 Protein phosphatase 2C, encoded by ptc1+, is important in the heat shock response of Schizosaccharomyces pombe. Molecular and cellular biology 62 8196617
2015 Association of TERT Promoter Mutation, But Not BRAF Mutation, With Increased Mortality in PTC. The Journal of clinical endocrinology and metabolism 60 26461266
2016 USP7 inhibitors, downregulating CCDC6, sensitize lung neuroendocrine cancer cells to PARP-inhibitor drugs. Lung cancer (Amsterdam, Netherlands) 56 27372520
2014 Histamine H4 and H1 receptors contribute to postinflammatory visceral hypersensitivity. Gut 56 24561612
2017 Molecular Pathways: Evaluating the Potential for B7-H4 as an Immunoregulatory Target. Clinical cancer research : an official journal of the American Association for Cancer Research 55 28325750
2009 B7-H4 expression promotes tumorigenesis in ovarian cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 55 19955922
2006 Modeling the human PTC bitter-taste receptor interactions with bitter tastants. Journal of molecular modeling 53 16607493
1998 Expression of the RET/PTC1 oncogene impairs the activity of TTF-1 and Pax-8 thyroid transcription factors. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 51 9438393
2023 The SnRK2.3-AREB1-TST1/2 cascade activated by cytosolic glucose regulates sugar accumulation across tonoplasts in apple and tomato. Nature plants 50 37291399
2005 RET gene rearrangements (RET/PTC1 and RET/PTC3) in papillary thyroid carcinomas from an iodine-rich country (Japan). Cancer 50 16015630
2015 TRPV1 and PLC Participate in Histamine H4 Receptor-Induced Itch. Neural plasticity 49 26819760
2000 Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative. International journal of cancer 49 10652431
2018 MicroRNA-146b-5p as an oncomiR promotes papillary thyroid carcinoma development by targeting CCDC6. Cancer letters 48 30503553
2004 Inhibition of heat shock protein 90, a novel RET/PTC1-associated protein, increases radioiodide accumulation in thyroid cells. The Journal of biological chemistry 48 15302866
1999 Early cellular abnormalities induced by RET/PTC1 oncogene in thyroid-targeted transgenic mice. Oncogene 46 10380889
2013 B7-H4 enhances oncogenicity and inhibits apoptosis in pancreatic cancer cells. Cell and tissue research 45 23660627
2003 Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1. Cellular and molecular life sciences : CMLS 45 12943231
2014 New therapeutic perspectives in CCDC6 deficient lung cancer cells. International journal of cancer 44 25302833
2008 Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement. Clinical cancer research : an official journal of the American Association for Cancer Research 44 18676765
2005 Constitutive activation of the shh-ptc1 pathway by a patched1 mutation identified in BCC. Oncogene 43 15592520
2006 The histamine H4 receptor in autoimmune disease. Expert opinion on investigational drugs 40 17040202
2002 cDNA cloning and characterization of porcine histamine H4 receptor. Biochimica et biophysica acta 40 12020829
1988 Histone H3 and H4 gene deletions in Saccharomyces cerevisiae. The Journal of cell biology 40 3279046
2007 Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice. Developmental biology 39 18036580
2017 Upregulation of B7-H4 promotes tumor progression of intrahepatic cholangiocarcinoma. Cell death & disease 38 29235470
2011 The histamine H₄ receptor: targeting inflammatory disorders. European journal of pharmacology 38 21741967
2010 CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1. Oncogene 38 20498639
2010 Dasatinib reduces FAK phosphorylation increasing the effects of RPI-1 inhibition in a RET/PTC1-expressing cell line. Molecular cancer 38 20955590
2012 RET/PTC rearrangement is prevalent in follicular Hürthle cell carcinomas. Histopathology 37 22803838
2009 Normal function of the yeast TOR pathway requires the type 2C protein phosphatase Ptc1. Molecular and cellular biology 37 19273591
2014 The association between BRAF (V600E) mutation and pathological features in PTC. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 36 24389984
2008 PTC1 is required for vacuole inheritance and promotes the association of the myosin-V vacuole-specific receptor complex. Molecular biology of the cell 36 19116310
2015 Histone H4 acetylation required for chromatin decompaction during DNA replication. Scientific reports 35 26223950
2018 Targeting of BMI-1 with PTC-209 inhibits glioblastoma development. Cell cycle (Georgetown, Tex.) 34 29886801
2019 AHLs Regulate Biofilm Formation and Swimming Motility of Hafnia alvei H4. Frontiers in microbiology 33 31275267
2017 EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells. Yonsei medical journal 33 27873490
2017 CCDC6: the identity of a protein known to be partner in fusion. International journal of cancer 33 29044514
2021 Histone H4 Tails in Nucleosomes: a Fuzzy Interaction with DNA. Angewandte Chemie (International ed. in English) 32 33522067
2018 Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases. Science signaling 32 29438012
2012 Modulation of plant TPC channels by polyunsaturated fatty acids. Journal of experimental botany 32 23105130
2011 The role of the histamine H4 receptor in atopic dermatitis. Current allergy and asthma reports 32 21104170
2018 Matrine inhibits TPC-1 human thyroid cancer cells via the miR-21/PTEN/Akt pathway. Oncology letters 31 30127885
2015 The role of H4 flagella in Escherichia coli ST131 virulence. Scientific reports 31 26548325
2012 Ophthalmic antihistamines and H1-H4 receptors. Current opinion in allergy and clinical immunology 31 22918191
2019 Pathophysiological Role of Histamine H4 Receptor in Cancer: Therapeutic Implications. Frontiers in pharmacology 30 31231212
2010 Histamine H4 receptor agonists. Bioorganic & medicinal chemistry letters 30 21044842
2007 Expression of histamine H4 receptor in synovial cells from rheumatoid arthritic patients. Biological & pharmaceutical bulletin 30 17978505
2022 Mcm2 promotes stem cell differentiation via its ability to bind H3-H4. eLife 29 36354740
2015 The histamine H4 -receptor (H4 R) regulates eosinophilic inflammation in ovalbumin-induced experimental allergic asthma in mice. European journal of immunology 29 25501767
2004 Histamine H4 receptor antagonists: the new antihistamines? Current opinion in investigational drugs (London, England : 2000) 29 15573868
2024 A B7-H4-Targeting Antibody-Drug Conjugate Shows Antitumor Activity in PARPi and Platinum-Resistant Cancers with B7-H4 Expression. Clinical cancer research : an official journal of the American Association for Cancer Research 27 37882675
2022 H3-H4 histone chaperones and cancer. Current opinion in genetics & development 27 35183848
2017 Histamine and Histamine H4 Receptor Promotes Osteoclastogenesis in Rheumatoid Arthritis. Scientific reports 27 28446753
2012 FBXW7-mediated degradation of CCDC6 is impaired by ATM during DNA damage response in lung cancer cells. FEBS letters 27 23108047
2015 Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting Through the MAPK Kinase Mkk1. Genetics 26 26546002
2015 RNA sequencing identifies crucial genes in papillary thyroid carcinoma (PTC) progression. Experimental and molecular pathology 25 26708423
1996 Development of mammary and cutaneous gland tumors in transgenic mice carrying the RET/PTC1 oncogene. Oncogene 25 8934550
2019 Clinical significance of the BRAFV600E mutation in PTC and its effect on radioiodine therapy. Endocrine connections 24 31071680
2015 A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC. Oncotarget 24 26392334
2008 PARP-1 cooperates with Ptc1 to suppress medulloblastoma and basal cell carcinoma. Carcinogenesis 24 18660545
2020 Metformin Inhibits Proliferation of Human Thyroid Cancer TPC-1 Cells by Decreasing LRP2 to Suppress the JNK Pathway. OncoTargets and therapy 22 32021253
2018 The rationale for druggability of CCDC6-tyrosine kinase fusions in lung cancer. Molecular cancer 22 29455670
2013 Critical role of CCDC6 in the neoplastic growth of testicular germ cell tumors. BMC cancer 22 24059746
2012 Role of histamine H4 receptors in the gastrointestinal tract. Frontiers in bioscience (Scholar edition) 21 22202056
2012 Azines as histamine H4 receptor antagonists. Frontiers in bioscience (Scholar edition) 21 22202103
2011 Role of H4 receptor in histamine-mediated responses in human melanoma. Melanoma research 21 21691231
2007 20 years of RET/PTC in thyroid cancer: clinico-pathological correlations. Arquivos brasileiros de endocrinologia e metabologia 21 17891236
2013 Hax-1 identified as a two-pore channel (TPC)-binding protein. FEBS letters 20 24188827
2009 Nickel binding to histone H4. Dalton transactions (Cambridge, England : 2003) 19 20066223
2012 Upregulation of Shh and Ptc1 in hyperoxia‑induced acute lung injury in neonatal rats. Molecular medicine reports 18 22641469
2011 Tricyclic aminopyrimidine histamine H4 receptor antagonists. Bioorganic & medicinal chemistry letters 18 21920744
2012 Loss of CCDC6 affects cell cycle through impaired intra-S-phase checkpoint control. PloS one 17 22363533