Affinage

CCDC6

Coiled-coil domain-containing protein 6 · UniProt Q16204

Length
474 aa
Mass
53.3 kDa
Annotated
2026-06-09
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCDC6 is a ubiquitously expressed, predominantly nuclear coiled-coil phosphoprotein that functions as a tumor suppressor coordinating transcriptional repression, the DNA damage response, and apoptosis (PMID:14712216, PMID:20498639, PMID:17420723). It directly binds CREB1 and represses CREB1-dependent transcription by recruiting HDAC1 and PP1 to CRE-containing promoters; loss of this function elevates CREB1 phosphorylation and target genes such as AREG and cyclin A, and a knock-in mouse lacking CCDC6 CREB1-repressor activity develops thyroid hyperplasia, establishing the pathway as physiologically protective (PMID:20498639, PMID:25970781). In the DNA damage response, CCDC6 is phosphorylated by ATM at Thr434, which stabilizes the nuclear protein and is required to enforce S-phase and G2 checkpoints; mechanistically CCDC6 restrains the γH2AX phosphatase PP4c to sustain damage signaling, and its depletion accelerates γH2AX dephosphorylation, shortens S-phase, and permits premature mitotic entry (PMID:17420723, PMID:22655027, PMID:22363533). CCDC6 also supports homologous-recombination repair—its loss reduces Rad51 foci and confers synthetic lethality with PARP inhibitors—and physically interacts with BAP1 in this context (PMID:25302833, PMID:31447003). CCDC6 abundance is cell-cycle-regulated, peaking at G2 and degraded in mitosis through phospho-degron–directed FBXW7 ubiquitination opposed by USP7 deubiquitination, while SUMO2 modification redistributes CCDC6 to the cytoplasm and relieves CREB1 repression (PMID:25885523, PMID:23108047, PMID:23145146). CCDC6 is recurrently disrupted by chromosomal rearrangements that fuse its N-terminal coiled-coil to receptor tyrosine kinases—RET (RET/PTC1) in papillary thyroid carcinoma, PDGFβR in chronic myeloid leukemia, and FGFR2 in cholangiocarcinoma—where the leucine-zipper drives constitutive dimerization required for kinase activation and transformation (PMID:1542652, PMID:10910073, PMID:27216979, PMID:9083029). For the CCDC6-RET oncoprotein, the fusion-driven liquid-liquid phase separation enhances autophosphorylation and assembles a GRB2-SHC1 signaling niche that amplifies Ras/MAPK output (PMID:38805286).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1992 High

    Established CCDC6 as a recurrent cancer gene by identifying its fusion to the RET kinase, defining the RET/PTC1 oncogene of papillary thyroid carcinoma.

    Evidence Cytogenetics, Southern blot, and FISH on papillary thyroid carcinoma samples

    PMID:1542652

    Open questions at the time
    • Did not define the normal cellular function of CCDC6
    • Mechanism of oncogenic activation by fusion unaddressed
  2. 1994 Medium

    Cloning revealed CCDC6 as a 585-residue coiled-coil protein, providing the structural basis for later dimerization and fusion studies.

    Evidence cDNA cloning/sequencing and structural prediction from human thyroid library

    PMID:8058316

    Open questions at the time
    • Cytoskeletal association inferred from sequence, not biochemically validated
    • No functional assay
  3. 1997 High

    Showed that the CCDC6 leucine zipper is the molecular driver of fusion oncogenicity, mediating dimerization needed for RET/PTC1 kinase activation and transformation.

    Evidence In vivo Co-IP, leucine-zipper mutagenesis, dominant-negative rescue, and focus formation in NIH3T3 cells

    PMID:9083029

    Open questions at the time
    • Did not address wild-type CCDC6 function
    • Biophysical basis of dimerization-driven activation unresolved until LLPS work
  4. 2000 High

    Extended CCDC6's fusion repertoire beyond thyroid cancer by identifying the CCDC6-PDGFβR fusion in BCR-ABL-negative CML, with the leucine zipper required for transformation.

    Evidence Southern blot, FISH, 5'-RACE, RT-PCR in CML; Ba/F3 transduction and murine bone marrow transplant

    PMID:10910073 PMID:11389034

    Open questions at the time
    • Did not test whether wild-type CCDC6 loss contributes to leukemogenesis
  5. 2004 High

    Defined wild-type CCDC6 as a ubiquitous nuclear/cytosolic phosphoprotein that is pro-apoptotic, with ERK-driven phosphorylation controlling nuclear-cytosolic shuttling and serine-244 required for apoptosis.

    Evidence Subcellular fractionation, immunofluorescence, ERK inhibitor, S244A mutagenesis, conditional expression in thyroid cells

    PMID:14712216

    Open questions at the time
    • Apoptotic effector pathway downstream of S244 not defined
    • Direct kinase acting on S244 not identified
  6. 2007 High

    Connected CCDC6 to the ATM-dependent DNA damage response, showing ATM phosphorylates Thr434 to stabilize nuclear CCDC6 and enforce cell-cycle arrest after damage.

    Evidence Co-IP, immunofluorescence in ATM-deficient/proficient cells, T434A mutagenesis, clonogenic and BrdU assays

    PMID:17420723

    Open questions at the time
    • Downstream effectors of nuclear CCDC6 in checkpoint enforcement not yet identified
    • Direct ATM-CCDC6 phosphorylation not shown in vitro
  7. 2010 High

    Identified the transcriptional repressor mechanism: CCDC6 binds CREB1 and recruits HDAC1 and PP1 to CRE sites, explaining how CCDC6 loss drives CREB1 target overexpression in thyroid cancer.

    Evidence Co-IP, ChIP for HDAC1/PP1 at CRE sites, CREB1 reporter assays, target gene RT-PCR in PTC samples

    PMID:20498639

    Open questions at the time
    • Stoichiometry/order of HDAC1 and PP1 recruitment unresolved
    • Genome-wide CREB1 targets controlled by CCDC6 not mapped
  8. 2012 Medium

    Resolved how CCDC6 sustains the damage checkpoint mechanistically—by restraining the γH2AX phosphatase PP4c and supporting intra-S-phase checkpoint components—linking its loss to genomic instability.

    Evidence Proteomic screen, Co-IP of CCDC6-PP4c, PP4c activity and γH2AX assays, shRNA knockdown with cell-cycle/CDC25C analyses

    PMID:22363533 PMID:22655027

    Open questions at the time
    • Whether CCDC6 inhibits PP4c directly or via an adaptor unresolved
    • Structural basis of PP4c modulation unknown
  9. 2012 Medium

    Established the degradation control of CCDC6 by FBXW7 and its coupling to damage signaling, showing ATM phosphorylation at Thr434 blocks FBXW7 binding to stabilize CCDC6, plus SUMO2-driven cytoplasmic sequestration that relieves CREB1 repression.

    Evidence Co-IP, in-cell ubiquitination, phosphomimetic mutagenesis (FBXW7); sumoylation-site mutagenesis with localization imaging and reporter assays

    PMID:23108047 PMID:23145146

    Open questions at the time
    • SUMO E3 ligase for CCDC6 not identified
    • Crosstalk between SUMOylation and FBXW7 turnover not tested
  10. 2014 Medium

    Demonstrated CCDC6's role in homologous recombination, showing its loss reduces Rad51 foci, impairs HR, and confers synthetic lethality with PARP inhibitors, defining a therapeutic vulnerability.

    Evidence Rad51 foci and HR reporter assays, clonogenic/viability assays with cisplatin and olaparib, combination index in NSCLC cells

    PMID:25302833

    Open questions at the time
    • Direct role of CCDC6 protein at HR sites not biochemically defined
    • Mechanism linking CCDC6 loss to reduced Rad51 loading unknown
  11. 2015 High

    Provided in vivo genetic proof that CCDC6-mediated CREB1 repression is tumor-suppressive, and refined cell-cycle-coupled turnover via FBXW7-USP7 antagonism affecting drug response.

    Evidence Ccdc6 exon-2 deletion knock-in mouse with thyroid IHC and reporter assays; cell-cycle synchronization, Co-IP, USP7 inhibitor and cycloheximide chase

    PMID:25885523 PMID:25970781

    Open questions at the time
    • Mitotic kinases generating the phospho-degron not fully enumerated
    • Whether CREB1 repression and checkpoint roles are genetically separable in vivo untested
  12. 2016 Medium

    Extended the turnover axis therapeutically, showing USP7 fine-tunes CCDC6 stability and its inhibition sensitizes neuroendocrine lung cancer to PARP inhibitors.

    Evidence Cycloheximide chase with USP7 inhibitor P5091, viability assays, CCDC6/USP7 TMA correlation in L-NET cells

    PMID:27372520

    Open questions at the time
    • USP7 may target other substrates contributing to sensitivity
    • Direct USP7-CCDC6 catalytic relationship not structurally defined
  13. 2019 Medium

    Linked CCDC6 to BAP1 in HR repair, showing physical interaction and additive HR defects and PARP-inhibitor sensitivity in mesothelioma.

    Evidence Co-IP of CCDC6-BAP1, HR reporter, viability assays, co-transfection with mutant BAP1 in MPM cells

    PMID:31447003

    Open questions at the time
    • Functional consequence of CCDC6-BAP1 binding at chromatin not defined
    • Single Co-IP context; reciprocal validation limited
  14. 2024 High

    Revealed the biophysical mechanism of CCDC6-RET fusion oncogenicity: LLPS driven by the CCDC6 partner enhances autophosphorylation and assembles a GRB2-SHC1 signaling niche to amplify Ras/MAPK signaling.

    Evidence In vitro/cellular LLPS assays, autophosphorylation kinase assays, Co-IP of the ternary complex, domain-deletion mutagenesis

    PMID:38805286

    Open questions at the time
    • Whether wild-type CCDC6 undergoes physiological LLPS untested
    • Therapeutic targetability of the condensate not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCDC6's distinct functions—CREB1 repression, PP4c restraint, HR support, and apoptosis—are mechanistically integrated and differentially deployed across tissues remains unresolved.
  • No structural model of CCDC6 in any of its complexes
  • Direct biochemical role of CCDC6 at HR/repair sites undefined
  • Tissue-specific determinants of which CCDC6 function dominates unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 2 GO:0008092 cytoskeletal protein binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-73894 DNA Repair 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-162582 Signal Transduction 1
Partners
BAP1CREB1FBXW7HDAC1PP1PP4CRETUSP7

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 CCDC6 (D10S170) is fused to the RET tyrosine kinase domain by a paracentric inversion of chromosome 10q [inv(10)(q11.2q21)], generating the RET/PTC1 oncogene in papillary thyroid carcinomas; cytogenetic and molecular analysis of tumor samples established that the chromosomal inversion breakpoints coincide with RET (10q11.2) and D10S170 (10q21) loci. Cytogenetic analysis combined with Southern blotting and FISH on papillary thyroid carcinoma samples Proceedings of the National Academy of Sciences of the United States of America High 1542652
1994 CCDC6 (H4/D10S170) encodes a 585-amino acid protein with no transmembrane domain, extensive alpha-helical coiled-coil regions homologous to cytoskeletal proteins (tropomyosin, vimentin, keratin, myosin heavy chain tail), and a putative SH3-binding site at the C-terminus, suggesting it is a cytoskeletal-associated protein. cDNA cloning and sequencing from human normal thyroid library; sequence analysis and structural prediction Oncogene Medium 8058316
1995 The N-terminal region of CCDC6 (H4/D10S170) contains a coiled-coil (leucine zipper-like) oligomerization domain; in vitro assays with recombinant proteins demonstrated that this region mediates oligomerization, and the H4 promoter drives ubiquitous expression of PTC1 in diverse human tissues including thyroid. In vitro oligomerization assay with recombinant proteins; luciferase promoter assay; primer extension mapping of transcriptional start sites Oncogene Medium 7753554
1997 CCDC6 leucine zipper-mediated dimerization is essential for the transforming activity of the PTC1 oncoprotein: the PTC1 oncoprotein forms a dimer in vivo via the H4 leucine zipper, leucine zipper-dependent dimerization is required for tyrosine hyperphosphorylation of PTC1 and for its ability to transform NIH3T3 cells, and a dominant-negative PTC1 mutant introduced into PTC1-transformed cells suppresses transformation by forming inactive heterodimers. Co-immunoprecipitation in vivo; dominant-negative transfection into NIH3T3 transformants; focus formation assay; immunokinase assay The Journal of biological chemistry High 9083029
2000 CCDC6 (H4/D10S170) is fused in-frame to the platelet-derived growth factor receptor beta (PDGFβR) in a t(5;10)(q33;q21.2) translocation in BCR-ABL-negative chronic myeloid leukemia; the H4-PDGFβR chimeric mRNA was detected by RT-PCR and 5'-RACE, establishing CCDC6 as a recurrent fusion partner in myeloid malignancies beyond thyroid cancer. Southern blotting, FISH, 5'-RACE PCR, RT-PCR, DNA sequencing Cancer research High 10910073
2001 The H4/CCDC6-PDGFβR fusion protein requires the CCDC6 leucine zipper domain (amino acids 55–93) as well as additional H4 sequences (aa 101–386) for efficient induction of factor-independent growth; retroviral transduction of H4/PDGFβR (but not a kinase-inactive mutant) conferred factor-independent growth to Ba/F3 cells and caused T-cell lymphoblastic lymphoma in a murine bone marrow transplantation model. Retroviral transduction of Ba/F3 cells; murine bone marrow transplantation assay; mutational analysis of leucine zipper and PDGFβR domains; factor-independent growth assay Blood High 11389034
2004 CCDC6 (H4/D10S170) protein is a ubiquitously expressed 55 kDa protein found in both the nucleus and cytosol; it is phosphorylated following serum stimulation in an ERK1/2-dependent manner, and this phosphorylation correlates with relocation from nucleus to cytosol. Overexpression of full-length CCDC6 induces apoptosis of thyroid follicular cells, whereas the C-terminally truncated mutant H4(1-101) (the portion retained in RET/PTC1) acts as a dominant negative on both the pro-apoptotic function and nuclear localization of CCDC6; substitution of serine 244 with alanine abrogates the apoptotic function. Subcellular fractionation and immunofluorescence; serum stimulation with ERK inhibitor treatment; overexpression and dominant-negative transfection assays in thyroid cells; site-directed mutagenesis (S244A); conditional expression system Oncogene High 14712216
2004 RET/PTC1 associates with hsp90 and its co-chaperone p50cdc37; proteomic analysis identified these as novel RET/PTC1-interacting proteins, and hsp90 inhibition with 17-AAG reduces RET/PTC1 protein levels. Proteomic analysis (Co-immunoprecipitation followed by mass spectrometry); Western blot of 17-AAG-treated cells The Journal of biological chemistry Medium 15302866
2007 CCDC6 (H4/D10S170) undergoes ATM-mediated phosphorylation at Thr434 in response to DNA damage (etoposide or ionizing radiation); this phosphorylation stabilizes CCDC6 in the nucleus. In ATM-deficient cells, CCDC6 is excluded from the nucleus and is not phosphorylated after IR. The T434A mutant fails to induce apoptosis and protects cells from genotoxic stress; silencing of CCDC6 after IR increases cell survival, permits DNA synthesis, and allows mitotic entry, demonstrating CCDC6's role in the ATM-dependent DNA damage response. Co-immunoprecipitation; immunofluorescence in ATM-deficient and proficient cells; site-directed mutagenesis (T434A); clonogenic assay after siRNA knockdown; BrdU incorporation assay; histone H3 phosphorylation assay Oncogene High 17420723
2010 CCDC6 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 genes; loss of CCDC6 function (as occurs in RET/PTC1 rearrangement) leads to increased CREB1 phosphorylation and elevated expression of CREB1 target genes AREG and cyclin A in PTCs. Co-immunoprecipitation (CCDC6-CREB1 interaction); chromatin immunoprecipitation showing HDAC1 and PP1 recruitment to CRE sites; reporter assays for CREB1 transcriptional activity; Western blot of CREB1 phosphorylation; RT-PCR of target gene expression in PTC samples Oncogene High 20498639
2012 CCDC6 loss accelerates dephosphorylation of γH2AX (pH2AX S139) following genotoxic stress, resulting in defective G2 arrest and premature mitotic entry. CCDC6 physically interacts with the catalytic subunit of protein phosphatase 4 (PP4c), the conserved pH2AX phosphatase, and CCDC6 depletion increases PP4c enzymatic activity; these data suggest CCDC6 negatively modulates PP4c to sustain the DNA damage checkpoint. High-throughput proteomic screening predicting CCDC6-PP4c interaction; Co-immunoprecipitation confirming CCDC6-PP4c binding; PP4c enzymatic activity assay in CCDC6-depleted cells; γH2AX S139 phosphorylation assay by flow cytometry/Western; cell cycle analysis PloS one Medium 22655027
2012 Loss of CCDC6 impairs the intra-S-phase checkpoint: CCDC6-depleted cells show shortened S-phase, fail to accumulate in S-phase upon etoposide treatment, accumulate DNA damage (elevated pH2AX Ser139), downregulate 14-3-3σ, and fail to sequester CDC25C phosphatase to the cytoplasm upon genotoxic stress — indicating CCDC6 is required for proper S-phase checkpoint control. Lentiviral shRNA knockdown of CCDC6 in multiple cell lines; cell cycle analysis by flow cytometry; Western blot for 14-3-3σ, CDC25C, pH2AX; immunofluorescence for CDC25C localization PloS one Medium 22363533
2012 FBXW7 E3 ubiquitin ligase interacts with CCDC6 and targets it for ubiquitin-mediated proteasomal degradation; ATM-mediated phosphorylation of CCDC6 at Thr434 during DNA damage response prevents the FBXW7-CCDC6 interaction and thereby stabilizes CCDC6, linking DNA damage signaling to CCDC6 protein stability. Co-immunoprecipitation of FBXW7 with CCDC6; ubiquitination assay; proteasome inhibitor treatment; site-directed mutagenesis (T434A/T434E) blocking/mimicking ATM phosphorylation; Western blot FEBS letters High 23108047
2012 CCDC6 contains three sumoylation sites (K74, K266, K424) conserved in vertebrates; SUMO2 modification at these sites sequesters CCDC6 in the cytosol and reduces its ability to repress CREB1 transcriptional activity. Mutation of all three sumoylation sites abolishes this cytosolic sequestration and restores CCDC6 repressive function on CREB1. In thyroid cells, SUMO2-mediated modification is induced by Forskolin/cAMP signaling. Site-directed mutagenesis of sumoylation sites (K74R, K266R, K424R); immunofluorescence for subcellular localization of SUMO2-modified CCDC6; CREB1 reporter assay; Forskolin treatment of thyroid cells PloS one Medium 23145146
2015 CCDC6 protein levels oscillate during the cell cycle, peaking at G2 and decreasing in mitosis; mitotic kinases promote CCDC6 degradation via phospho-degron motifs that recruit the FBXW7 E3 ubiquitin ligase, while the deubiquitinase USP7 counteracts this to stabilize CCDC6. Both FBXW7 and USP7 affect CCDC6 protein levels and, consequently, cell drug response in NSCLC cells. Cell cycle synchronization followed by Western blot and phosphorylation assays; Co-immunoprecipitation of CCDC6 with FBXW7 and USP7; USP7 inhibitor treatment; cycloheximide chase assay Oncotarget High 25885523
2015 Mice carrying a Ccdc6 exon-2 deletion knock-in (which specifically impairs CCDC6-mediated CREB1 repression) develop thyroid hyperplasia with enhanced CREB1 activity and increased expression of CREB1-regulated target genes, demonstrating that CCDC6 repression of CREB1 is functionally required to prevent thyroid hyperplasia in vivo. Knock-in mouse model with Ccdc6 exon-2 deletion; immunohistochemistry of thyroid; luciferase reporter assay comparing wild-type vs. mutant Ccdc6 repression of CREB1; RT-PCR of CREB1 target genes Oncotarget High 25970781
2016 USP7 deubiquitinase is responsible for fine-tuning CCDC6 protein stability; inhibition of USP7 with P5091 accelerates CCDC6 degradation in cycloheximide chase assays and sensitizes lung neuroendocrine cancer cells to PARP inhibitors, establishing a USP7→CCDC6→PARP-inhibitor sensitivity axis. Cycloheximide chase assay with USP7 inhibitor P5091 in L-NET cells; cell viability assays with PARP inhibitor alone and in combination with cisplatinum; immunostaining correlation of CCDC6 and USP7 in TMA Lung cancer (Amsterdam, Netherlands) Medium 27372520
2016 The FGFR2-CCDC6 fusion protein in intrahepatic cholangiocarcinoma acts as a constitutively active oncogenic kinase; in a patient-derived xenograft model endogenously expressing FGFR2-CCDC6, FGFR inhibitors (ponatinib, dovitinib, BGJ398) modulate FGFR signaling, inhibit cell proliferation and induce apoptosis, with BGJ398 showing superior potency. Patient-derived xenograft (PDX) model; Western blot for FGFR signaling (pFGFR, downstream targets); cell proliferation assay; apoptosis assay; comparison of three FGFR inhibitors in vivo Cancer letters Medium 27216979
2018 miR-146b-5p directly targets CCDC6 mRNA, reducing CCDC6 protein levels and thereby promoting PTC cell proliferation, migration, invasion, and cell cycle progression; overexpression of CCDC6 reverses these effects both in vitro and in a subcutaneous mouse model, identifying CCDC6 as a functional tumor suppressor target of miR-146b-5p in papillary thyroid cancer. Luciferase reporter assay with CCDC6 3'UTR confirming direct miR-146b-5p targeting; gain- and loss-of-function studies (miR-146b-5p overexpression and CCDC6 overexpression/knockdown) with cell proliferation, migration, invasion, and cell cycle assays; subcutaneous mouse tumor model Cancer letters Medium 30503553
2019 CCDC6 physically interacts with BAP1 (BRCA1-associated protein-1) in malignant pleural mesothelioma cells; depletion of CCDC6 impairs homologous recombination-mediated DSB repair and sensitizes MPM cells to PARP inhibitors, and combined loss of CCDC6 and expression of mutant BAP1 (Δ221-238) further enhances HR-repair defects and PARP inhibitor sensitivity. Co-immunoprecipitation of CCDC6 with BAP1 in MPM cells; HR reporter assay; cell viability assay with PARP inhibitors; co-transfection of CCDC6 siRNA and BAP1 mutant construct Lung cancer (Amsterdam, Netherlands) Medium 31447003
2024 CCDC6-RET fusion protein undergoes liquid-liquid phase separation (LLPS) dependent on both its kinase domain and the CCDC6 fusion partner; this LLPS promotes autophosphorylation and enhances kinase activity of the RET fusion. Within the resulting condensate, a ternary signal niche comprising CCDC6-RET, adaptor GRB2, and effector SHC1 is assembled, amplifying Ras/MAPK signaling efficiency in a tyrosine kinase-dependent manner. In vitro and cellular LLPS assays; autophosphorylation kinase assays; Co-immunoprecipitation of the CCDC6-RET/GRB2/SHC1 ternary complex; domain deletion mutants to define LLPS requirements; biochemical signaling assays Proceedings of the National Academy of Sciences of the United States of America High 38805286
2014 CCDC6-deficient NSCLC cells show defective homologous recombination (reduced Rad51 foci), impaired DNA damage response, resistance to cisplatin, and sensitization to PARP1/2 inhibitor olaparib with a synthetic lethal effect; combining olaparib and cisplatin in CCDC6-deficient cells produces combination index <1 (synergy). Characterization of NSCLC cell lines by Western blot for CCDC6; Rad51 foci assay; HR reporter assay; clonogenic/viability assays with cisplatin, olaparib, and combination; combination index calculation International journal of cancer Medium 25302833
2013 CCDC6 loss in germ cell-derived GC1 cells attenuates apoptotic signaling (decreased cytochrome c oxidation, reduced Bad, PARP-1, and caspase-3) and impairs γH2AX activation upon H₂O₂ oxidative damage, while reducing reactive oxygen species release and protecting cell viability; CCDC6 expression is present in Sertoli cells and spermatogonial cells of the testis but is lost in testicular germ cell tumors. shRNA silencing of CCDC6 in GC1 cells; H₂O₂ treatment; Western blot for apoptosis markers (cytochrome c, Bad, PARP-1, caspase-3); γH2AX immunofluorescence; ROS assay; immunohistochemistry of mouse and human testis sections BMC cancer Medium 24059746
2022 In CCDC6-RET-rearranged thyroid cancer, adaptive resistance to RET inhibitors is mediated by rapid reactivation of ERK signaling via FGFR pathway activation within hours of drug exposure; combined FGFR and RET inhibition prevents adaptive ERK reactivation, reduces cell viability, and decreases tumor growth in cellular and animal models. Drug screening on CCDC6-RET patient-derived models; proteomic and biochemical profiling (phosphoproteomics, Western blot); combined RET+FGFR inhibitor treatment in vitro and in vivo xenograft The Journal of experimental medicine Medium 35510953

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice. Cancer cell 415 15380514
2001 Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 414 11389830
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 264 16203990
1996 Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 241 8536638
1992 Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proceedings of the National Academy of Sciences of the United States of America 213 1542652
1996 Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 209 8622903
2003 Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Human mutation 165 12955717
2001 Ptc1, a type 2C Ser/Thr phosphatase, inactivates the HOG pathway by dephosphorylating the mitogen-activated protein kinase Hog1. Molecular and cellular biology 147 11113180
1993 Mutations in a protein tyrosine phosphatase gene (PTP2) and a protein serine/threonine phosphatase gene (PTC1) cause a synthetic growth defect in Saccharomyces cerevisiae. Molecular and cellular biology 147 8395005
2005 Gli1 is important for medulloblastoma formation in Ptc1+/- mice. Oncogene 130 15806168
1991 Tst-1, a member of the POU domain gene family, binds the promoter of the gene encoding the cell surface adhesion molecule P0. Molecular and cellular biology 121 1705013
2000 Fusion of H4/D10S170 to the platelet-derived growth factor receptor beta in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21). Cancer research 100 10910073
2001 H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22). Blood 99 11389034
2002 High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice. Oncogene 86 12386820
1993 Regulation of JC virus by the POU-domain transcription factor Tst-1: implications for progressive multifocal leukoencephalopathy. Proceedings of the National Academy of Sciences of the United States of America 84 8389455
2000 Loss of p53 promotes anaplasia and local invasion in ret/PTC1-induced thyroid carcinomas. The American journal of pathology 81 10934169
2000 Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. Oncogene 80 10656692
1995 Regulation of cell wall beta-glucan assembly: PTC1 negatively affects PBS2 action in a pathway that includes modulation of EXG1 transcription. Molecular & general genetics : MGG 80 7565587
2000 A C. elegans patched gene, ptc-1, functions in germ-line cytokinesis. Genes & development 79 10921907
2016 Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein. Cancer letters 76 27216979
2012 Identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line, LC-2/ad. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 75 23154560
1997 Leucine zipper-mediated dimerization is essential for the PTC1 oncogenic activity. The Journal of biological chemistry 73 9083029
2010 Role of H2O2 in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells. Cancer research 72 20424115
2001 Ptc1 and Ptc2 transcripts provide distinct readouts of Hedgehog signaling activity during chick embryogenesis. Developmental biology 69 11784016
1998 The ret/ptc1 oncogene is activated in familial adenomatous polyposis-associated thyroid papillary carcinomas. The Journal of clinical endocrinology and metabolism 69 9506763
2003 Nbp2 targets the Ptc1-type 2C Ser/Thr phosphatase to the HOG MAPK pathway. The EMBO journal 65 14685261
1995 Suppressors of a Saccharomyces cerevisiae pkc1 mutation identify alleles of the phosphatase gene PTC1 and of a novel gene encoding a putative basic leucine zipper protein. Genetics 64 8601473
1999 Overexpression of ptc1 inhibits induction of Shh target genes and prevents normal patterning in the neural tube. Developmental biology 63 10395791
1994 Protein phosphatase 2C, encoded by ptc1+, is important in the heat shock response of Schizosaccharomyces pombe. Molecular and cellular biology 62 8196617
1994 Cloning and characterization of H4 (D10S170), a gene involved in RET rearrangements in vivo. Oncogene 58 8058316
2016 USP7 inhibitors, downregulating CCDC6, sensitize lung neuroendocrine cancer cells to PARP-inhibitor drugs. Lung cancer (Amsterdam, Netherlands) 57 27372520
2013 Identification of a lung adenocarcinoma cell line with CCDC6-RET fusion gene and the effect of RET inhibitors in vitro and in vivo. Cancer science 56 23578175
2010 Detection of papillary thyroid carcinoma by analysis of BRAF and RET/PTC1 mutations in fine-needle aspiration biopsies of thyroid nodules. World journal of surgery 56 20652698
2008 Identification of the putative protein phosphatase gene PTC1 as a virulence-related gene using a silkworm model of Candida albicans infection. Eukaryotic cell 56 18708562
2004 H4(D10S170), a gene frequently rearranged with RET in papillary thyroid carcinomas: functional characterization. Oncogene 56 14712216
2023 The SnRK2.3-AREB1-TST1/2 cascade activated by cytosolic glucose regulates sugar accumulation across tonoplasts in apple and tomato. Nature plants 54 37291399
2009 RET/PTC1-driven neoplastic transformation and proinvasive phenotype of human thyrocytes involve Met induction and beta-catenin nuclear translocation. Neoplasia (New York, N.Y.) 53 19107227
2006 Transcriptional profiling of the protein phosphatase 2C family in yeast provides insights into the unique functional roles of Ptc1. The Journal of biological chemistry 53 16973600
1998 Mitochondrial inheritance is delayed in Saccharomyces cerevisiae cells lacking the serine/threonine phosphatase PTC1. Molecular biology of the cell 53 9529388
2005 RET gene rearrangements (RET/PTC1 and RET/PTC3) in papillary thyroid carcinomas from an iodine-rich country (Japan). Cancer 51 16015630
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
2018 MicroRNA-146b-5p as an oncomiR promotes papillary thyroid carcinoma development by targeting CCDC6. Cancer letters 49 30503553
2000 Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative. International journal of cancer 49 10652431
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
2015 FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC. Oncotarget 47 25885523
1999 Early cellular abnormalities induced by RET/PTC1 oncogene in thyroid-targeted transgenic mice. Oncogene 46 10380889
2008 Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement. Clinical cancer research : an official journal of the American Association for Cancer Research 45 18676765
2007 Involvement of H4(D10S170) protein in ATM-dependent response to DNA damage. Oncogene 45 17420723
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
2004 Real-time quantitative RT-PCR identifies distinct c-RET, RET/PTC1 and RET/PTC3 expression patterns in papillary thyroid carcinoma. Laboratory investigation; a journal of technical methods and pathology 44 15502856
2005 Constitutive activation of the shh-ptc1 pathway by a patched1 mutation identified in BCC. Oncogene 43 15592520
2002 Establishment of a non-tumorigenic papillary thyroid cell line (FB-2) carrying the RET/PTC1 rearrangement. International journal of cancer 42 11807785
2007 Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice. Developmental biology 39 18036580
2001 RET/PTC1 oncogene signaling in PC Cl 3 thyroid cells requires the small GTP-binding protein Rho. Oncogene 39 11704822
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 Loss of CCDC6, the first identified RET partner gene, affects pH2AX S139 levels and accelerates mitotic entry upon DNA damage. PloS one 37 22655027
2009 Normal function of the yeast TOR pathway requires the type 2C protein phosphatase Ptc1. Molecular and cellular biology 37 19273591
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
2017 EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells. Yonsei medical journal 35 27873490
2013 Ptc1 protein phosphatase 2C contributes to glucose regulation of SNF1/AMP-activated protein kinase (AMPK) in Saccharomyces cerevisiae. The Journal of biological chemistry 35 24019512
2002 Identification of genes that are downregulated in the absence of the POU domain transcription factor pou3f1 (Oct-6, Tst-1, SCIP) in sciatic nerve. The Journal of neuroscience : the official journal of the Society for Neuroscience 34 12451123
2017 CCDC6: the identity of a protein known to be partner in fusion. International journal of cancer 33 29044514
1995 Characterization of the promoter region and oligomerization domain of H4 (D10S170), a gene frequently rearranged with the ret proto-oncogene. Oncogene 31 7753554
1998 Expression of Ret/PTC1, -2, -3, -delta3 and -4 in German papillary thyroid carcinoma. British journal of cancer 30 9528832
2011 Orthovanadate-induced cell death in RET/PTC1-harboring cancer cells involves the activation of caspases and altered signaling through PI3K/Akt/mTOR. Life sciences 28 21807000
2012 FBXW7-mediated degradation of CCDC6 is impaired by ATM during DNA damage response in lung cancer cells. FEBS letters 27 23108047
2002 The roles of phosphotyrosines-294, -404, and -451 in RET/PTC1-induced thyroid tumor formation. Oncogene 27 12444552
2015 Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting Through the MAPK Kinase Mkk1. Genetics 26 26546002
2014 Effects of silencing the RET/PTC1 oncogene in papillary thyroid carcinoma by siRNA-squalene nanoparticles with and without fusogenic companion GALA-cholesterol. Thyroid : official journal of the American Thyroid Association 26 23885719
1996 Development of mammary and cutaneous gland tumors in transgenic mice carrying the RET/PTC1 oncogene. Oncogene 25 8934550
1996 A novel multicolor hybridization scheme applied to localization of a transcribed sequence (D10S170/H4) and deletion mapping in the thyroid cancer cell line TPC-1. Cytogenetics and cell genetics 25 9067436
2008 PARP-1 cooperates with Ptc1 to suppress medulloblastoma and basal cell carcinoma. Carcinogenesis 24 18660545
2018 The rationale for druggability of CCDC6-tyrosine kinase fusions in lung cancer. Molecular cancer 23 29455670
2005 Low prevalence of RET rearrangements (RET/PTC1, RET/PTC2, RET/PTC3, and ELKS-RET) in sporadic papillary thyroid carcinomas in Taiwan Chinese. Thyroid : official journal of the American Thyroid Association 23 15876154
2016 miRNA profiling, detection of BRAF V600E mutation and RET-PTC1 translocation in patients from Novosibirsk oblast (Russia) with different types of thyroid tumors. BMC cancer 22 26960768
2015 Ccdc6 knock-in mice develop thyroid hyperplasia associated to an enhanced CREB1 activity. Oncotarget 22 25970781
2013 Critical role of CCDC6 in the neoplastic growth of testicular germ cell tumors. BMC cancer 22 24059746
2005 Ptc1 heterozygous knockout mice as a model of multi-organ tumorigenesis. Cancer letters 22 15925443
1997 Thyroid-stimulating hormone promotes growth of thyroid carcinomas in transgenic mice with targeted expression of the ret/PTC1 oncogene. Laboratory investigation; a journal of technical methods and pathology 22 9121114
1998 The ret/PTC1 rearrangement is a common feature of Chernobyl-associated papillary thyroid carcinomas from Belarus. Thyroid : official journal of the American Thyroid Association 21 9510121
2007 Differential responses of human papillary thyroid cancer cell lines carrying the RET/PTC1 rearrangement or a BRAF mutation to MEK1/2 inhibitors. Archives of otolaryngology--head & neck surgery 19 17709622
2012 Upregulation of Shh and Ptc1 in hyperoxia‑induced acute lung injury in neonatal rats. Molecular medicine reports 18 22641469
2012 Loss of CCDC6 affects cell cycle through impaired intra-S-phase checkpoint control. PloS one 17 22363533
2012 Identification of sumoylation sites in CCDC6, the first identified RET partner gene in papillary thyroid carcinoma, uncovers a mode of regulating CCDC6 function on CREB1 transcriptional activity. PloS one 17 23145146
2022 Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer. The Journal of experimental medicine 16 35510953
2021 Circular RNA circDNA2 upregulates CCDC6 expression to promote the progression of gastric cancer via miR-149-5p suppression. Molecular therapy. Nucleic acids 16 34552818
2019 Analysis of CCDC6 as a novel biomarker for the clinical use of PARP1 inhibitors in malignant pleural mesothelioma. Lung cancer (Amsterdam, Netherlands) 16 31447003
2019 Establishment and Characterization of Four Novel Thyroid Cancer Cell Lines and PDX Models Expressing the RET/PTC1 Rearrangement, BRAFV600E, or RASQ61R as Drivers. Molecular cancer research : MCR 15 30733375
2017 Lentivirus-mediated silencing of the PTC1 and PTC2 genes promotes recovery from spinal cord injury by activating the Hedgehog signaling pathway in a rat model. Experimental & molecular medicine 15 29244790
2006 The expression of Hedgehog genes (Ihh, Dhh) and Hedgehog target genes (Ptc1, Gli1, Coup-TfII) is affected by estrogenic stimuli in the uterus of immature female rats. Toxicology and applied pharmacology 15 17109907
2024 CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche. Proceedings of the National Academy of Sciences of the United States of America 14 38805286
2020 Suppression of CCDC6 sensitizes tumor to oncolytic virus M1. Neoplasia (New York, N.Y.) 14 33338804
2011 Assessment of RET/PTC1 and RET/PTC3 rearrangements in fine-needle aspiration biopsy specimens collected from patients with Hashimoto's thyroiditis. Thyroid research 14 21219595
2010 Developmental and oncogenic effects of insulin-like growth factor-I in Ptc1+/- mouse cerebellum. Molecular cancer 14 20214787
2006 Matrix metalloproteinase-19 expression in keratinocytes is repressed by transcription factors Tst-1 and Skn-1a: implications for keratinocyte differentiation. The Journal of investigative dermatology 14 17195013
2005 Transcriptional control of Shh/Ptc1 signaling in embryonic development. Gene 14 16330160
2004 Forskolin, 8-Br-3',5'-cyclic adenosine 5'-monophosphate, and catalytic protein kinase A expression in the nucleus increase radioiodide uptake and sodium/iodide symporter protein levels in RET/PTC1-expressing cells. The Journal of clinical endocrinology and metabolism 14 15579773
2001 Chemoprevention of basal cell carcinomas in the ptc1+/- mouse--green and black tea. Skin pharmacology and applied skin physiology 14 11598435

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