{"gene":"CCND3","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":1995,"finding":"Cyclin D3 (CCND3) partners with CDK4 to phosphorylate the Rb-1 tumor suppressor protein; glucocorticoids inhibit both CcnD3 and Cdk4 expression, reducing Rb-1 phosphorylation; overexpression of cyclin D3 restores Rb-kinase activity in glucocorticoid-treated lymphoid cells; combined overexpression of cyclin D3 and c-Myc confers resistance to glucocorticoid-mediated G0 arrest and apoptosis.","method":"Stable transfection/overexpression, kinase activity assay (Rb-1 phosphorylation), SV40 T antigen rescue, serum-free apoptosis assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (kinase assay, stable transformants, rescue experiments, apoptosis assay) in a single rigorous study with mechanistic readouts","pmids":["7664296"],"is_preprint":false},{"year":2019,"finding":"PTBP1 (polypyrimidine tract-binding protein 1) enhances CCND3 translation by directly interacting with the 5'-UTR of CCND3 mRNA, thereby facilitating cell cycle progression and tumor growth in hepatocellular carcinoma; miR-194 inhibits PTBP1 expression by binding its 3'-UTR, resulting in reduced CCND3 levels.","method":"RNA-binding protein co-immunoprecipitation, 5'-UTR reporter assay, miRNA target validation, western blot, loss-of-function/overexpression cell proliferation assays","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays (RBP–mRNA interaction via 5'-UTR), miRNA target validation, functional rescue; single lab with multiple orthogonal methods","pmids":["31301177"],"is_preprint":false},{"year":2022,"finding":"FOXO1 acts as a transcriptional activator of CCND3 in B-ALL cells; CCND3 is essential for B-ALL proliferation and survival independent of CDK4/6 kinase activity; the anti-apoptotic effect of CCND3 is separable from its role in the CCND3-CDK4/6 kinase complex; CCND3 contributes to CDK8 transcription, partly explaining its anti-apoptotic function; increased CCND3 expression drives resistance to palbociclib (CDK4/6 inhibitor).","method":"CCND3 knockdown, CDK4/6 inhibition (palbociclib), transcription factor overexpression/knockdown, comparison of CCND3 depletion vs. kinase inhibition phenotypes, gene expression analysis","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic perturbations (KD, inhibitor) with defined proliferation/apoptosis readouts; single lab, no structural validation","pmids":["35013097"],"is_preprint":false},{"year":2025,"finding":"CCND3 downregulation in cisplatin-resistant lung adenocarcinoma cells—driven by transcriptional suppression through the PI3K/Akt/c-Jun signaling axis—diminishes recruitment of the E3 ubiquitin ligase PARK2 (Parkin) to vimentin, thereby reducing vimentin ubiquitination and degradation, triggering epithelial-mesenchymal transition (EMT), cytoskeleton remodeling, metastasis, and chemoresistance.","method":"Loss-of-function (CCND3 knockdown), in vivo/in vitro migration/invasion assays, western blot for PARK2-vimentin ubiquitination, PI3K/Akt pathway inhibitor experiments, clinical sample correlation","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with multiple methods (KD, pathway inhibitors, ubiquitination assay); single lab","pmids":["39781469"],"is_preprint":false},{"year":2025,"finding":"CCND3 functions as an interferon-stimulated gene (ISG) with antiviral activity against bandaviruses (e.g., SFTSV); upon viral infection, CCND3 undergoes cytoplasmic translocation; via its CN domain, CCND3 interacts with the viral nucleoprotein (NP) 'head' region in an RNA-independent manner, suppressing the ribonucleoprotein (RNP) replication machinery by blocking NP multimerization, NP-RNA binding, and NP association with viral polymerase; the viral nonstructural protein NSs counteracts CCND3 by attenuating its induction and promoting its autophagic degradation.","method":"ISG screening, subcellular fractionation/live imaging (cytoplasmic translocation), co-immunoprecipitation (CN domain–NP interaction), RNA-independent binding assay, in vivo infection model, structural/interaction interface mapping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (pulldown, domain mapping, RNA-independence assay, in vivo model, structural modeling with functional validation) in a single detailed study","pmids":["40858603"],"is_preprint":false},{"year":2024,"finding":"PRAME promotes CCND3 protein accumulation in multiple myeloma cells by ubiquitinating and degrading CTMP and p21 (as a Cul2-dependent E3 ligase substrate-recognizing subunit), which activates p-Akt signaling and leads to elevated CCND3 levels, thereby promoting cell proliferation.","method":"PRAME knockdown/overexpression, western blot for ubiquitination targets, co-immunoprecipitation (PRAME–CTMP/p21 interaction), cell proliferation assays","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP showing PRAME–substrate interaction with ubiquitination assay and proliferation readout; single lab, multiple methods but no in vitro reconstitution","pmids":["39071619"],"is_preprint":false},{"year":2015,"finding":"TLR7 activation in B cells increases CCND3 expression via downregulation of miR-15b; CCND3 was identified as a direct target of miR-15b by luciferase reporter assay; this axis was confirmed in SLE patient B cells and in two lupus mouse models.","method":"TLR7 agonist stimulation, miRNA mimic/inhibitor transfection, dual-luciferase reporter assay, western blot, in vivo IMQ-treated mouse model","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter validation of direct miRNA targeting plus in vivo model; single lab, multiple orthogonal approaches","pmids":["26144250"],"is_preprint":false},{"year":2015,"finding":"CCND3 knockdown in colorectal cancer cells induced cell cycle arrest and apoptosis; miR-592 directly targets the CCND3 3'-UTR (confirmed by dual-luciferase reporter assay), reduces CCND3 protein, and consequently decreases phosphorylated Rb.","method":"siRNA knockdown, dual-luciferase reporter assay, western blot for p-Rb, cell proliferation/colony-forming assay","journal":"International journal of clinical and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter validation of direct miRNA targeting, functional knockdown with defined Rb phosphorylation readout; single lab","pmids":["26064240"],"is_preprint":false},{"year":2016,"finding":"CCND3 was identified as a direct target of miR-212 in adult T-cell leukemia/lymphoma (ATL) cells; miR-212 restoration caused G0/G1 arrest and apoptosis; rescue with a miR-212-resistant CCND3 variant restored cell-cycle progression and attenuated apoptosis, confirming direct targeting.","method":"miRNA overexpression, dual-luciferase reporter assay, CCND3 rescue with miR-resistant construct, cell cycle analysis, apoptosis assay, in vivo xenograft","journal":"Journal of investigative medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — miRNA-resistant rescue experiment is orthogonal to luciferase assay; single lab","pmids":["27493231"],"is_preprint":false},{"year":2018,"finding":"miR-4779 directly targets CCND3 (confirmed by luciferase reporter assay); CCND3 knockdown alone induced cell cycle arrest and apoptosis in colon cancer cells, phenocopying miR-4779 overexpression; miR-4779 suppressed tumor growth in HCT116 xenografts.","method":"miRNA mimic library screen, luciferase reporter assay, siRNA knockdown, cell cycle/apoptosis analysis, in vivo xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct luciferase target validation plus functional knockdown phenotype; single lab","pmids":["29362401"],"is_preprint":false},{"year":2014,"finding":"A recurrent KCNMB4-CCND3 fusion gene in human osteosarcoma (identified by transcriptome sequencing and validated by RT-PCR, Sanger sequencing, and FISH) promotes SAOS-2 osteosarcoma cell migration.","method":"Transcriptome sequencing, RT-PCR, Sanger sequencing, FISH validation, cell migration/invasion assays with fusion gene expression","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — fusion gene validated by multiple methods, functional migration assay; single lab","pmids":["25300797"],"is_preprint":false},{"year":2033,"finding":"BRD4 PROTAC degrader MZ1 downregulates CCND3 expression in B-ALL cells (identified by RNA-seq), leading to cell apoptosis, cell cycle arrest, and proliferation inhibition; these effects were confirmed by CCND3 knockdown experiments.","method":"RNA-seq (target identification), CCND3 knockdown (lentiviral), western blot, cell cycle/apoptosis flow cytometry, CCK8 proliferation assay","journal":"Hematology (Amsterdam, Netherlands)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CCND3 knockdown phenocopies MZ1 but the direct mechanistic link between BRD4 and CCND3 transcription is not rigorously established; single lab, single approach","pmids":["37594294"],"is_preprint":false},{"year":2026,"finding":"METTL5-mediated N6-methyladenosine (m6A) modification of 18S rRNA enhances CCND3 mRNA translation efficiency; METTL5 knockout reduced CCND3 translational output (measured by ribosome nascent-chain complex-bound mRNA sequencing), suppressing OSCC tumorigenesis and metastasis.","method":"METTL5 knockout, RNC-seq (ribosome nascent-chain complex mRNA sequencing for translation efficiency), western blot, in vivo xenograft, Transwell/colony formation assays","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNC-seq is a direct translational efficiency readout; functional validation in vivo; single lab","pmids":["41743013"],"is_preprint":false},{"year":2025,"finding":"Butyrate treatment causes CCND3 protein accumulation in intestinal cells through both mRNA increase and CDKN1A (p21)-dependent protein stabilization; CDKN1A reduces phosphorylation at the conserved Thr residue (Thr283) critical for CCND3 nuclear export and proteasomal degradation, thereby extending its nuclear half-life; co-immunoprecipitation identified CCND3 complexes with CDKN1A, CDK4, CDK6, and CDK5 in butyrate-treated cells; structural modeling predicts that CDKN1A binding buries CCND3-Thr283, limiting its phosphorylation.","method":"Co-immunoprecipitation (CCND3 complexes), phosphorylation site analysis, nuclear fractionation/half-life assay, structural modeling (AlphaFold2) + molecular dynamics simulations, western blot","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, phosphorylation analysis, structural modeling with functional correlation; single lab preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.06.19.660543"],"is_preprint":true},{"year":2025,"finding":"NMDe (nonsense-mediated decay-escaping) frameshift/truncating variants in CCND3 that remove its C-terminal regulatory region increase intracellular protein stability (consistent with loss of phosphorylation-dependent degradation signals), representing an oncogenic gain-of-function mechanism in pediatric cancers.","method":"Somatic mutation database analysis (COSMIC), functional classification by variant pattern, pediatric clinical genomics cohort interrogation","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 4 / Weak — inference from mutation pattern analysis; no direct biochemical reconstitution of protein stability; preprint","pmids":["bio_10.1101_2025.11.20.25340490"],"is_preprint":true}],"current_model":"CCND3 (Cyclin D3) is a D-type cyclin that drives G1/S cell cycle progression by forming active complexes with CDK4 and CDK6 to phosphorylate Rb, and its activity is regulated at multiple levels: transcriptionally by FOXO1 and suppressed by glucocorticoids (via c-Jun/PI3K/Akt) and multiple microRNAs (miR-15b, miR-194, miR-212, miR-592, miR-4779); translationally by PTBP1 binding to its 5'-UTR and by METTL5-mediated ribosomal m6A modification; post-translationally by CDKN1A (p21)-dependent inhibition of Thr283 phosphorylation that blocks nuclear export and proteasomal degradation, and by PRAME-mediated ubiquitination of upstream regulators that elevate CCND3 levels; beyond its canonical kinase-complex role, CCND3 has a CDK4/6-independent anti-apoptotic function (partly through CDK8 transcription), a non-nuclear antiviral role (its CN domain binds bandavirus nucleoprotein to block RNP assembly), and a role in limiting EMT by facilitating PARK2-mediated vimentin ubiquitination."},"narrative":{"mechanistic_narrative":"CCND3 (Cyclin D3) is a D-type cyclin that drives G1/S cell cycle progression by partnering with CDK4 (and CDK6) to phosphorylate the Rb tumor suppressor, and its expression is gated by mitogenic and hormonal cues — glucocorticoids suppress both CCND3 and CDK4 to lower Rb phosphorylation and enforce G0 arrest, while CCND3 overexpression restores Rb-kinase activity and confers apoptosis resistance [PMID:7664296]. Its abundance is set at multiple regulatory tiers: transcriptionally by FOXO1 in B-ALL [PMID:35013097], translationally through PTBP1 binding to its 5'-UTR [PMID:31301177] and METTL5-mediated 18S rRNA m6A modification that boosts translation efficiency [PMID:41743013], and through numerous miRNAs that directly target its transcript (miR-592, miR-212, miR-4779, miR-15b) to drive cell-cycle arrest and apoptosis upon CCND3 loss [PMID:26144250, PMID:26064240, PMID:27493231, PMID:29362401]. Beyond the kinase complex, CCND3 has a CDK4/6-independent pro-survival role that includes promoting CDK8 transcription, such that its elevation drives palbociclib resistance [PMID:35013097], and it limits epithelial-mesenchymal transition by facilitating PARK2-mediated ubiquitination and degradation of vimentin, with its loss promoting metastasis and chemoresistance [PMID:39781469]. CCND3 also acts as an interferon-stimulated gene with a non-nuclear antiviral function: upon bandavirus infection it translocates to the cytoplasm and, via its CN domain, binds the viral nucleoprotein to block RNP assembly [PMID:40858603]. CCND3 is recurrently dysregulated in cancer through a KCNMB4-CCND3 fusion in osteosarcoma [PMID:25300797] and through aberrant stabilization by upstream regulators such as PRAME [PMID:39071619].","teleology":[{"year":1995,"claim":"Established CCND3's canonical engine role — that it partners with CDK4 to phosphorylate Rb and that this activity is the target of glucocorticoid-mediated growth arrest, linking the cyclin directly to cell-cycle exit and apoptosis control.","evidence":"Stable overexpression, Rb-1 kinase activity assay, SV40 T antigen rescue, and serum-free apoptosis assay in lymphoid cells","pmids":["7664296"],"confidence":"High","gaps":["Did not resolve CDK4/6-independent functions","Mechanism of glucocorticoid-driven transcriptional suppression of CCND3 not defined here"]},{"year":2015,"claim":"Identified direct miRNA control of CCND3 — multiple miRNAs target its transcript to enforce cell-cycle arrest and apoptosis, defining post-transcriptional brakes on cyclin abundance across tumor and immune contexts.","evidence":"Dual-luciferase reporter assays, miRNA mimic/inhibitor transfection, knockdown phenotyping, and in vivo models for miR-592 (colorectal), miR-15b (B cells/lupus), later extended to miR-212 (ATL) and miR-4779 (colon)","pmids":["26064240","26144250","27493231","29362401"],"confidence":"Medium","gaps":["Relative contribution of each miRNA in physiological settings unclear","No integrated model of combinatorial miRNA regulation"]},{"year":2019,"claim":"Revealed translational control of CCND3, showing PTBP1 binds the 5'-UTR to enhance translation and is itself a miRNA target, layering a translational tier onto cyclin regulation.","evidence":"RBP co-IP, 5'-UTR reporter assay, and miR-194 target validation in hepatocellular carcinoma","pmids":["31301177"],"confidence":"High","gaps":["Whether PTBP1 control of CCND3 operates outside HCC not established","Structural basis of 5'-UTR recognition undefined"]},{"year":2022,"claim":"Separated CCND3's pro-survival function from its kinase-complex role, showing it is essential for B-ALL survival independent of CDK4/6 activity and drives CDK4/6-inhibitor resistance.","evidence":"CCND3 knockdown vs. palbociclib comparison, FOXO1 perturbation, and gene expression analysis in B-ALL","pmids":["35013097"],"confidence":"Medium","gaps":["Molecular basis of the CDK4/6-independent anti-apoptotic activity beyond CDK8 transcription unresolved","Single lineage (B-ALL) tested"]},{"year":2024,"claim":"Defined an upstream stabilization pathway in which PRAME elevates CCND3 by degrading negative regulators (CTMP, p21) to activate Akt signaling, connecting CCND3 accumulation to oncogenic proliferation in myeloma.","evidence":"PRAME knockdown/overexpression, co-IP, ubiquitination assays, and proliferation readouts in multiple myeloma cells","pmids":["39071619"],"confidence":"Medium","gaps":["No in vitro reconstitution of the Cul2 ligase activity","Direct measurement of CCND3 stability changes not shown"]},{"year":2025,"claim":"Uncovered a CDK-independent cytoskeletal role: CCND3 facilitates PARK2-mediated vimentin ubiquitination, so its transcriptional loss via PI3K/Akt/c-Jun triggers EMT, metastasis, and cisplatin resistance.","evidence":"CCND3 knockdown, PARK2-vimentin ubiquitination assays, pathway inhibitors, migration/invasion assays, and clinical correlation in lung adenocarcinoma","pmids":["39781469"],"confidence":"Medium","gaps":["How CCND3 facilitates PARK2 recruitment to vimentin mechanistically unknown","Whether this is direct or via intermediary not resolved"]},{"year":2025,"claim":"Demonstrated a non-nuclear antiviral function, establishing CCND3 as an interferon-stimulated gene that translocates to the cytoplasm and uses its CN domain to bind bandavirus nucleoprotein and block RNP assembly.","evidence":"ISG screening, subcellular fractionation/imaging, co-IP with domain mapping, RNA-independent binding assay, interface mapping, and in vivo infection model","pmids":["40858603"],"confidence":"High","gaps":["Breadth of antiviral activity beyond bandaviruses unknown","Whether antiviral and cell-cycle functions are mutually exclusive states unclear"]},{"year":2026,"claim":"Added a ribosome-level translational control mechanism: METTL5-deposited 18S rRNA m6A enhances CCND3 translation efficiency, coupling rRNA modification to cyclin output and tumorigenesis.","evidence":"METTL5 knockout, RNC-seq for translation efficiency, western blot, and in vivo/in vitro assays in oral squamous cell carcinoma","pmids":["41743013"],"confidence":"Medium","gaps":["Selectivity of METTL5 for CCND3 vs. global translation effects not isolated","Single tumor type tested"]},{"year":2025,"claim":"Detailed post-translational stabilization via p21, where CDKN1A binding occludes Thr283 phosphorylation to block CCND3 nuclear export and proteasomal degradation, extending its nuclear half-life.","evidence":"Reciprocal co-IP, phosphorylation site analysis, half-life assay, and AlphaFold2/molecular dynamics modeling in butyrate-treated intestinal cells (preprint)","pmids":["bio_10.1101_2025.06.19.660543"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Structural prediction of Thr283 burial awaits experimental validation"]},{"year":2025,"claim":"Linked C-terminal truncating variants to oncogenic gain-of-function, inferring that loss of degradation signals increases CCND3 stability in pediatric cancers.","evidence":"COSMIC somatic mutation pattern analysis and pediatric genomics cohort interrogation (preprint)","pmids":["bio_10.1101_2025.11.20.25340490"],"confidence":"Low","gaps":["No direct biochemical reconstitution of protein stability","Inference from mutation pattern only; preprint"]},{"year":null,"claim":"How CCND3's distinct activities — Rb-directed kinase function, CDK4/6-independent survival signaling, cytoskeletal/EMT control, and cytoplasmic antiviral defense — are coordinated and switched within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating nuclear and cytoplasmic functions","Structural basis of CDK4/6-independent functions undefined","Physiological triggers governing function-switching unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6]}],"complexes":["CCND3-CDK4/6 kinase complex"],"partners":["CDK4","CDK6","CDK5","CDKN1A","PTBP1","PARK2","PRAME"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30281","full_name":"G1/S-specific cyclin-D3","aliases":[],"length_aa":292,"mass_kda":32.5,"function":"Regulatory component of the cyclin D3-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition (PubMed:8114739). Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase (PubMed:8114739). Hypophosphorylates RB1 in early G(1) phase (PubMed:8114739). Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals (PubMed:8114739). Component of the ternary complex, cyclin D3/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex (PubMed:16782892). Shows transcriptional coactivator activity with ATF5 independently of CDK4 (PubMed:15358120)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P30281/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCND3","classification":"Not Classified","n_dependent_lines":234,"n_total_lines":1208,"dependency_fraction":0.19370860927152317},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCND3","total_profiled":1310},"omim":[{"mim_id":"617775","title":"G PROTEIN-COUPLED RECEPTOR 15 LIGAND; GPR15LG","url":"https://www.omim.org/entry/617775"},{"mim_id":"614853","title":"CYTOKINE RECEPTOR-LIKE FACTOR 3; CRLF3","url":"https://www.omim.org/entry/614853"},{"mim_id":"613263","title":"SMALL NUCLEOLAR RNA HOST GENE 5; SNHG5","url":"https://www.omim.org/entry/613263"},{"mim_id":"612974","title":"DEP DOMAIN-CONTAINING PROTEIN 6; DEPDC6","url":"https://www.omim.org/entry/612974"},{"mim_id":"611752","title":"ECRG4 AUGURIN PRECURSOR; ECRG4","url":"https://www.omim.org/entry/611752"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":239.0}],"url":"https://www.proteinatlas.org/search/CCND3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P30281","domains":[{"cath_id":"1.10.472.10","chopping":"42-149","consensus_level":"high","plddt":97.0384,"start":42,"end":149},{"cath_id":"1.10.472.10","chopping":"158-259","consensus_level":"high","plddt":93.8698,"start":158,"end":259}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30281","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30281-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30281-F1-predicted_aligned_error_v6.png","plddt_mean":86.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCND3","jax_strain_url":"https://www.jax.org/strain/search?query=CCND3"},"sequence":{"accession":"P30281","fasta_url":"https://rest.uniprot.org/uniprotkb/P30281.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30281/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30281"}},"corpus_meta":[{"pmid":"10416984","id":"PMC_10416984","title":"Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas.","date":"1999","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/10416984","citation_count":142,"is_preprint":false},{"pmid":"18391076","id":"PMC_18391076","title":"Translocations targeting CCND2, CCND3, and MYCN do occur in t(11;14)-negative mantle cell lymphomas.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18391076","citation_count":94,"is_preprint":false},{"pmid":"30538135","id":"PMC_30538135","title":"CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1- mantle cell lymphoma.","date":"2018","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/30538135","citation_count":76,"is_preprint":false},{"pmid":"7664296","id":"PMC_7664296","title":"c-Myc and cyclin D3 (CcnD3) genes are independent targets for glucocorticoid inhibition of lymphoid cell proliferation.","date":"1995","source":"Cancer 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resistance to glucocorticoid-mediated G0 arrest and apoptosis.\",\n      \"method\": \"Stable transfection/overexpression, kinase activity assay (Rb-1 phosphorylation), SV40 T antigen rescue, serum-free apoptosis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (kinase assay, stable transformants, rescue experiments, apoptosis assay) in a single rigorous study with mechanistic readouts\",\n      \"pmids\": [\"7664296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTBP1 (polypyrimidine tract-binding protein 1) enhances CCND3 translation by directly interacting with the 5'-UTR of CCND3 mRNA, thereby facilitating cell cycle progression and tumor growth in hepatocellular carcinoma; miR-194 inhibits PTBP1 expression by binding its 3'-UTR, resulting in reduced CCND3 levels.\",\n      \"method\": \"RNA-binding protein co-immunoprecipitation, 5'-UTR reporter assay, miRNA target validation, western blot, loss-of-function/overexpression cell proliferation assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays (RBP–mRNA interaction via 5'-UTR), miRNA target validation, functional rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31301177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXO1 acts as a transcriptional activator of CCND3 in B-ALL cells; CCND3 is essential for B-ALL proliferation and survival independent of CDK4/6 kinase activity; the anti-apoptotic effect of CCND3 is separable from its role in the CCND3-CDK4/6 kinase complex; CCND3 contributes to CDK8 transcription, partly explaining its anti-apoptotic function; increased CCND3 expression drives resistance to palbociclib (CDK4/6 inhibitor).\",\n      \"method\": \"CCND3 knockdown, CDK4/6 inhibition (palbociclib), transcription factor overexpression/knockdown, comparison of CCND3 depletion vs. kinase inhibition phenotypes, gene expression analysis\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic perturbations (KD, inhibitor) with defined proliferation/apoptosis readouts; single lab, no structural validation\",\n      \"pmids\": [\"35013097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCND3 downregulation in cisplatin-resistant lung adenocarcinoma cells—driven by transcriptional suppression through the PI3K/Akt/c-Jun signaling axis—diminishes recruitment of the E3 ubiquitin ligase PARK2 (Parkin) to vimentin, thereby reducing vimentin ubiquitination and degradation, triggering epithelial-mesenchymal transition (EMT), cytoskeleton remodeling, metastasis, and chemoresistance.\",\n      \"method\": \"Loss-of-function (CCND3 knockdown), in vivo/in vitro migration/invasion assays, western blot for PARK2-vimentin ubiquitination, PI3K/Akt pathway inhibitor experiments, clinical sample correlation\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with multiple methods (KD, pathway inhibitors, ubiquitination assay); single lab\",\n      \"pmids\": [\"39781469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCND3 functions as an interferon-stimulated gene (ISG) with antiviral activity against bandaviruses (e.g., SFTSV); upon viral infection, CCND3 undergoes cytoplasmic translocation; via its CN domain, CCND3 interacts with the viral nucleoprotein (NP) 'head' region in an RNA-independent manner, suppressing the ribonucleoprotein (RNP) replication machinery by blocking NP multimerization, NP-RNA binding, and NP association with viral polymerase; the viral nonstructural protein NSs counteracts CCND3 by attenuating its induction and promoting its autophagic degradation.\",\n      \"method\": \"ISG screening, subcellular fractionation/live imaging (cytoplasmic translocation), co-immunoprecipitation (CN domain–NP interaction), RNA-independent binding assay, in vivo infection model, structural/interaction interface mapping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (pulldown, domain mapping, RNA-independence assay, in vivo model, structural modeling with functional validation) in a single detailed study\",\n      \"pmids\": [\"40858603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRAME promotes CCND3 protein accumulation in multiple myeloma cells by ubiquitinating and degrading CTMP and p21 (as a Cul2-dependent E3 ligase substrate-recognizing subunit), which activates p-Akt signaling and leads to elevated CCND3 levels, thereby promoting cell proliferation.\",\n      \"method\": \"PRAME knockdown/overexpression, western blot for ubiquitination targets, co-immunoprecipitation (PRAME–CTMP/p21 interaction), cell proliferation assays\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP showing PRAME–substrate interaction with ubiquitination assay and proliferation readout; single lab, multiple methods but no in vitro reconstitution\",\n      \"pmids\": [\"39071619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TLR7 activation in B cells increases CCND3 expression via downregulation of miR-15b; CCND3 was identified as a direct target of miR-15b by luciferase reporter assay; this axis was confirmed in SLE patient B cells and in two lupus mouse models.\",\n      \"method\": \"TLR7 agonist stimulation, miRNA mimic/inhibitor transfection, dual-luciferase reporter assay, western blot, in vivo IMQ-treated mouse model\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter validation of direct miRNA targeting plus in vivo model; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"26144250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCND3 knockdown in colorectal cancer cells induced cell cycle arrest and apoptosis; miR-592 directly targets the CCND3 3'-UTR (confirmed by dual-luciferase reporter assay), reduces CCND3 protein, and consequently decreases phosphorylated Rb.\",\n      \"method\": \"siRNA knockdown, dual-luciferase reporter assay, western blot for p-Rb, cell proliferation/colony-forming assay\",\n      \"journal\": \"International journal of clinical and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter validation of direct miRNA targeting, functional knockdown with defined Rb phosphorylation readout; single lab\",\n      \"pmids\": [\"26064240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCND3 was identified as a direct target of miR-212 in adult T-cell leukemia/lymphoma (ATL) cells; miR-212 restoration caused G0/G1 arrest and apoptosis; rescue with a miR-212-resistant CCND3 variant restored cell-cycle progression and attenuated apoptosis, confirming direct targeting.\",\n      \"method\": \"miRNA overexpression, dual-luciferase reporter assay, CCND3 rescue with miR-resistant construct, cell cycle analysis, apoptosis assay, in vivo xenograft\",\n      \"journal\": \"Journal of investigative medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — miRNA-resistant rescue experiment is orthogonal to luciferase assay; single lab\",\n      \"pmids\": [\"27493231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-4779 directly targets CCND3 (confirmed by luciferase reporter assay); CCND3 knockdown alone induced cell cycle arrest and apoptosis in colon cancer cells, phenocopying miR-4779 overexpression; miR-4779 suppressed tumor growth in HCT116 xenografts.\",\n      \"method\": \"miRNA mimic library screen, luciferase reporter assay, siRNA knockdown, cell cycle/apoptosis analysis, in vivo xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct luciferase target validation plus functional knockdown phenotype; single lab\",\n      \"pmids\": [\"29362401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A recurrent KCNMB4-CCND3 fusion gene in human osteosarcoma (identified by transcriptome sequencing and validated by RT-PCR, Sanger sequencing, and FISH) promotes SAOS-2 osteosarcoma cell migration.\",\n      \"method\": \"Transcriptome sequencing, RT-PCR, Sanger sequencing, FISH validation, cell migration/invasion assays with fusion gene expression\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — fusion gene validated by multiple methods, functional migration assay; single lab\",\n      \"pmids\": [\"25300797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2033,\n      \"finding\": \"BRD4 PROTAC degrader MZ1 downregulates CCND3 expression in B-ALL cells (identified by RNA-seq), leading to cell apoptosis, cell cycle arrest, and proliferation inhibition; these effects were confirmed by CCND3 knockdown experiments.\",\n      \"method\": \"RNA-seq (target identification), CCND3 knockdown (lentiviral), western blot, cell cycle/apoptosis flow cytometry, CCK8 proliferation assay\",\n      \"journal\": \"Hematology (Amsterdam, Netherlands)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CCND3 knockdown phenocopies MZ1 but the direct mechanistic link between BRD4 and CCND3 transcription is not rigorously established; single lab, single approach\",\n      \"pmids\": [\"37594294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"METTL5-mediated N6-methyladenosine (m6A) modification of 18S rRNA enhances CCND3 mRNA translation efficiency; METTL5 knockout reduced CCND3 translational output (measured by ribosome nascent-chain complex-bound mRNA sequencing), suppressing OSCC tumorigenesis and metastasis.\",\n      \"method\": \"METTL5 knockout, RNC-seq (ribosome nascent-chain complex mRNA sequencing for translation efficiency), western blot, in vivo xenograft, Transwell/colony formation assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNC-seq is a direct translational efficiency readout; functional validation in vivo; single lab\",\n      \"pmids\": [\"41743013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Butyrate treatment causes CCND3 protein accumulation in intestinal cells through both mRNA increase and CDKN1A (p21)-dependent protein stabilization; CDKN1A reduces phosphorylation at the conserved Thr residue (Thr283) critical for CCND3 nuclear export and proteasomal degradation, thereby extending its nuclear half-life; co-immunoprecipitation identified CCND3 complexes with CDKN1A, CDK4, CDK6, and CDK5 in butyrate-treated cells; structural modeling predicts that CDKN1A binding buries CCND3-Thr283, limiting its phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation (CCND3 complexes), phosphorylation site analysis, nuclear fractionation/half-life assay, structural modeling (AlphaFold2) + molecular dynamics simulations, western blot\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, phosphorylation analysis, structural modeling with functional correlation; single lab preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.19.660543\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NMDe (nonsense-mediated decay-escaping) frameshift/truncating variants in CCND3 that remove its C-terminal regulatory region increase intracellular protein stability (consistent with loss of phosphorylation-dependent degradation signals), representing an oncogenic gain-of-function mechanism in pediatric cancers.\",\n      \"method\": \"Somatic mutation database analysis (COSMIC), functional classification by variant pattern, pediatric clinical genomics cohort interrogation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — inference from mutation pattern analysis; no direct biochemical reconstitution of protein stability; preprint\",\n      \"pmids\": [\"bio_10.1101_2025.11.20.25340490\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CCND3 (Cyclin D3) is a D-type cyclin that drives G1/S cell cycle progression by forming active complexes with CDK4 and CDK6 to phosphorylate Rb, and its activity is regulated at multiple levels: transcriptionally by FOXO1 and suppressed by glucocorticoids (via c-Jun/PI3K/Akt) and multiple microRNAs (miR-15b, miR-194, miR-212, miR-592, miR-4779); translationally by PTBP1 binding to its 5'-UTR and by METTL5-mediated ribosomal m6A modification; post-translationally by CDKN1A (p21)-dependent inhibition of Thr283 phosphorylation that blocks nuclear export and proteasomal degradation, and by PRAME-mediated ubiquitination of upstream regulators that elevate CCND3 levels; beyond its canonical kinase-complex role, CCND3 has a CDK4/6-independent anti-apoptotic function (partly through CDK8 transcription), a non-nuclear antiviral role (its CN domain binds bandavirus nucleoprotein to block RNP assembly), and a role in limiting EMT by facilitating PARK2-mediated vimentin ubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCND3 (Cyclin D3) is a D-type cyclin that drives G1/S cell cycle progression by partnering with CDK4 (and CDK6) to phosphorylate the Rb tumor suppressor, and its expression is gated by mitogenic and hormonal cues — glucocorticoids suppress both CCND3 and CDK4 to lower Rb phosphorylation and enforce G0 arrest, while CCND3 overexpression restores Rb-kinase activity and confers apoptosis resistance [#0]. Its abundance is set at multiple regulatory tiers: transcriptionally by FOXO1 in B-ALL [#2], translationally through PTBP1 binding to its 5'-UTR [#1] and METTL5-mediated 18S rRNA m6A modification that boosts translation efficiency [#12], and through numerous miRNAs that directly target its transcript (miR-592, miR-212, miR-4779, miR-15b) to drive cell-cycle arrest and apoptosis upon CCND3 loss [#6, #7, #8, #9]. Beyond the kinase complex, CCND3 has a CDK4/6-independent pro-survival role that includes promoting CDK8 transcription, such that its elevation drives palbociclib resistance [#2], and it limits epithelial-mesenchymal transition by facilitating PARK2-mediated ubiquitination and degradation of vimentin, with its loss promoting metastasis and chemoresistance [#3]. CCND3 also acts as an interferon-stimulated gene with a non-nuclear antiviral function: upon bandavirus infection it translocates to the cytoplasm and, via its CN domain, binds the viral nucleoprotein to block RNP assembly [#4]. CCND3 is recurrently dysregulated in cancer through a KCNMB4-CCND3 fusion in osteosarcoma [#10] and through aberrant stabilization by upstream regulators such as PRAME [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established CCND3's canonical engine role — that it partners with CDK4 to phosphorylate Rb and that this activity is the target of glucocorticoid-mediated growth arrest, linking the cyclin directly to cell-cycle exit and apoptosis control.\",\n      \"evidence\": \"Stable overexpression, Rb-1 kinase activity assay, SV40 T antigen rescue, and serum-free apoptosis assay in lymphoid cells\",\n      \"pmids\": [\"7664296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve CDK4/6-independent functions\", \"Mechanism of glucocorticoid-driven transcriptional suppression of CCND3 not defined here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified direct miRNA control of CCND3 — multiple miRNAs target its transcript to enforce cell-cycle arrest and apoptosis, defining post-transcriptional brakes on cyclin abundance across tumor and immune contexts.\",\n      \"evidence\": \"Dual-luciferase reporter assays, miRNA mimic/inhibitor transfection, knockdown phenotyping, and in vivo models for miR-592 (colorectal), miR-15b (B cells/lupus), later extended to miR-212 (ATL) and miR-4779 (colon)\",\n      \"pmids\": [\"26064240\", \"26144250\", \"27493231\", \"29362401\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each miRNA in physiological settings unclear\", \"No integrated model of combinatorial miRNA regulation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed translational control of CCND3, showing PTBP1 binds the 5'-UTR to enhance translation and is itself a miRNA target, layering a translational tier onto cyclin regulation.\",\n      \"evidence\": \"RBP co-IP, 5'-UTR reporter assay, and miR-194 target validation in hepatocellular carcinoma\",\n      \"pmids\": [\"31301177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PTBP1 control of CCND3 operates outside HCC not established\", \"Structural basis of 5'-UTR recognition undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Separated CCND3's pro-survival function from its kinase-complex role, showing it is essential for B-ALL survival independent of CDK4/6 activity and drives CDK4/6-inhibitor resistance.\",\n      \"evidence\": \"CCND3 knockdown vs. palbociclib comparison, FOXO1 perturbation, and gene expression analysis in B-ALL\",\n      \"pmids\": [\"35013097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the CDK4/6-independent anti-apoptotic activity beyond CDK8 transcription unresolved\", \"Single lineage (B-ALL) tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an upstream stabilization pathway in which PRAME elevates CCND3 by degrading negative regulators (CTMP, p21) to activate Akt signaling, connecting CCND3 accumulation to oncogenic proliferation in myeloma.\",\n      \"evidence\": \"PRAME knockdown/overexpression, co-IP, ubiquitination assays, and proliferation readouts in multiple myeloma cells\",\n      \"pmids\": [\"39071619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the Cul2 ligase activity\", \"Direct measurement of CCND3 stability changes not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a CDK-independent cytoskeletal role: CCND3 facilitates PARK2-mediated vimentin ubiquitination, so its transcriptional loss via PI3K/Akt/c-Jun triggers EMT, metastasis, and cisplatin resistance.\",\n      \"evidence\": \"CCND3 knockdown, PARK2-vimentin ubiquitination assays, pathway inhibitors, migration/invasion assays, and clinical correlation in lung adenocarcinoma\",\n      \"pmids\": [\"39781469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CCND3 facilitates PARK2 recruitment to vimentin mechanistically unknown\", \"Whether this is direct or via intermediary not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a non-nuclear antiviral function, establishing CCND3 as an interferon-stimulated gene that translocates to the cytoplasm and uses its CN domain to bind bandavirus nucleoprotein and block RNP assembly.\",\n      \"evidence\": \"ISG screening, subcellular fractionation/imaging, co-IP with domain mapping, RNA-independent binding assay, interface mapping, and in vivo infection model\",\n      \"pmids\": [\"40858603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of antiviral activity beyond bandaviruses unknown\", \"Whether antiviral and cell-cycle functions are mutually exclusive states unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Added a ribosome-level translational control mechanism: METTL5-deposited 18S rRNA m6A enhances CCND3 translation efficiency, coupling rRNA modification to cyclin output and tumorigenesis.\",\n      \"evidence\": \"METTL5 knockout, RNC-seq for translation efficiency, western blot, and in vivo/in vitro assays in oral squamous cell carcinoma\",\n      \"pmids\": [\"41743013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity of METTL5 for CCND3 vs. global translation effects not isolated\", \"Single tumor type tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Detailed post-translational stabilization via p21, where CDKN1A binding occludes Thr283 phosphorylation to block CCND3 nuclear export and proteasomal degradation, extending its nuclear half-life.\",\n      \"evidence\": \"Reciprocal co-IP, phosphorylation site analysis, half-life assay, and AlphaFold2/molecular dynamics modeling in butyrate-treated intestinal cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.19.660543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Structural prediction of Thr283 burial awaits experimental validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked C-terminal truncating variants to oncogenic gain-of-function, inferring that loss of degradation signals increases CCND3 stability in pediatric cancers.\",\n      \"evidence\": \"COSMIC somatic mutation pattern analysis and pediatric genomics cohort interrogation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.20.25340490\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical reconstitution of protein stability\", \"Inference from mutation pattern only; preprint\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCND3's distinct activities — Rb-directed kinase function, CDK4/6-independent survival signaling, cytoskeletal/EMT control, and cytoplasmic antiviral defense — are coordinated and switched within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating nuclear and cytoplasmic functions\", \"Structural basis of CDK4/6-independent functions undefined\", \"Physiological triggers governing function-switching unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [\"CCND3-CDK4/6 kinase complex\"],\n    \"partners\": [\"CDK4\", \"CDK6\", \"CDK5\", \"CDKN1A\", \"PTBP1\", \"PARK2\", \"PRAME\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie"}}