{"gene":"LDOC1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1999,"finding":"LDOC1 encodes a nuclear protein with a leucine zipper-like motif at the N-terminal region and a proline-rich region similar to an SH3-binding domain; EGFP-LDOC1 fusion protein localizes to the nucleus.","method":"EGFP fusion protein localization assay, Northern blot, chromosomal mapping","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment with functional implication, single lab, single method","pmids":["10403563"],"is_preprint":false},{"year":2003,"finding":"LDOC1 inhibits NF-κB transcriptional activity; transient LDOC1 expression blocked NF-κB reporter activity driven by MEKK1, TNF-α, or PMA in a dose-dependent manner, without affecting p53, AP-1, or CRE-dependent reporter expression.","method":"NF-κB luciferase reporter assay, stable transfection, cell viability assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple reporter assays with pathway specificity controls, single lab","pmids":["12712434"],"is_preprint":false},{"year":2005,"finding":"LDOC1 overexpression induces apoptosis via loss of mitochondrial membrane potential, leading to both caspase-3-dependent and -independent pathways; transcription factor MZF-1 physically interacts with LDOC1 and enhances its pro-apoptotic activity.","method":"Phosphatidylserine externalization assay, mitochondrial membrane potential measurement, caspase-3 activity assay, co-immunoprecipitation (MZF-1/LDOC1 interaction)","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (apoptosis assays + Co-IP), single lab","pmids":["15670815"],"is_preprint":false},{"year":2005,"finding":"LDOC1 binds directly to the verprolin homology (V) domain of WAVE3; WAVE3 expression induces translocation of LDOC1 from the nucleus to the cytoplasm, inhibiting LDOC1-induced apoptosis; LDOC1-induced apoptosis is accompanied by increased p53 protein (not transcription), suggesting LDOC1 inhibits p53 degradation.","method":"Direct binding assay (pulldown), subcellular localization (fluorescence microscopy), apoptosis assay, p53 protein/mRNA analysis","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated plus functional localization consequence, single lab, multiple orthogonal methods","pmids":["16272576"],"is_preprint":false},{"year":2013,"finding":"Restored expression of BEX1 and LDOC1 in OSCC cells suppresses NF-κB signaling, specifically decreasing p50 and p65 expression, and exerts growth inhibitory effects in vitro and in vivo.","method":"Ectopic expression, NF-κB pathway analysis (western blot for p50/p65), in vivo tumor model","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional experiments with defined molecular readouts, single lab","pmids":["23362108"],"is_preprint":false},{"year":2014,"finding":"Sirh7/Ldoc1 knockout mice show abnormal placental trophoblast giant cell (TGC) differentiation/maturation, leading to overproduction of placental progesterone (P4) and placental lactogen 1 (PL1), and delayed parturition with low pup weaning rate.","method":"Knockout mouse model, hormonal assays (P4, PL1 measurement), histological analysis of placenta","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific endocrine and cellular phenotypic readouts, multiple orthogonal methods","pmids":["25468940"],"is_preprint":false},{"year":2016,"finding":"LDOC1 physically interacts with GNL3L (a nucleolar GTPase); ectopic LDOC1 expression destabilizes endogenous GNL3L and down-modulates GNL3L-induced cell proliferation; GNL3L upregulates NF-κB-dependent transcriptional activity via p65, which is reversed by co-expression of LDOC1.","method":"Co-immunoprecipitation (protein-protein interaction assays), ectopic expression/knockdown, NF-κB reporter assay, cell proliferation assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction assays plus functional reporter and proliferation assays, single lab","pmids":["27764577"],"is_preprint":false},{"year":2015,"finding":"LDOC1 promoter is hypermethylated by cigarette smoke condensate (CSC) exposure via increased nuclear DNMT1 and DNMT3A accumulation; LDOC1 knockdown confers proliferative and clonogenic capacity on untransformed oral cells.","method":"Quantitative methylation-specific PCR, CSC treatment, DNMT immunofluorescence, loss-of-function knockdown with clonogenicity assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link between CSC exposure, DNMT accumulation, and LDOC1 silencing with functional consequence, single lab","pmids":["26317789"],"is_preprint":false},{"year":2015,"finding":"LDOC1 overexpression in PTC cells suppresses proliferation and induces apoptosis by inhibiting NF-κB activation; LDOC1-overexpressing cells recover responsiveness to TGF-β1 antiproliferative signaling.","method":"Lentiviral ectopic expression, NF-κB luciferase reporter assay, western blot (p65, IκBα, c-Myc, Bax, Bcl-xL), flow cytometry","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods, single lab","pmids":["26637328"],"is_preprint":false},{"year":2017,"finding":"LDOC1 expression decreases Wnt5a levels in osteosarcoma cells and suppresses osteosarcoma cell migration and invasion in vitro; in a xenograft model, LDOC1 expression is associated with reduced lung metastasis.","method":"Lentiviral stable expression, transwell migration/invasion assay, qRT-PCR array for metastasis genes, xenograft model with micro-CT imaging","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo assays with a specific downstream target (Wnt5a), single lab","pmids":["28240050"],"is_preprint":false},{"year":2019,"finding":"LDOC1 forms protein complexes with phospho-JAK2 (pJAK2) and E3 ubiquitin ligase LNX1, targeting pJAK2 for ubiquitin-dependent proteasomal degradation; LDOC1 deficiency reduces LNX1-pJAK2 interaction, leading to ineffective pJAK2 ubiquitination and consequent STAT3 activation.","method":"Co-immunoprecipitation, immunofluorescent confocal microscopy, in vivo xenograft with phosphorylation analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus confocal colocalization and in vivo functional validation, single lab","pmids":["30634502"],"is_preprint":false},{"year":2019,"finding":"AML cell-derived exosomes deliver miR-4532 into hematopoietic stem cells (CD34+), where miR-4532 targets LDOC1 mRNA; loss of LDOC1 activates JAK2/STAT3 phosphorylation and increases DKK1, suppressing normal hematopoiesis; ectopic LDOC1 expression or JAK2 inhibition reverses these effects.","method":"miRNA target validation (luciferase/binding assay implied), gain- and loss-of-function in CD34+ HSCs, exosome co-culture, colony-forming unit assays, western blot for pJAK2/pSTAT3","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional gain/loss experiments with pathway readouts, multiple methods, single lab","pmids":["31842997"],"is_preprint":false},{"year":2019,"finding":"LDOC1 overexpression in colorectal cancer cells inhibits Wnt/β-catenin signaling, reducing nuclear β-catenin levels and suppressing proliferation, migration, and invasion while promoting apoptosis.","method":"Lentiviral ectopic expression, western blot, cellular immunofluorescence for β-catenin localization, Transwell and Matrigel assays, flow cytometry","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional and molecular assays, single lab","pmids":["31002361"],"is_preprint":false},{"year":2020,"finding":"LDOC1 deficiency increases Akt phosphorylation and subsequent inhibitory phosphorylation of GSK-3β (Ser9) upon Candida albicans stimulation, leading to increased IL-1β production; PI3K/Akt inhibitors or constitutively active GSK-3β (S9A mutant) reduce IL-1β in LDOC1-deficient cells, placing LDOC1 upstream of the PI3K/Akt/GSK-3β axis.","method":"Gain/loss-of-function (ectopic expression and knockdown), western blot for pAkt and pGSK-3β, pharmacological inhibitors (PI3K/Akt), active mutant GSK-3β (S9A) rescue experiment","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via active mutant plus inhibitor validation, multiple orthogonal methods, single lab","pmids":["33120999"],"is_preprint":false},{"year":2020,"finding":"LDOC1 is translocated from the nucleus to the cytoplasm in human thyroid cancer; LDOC1 ablation in PTC cells facilitates nuclear p65 expression and NF-κB activity; NF-κB inhibition reverses the effects of LDOC1 ablation on proliferation, apoptosis, migration, and invasion.","method":"Subcellular fractionation/immunofluorescence, lentiviral KD and OE, NF-κB luciferase reporter, NF-κB inhibitor epistasis experiment","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with NF-κB inhibitor plus localization and functional assays, single lab","pmids":["31889386"],"is_preprint":false},{"year":2024,"finding":"LINC01270 acts as a competing endogenous RNA (ceRNA) for miR-326, maintaining LDOC1 expression; knockdown of LINC01270 downregulates LDOC1 and enhances NF-κB activity; luciferase reporter assay confirmed the LINC01270/miR-326/LDOC1 regulatory axis in NF-κB modulation.","method":"siRNA knockdown, luciferase reporter assay, RNA immunoprecipitation (RIP), synthetic RNA perturbation experiments","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, largely ceRNA mechanism with LDOC1 as downstream effector; mechanistic detail on LDOC1 itself is indirect","pmids":["39682774"],"is_preprint":false},{"year":2025,"finding":"LDOC1 loss in PFA1 ependymoma results from H3K27me3-mediated chromatin compaction at the LDOC1 locus; restoration of LDOC1 reduces proliferation, NF-κB signaling, and IL-6 secretion; in vivo competition assay showed LDOC1-transduced tumor cells were outcompeted, indicating loss of LDOC1 is required for PFA tumor growth.","method":"ChIP (H3K27me3), lentiviral LDOC1 restoration, NF-κB pathway analysis, IL-6 ELISA, in vivo tumor competition model","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including ChIP and in vivo competition assay, single lab","pmids":["39901723"],"is_preprint":false},{"year":2026,"finding":"LDOC1 physically interacts with histone H2B, H2Bub1, PSMA1, and THAP12; LDOC1 promotes proteasomal degradation of H2B and H2Bub1 via PSMA1, limiting global H2Bub1 levels; LDOC1 knockdown causes loss of chromatin-bound H2Bub1 and enhanced chromatin compaction partly through THAP12; the LDOC1-H2Bub1 axis regulates metastasis-related genes (cytoskeletal remodeling, cell adhesion, EMT); LDOC1 loss enhances TGF-β-induced epithelial-mesenchymal plasticity and promotes a hybrid E/M phenotype.","method":"Co-immunoprecipitation, proximity ligation assay, ChIP-seq, ATAC-seq, MNase digestion, transcriptomic profiling, immunofluorescence, flow cytometry, functional migration/adhesion assays","journal":"Cell communication and signaling : CCS","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple rigorous orthogonal methods (Co-IP, PLA, ChIP-seq, ATAC-seq, MNase, transcriptomics) in one study establishing a mechanistic epigenetic role","pmids":["41484780"],"is_preprint":false},{"year":2026,"finding":"LDOC1 regulates STAT1 transcription and phosphorylation in an unexpected bidirectional manner: both gain- and loss-of-function of LDOC1 upregulate STAT1 transcription, revealing a novel role for LDOC1 in modulating STAT1-dependent pro-inflammatory signaling.","method":"Gain- and loss-of-function (siRNA and overexpression), RT-qPCR, western blot for pSTAT1, downstream target gene analysis","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single set of methods, paradoxical bidirectional result not yet clarified mechanistically","pmids":["41828328"],"is_preprint":false}],"current_model":"LDOC1 is a nuclear leucine-zipper protein that acts as a tumor suppressor by (1) inhibiting NF-κB signaling through interaction with GNL3L and suppression of p65 activity; (2) targeting phospho-JAK2 for ubiquitin-dependent proteasomal degradation via a complex with E3 ligase LNX1, thereby suppressing the IL-6/JAK2/STAT3 loop; (3) regulating histone H2Bub1 levels through interaction with PSMA1 and THAP12, controlling chromatin accessibility and metastatic transcriptional programs including EMT; (4) interacting with MZF-1 to promote apoptosis via mitochondrial membrane potential loss; (5) being negatively regulated by WAVE3, which binds its V-domain and relocalizes it from nucleus to cytoplasm; and (6) controlling placental progesterone and lactogen production to regulate parturition timing in mammals."},"narrative":{"mechanistic_narrative":"LDOC1 is a nuclear leucine-zipper protein that functions as a tumor suppressor by restraining inflammatory and proliferative signaling and by shaping chromatin state [PMID:10403563, PMID:12712434, PMID:41484780]. A core activity is inhibition of NF-κB transcription: LDOC1 blocks NF-κB reporter activity downstream of MEKK1, TNF-α, and PMA without affecting p53, AP-1, or CRE outputs, and its restoration lowers p50/p65 levels and suppresses tumor growth across oral, thyroid, and ependymoma models [PMID:12712434, PMID:23362108, PMID:31889386, PMID:39901723]. LDOC1 also interacts with the nucleolar GTPase GNL3L, destabilizing it and reversing GNL3L-driven p65 activation [PMID:27764577]. In parallel, LDOC1 nucleates a complex with phospho-JAK2 and the E3 ligase LNX1 that drives ubiquitin-dependent proteasomal degradation of pJAK2, thereby damping the IL-6/JAK2/STAT3 axis; loss of LDOC1 weakens LNX1-pJAK2 engagement and unleashes STAT3 activation [PMID:30634502, PMID:39901723]. At the chromatin level, LDOC1 binds histone H2B, H2Bub1, PSMA1, and THAP12 and promotes proteasomal turnover of H2B/H2Bub1, limiting global H2Bub1 and controlling chromatin accessibility over metastasis genes; its loss enhances TGF-β-induced epithelial-mesenchymal plasticity [PMID:41484780]. LDOC1 additionally promotes apoptosis through MZF-1-enhanced loss of mitochondrial membrane potential, and is negatively regulated by WAVE3, which binds its V-domain and relocalizes it from nucleus to cytoplasm [PMID:15670815, PMID:16272576]. A genetic knockout establishes a developmental role in which LDOC1 controls placental trophoblast giant cell maturation and progesterone/lactogen output to time parturition [PMID:25468940]. Across cancers LDOC1 is silenced epigenetically, by cigarette-smoke-induced DNMT-mediated promoter hypermethylation and by H3K27me3 chromatin compaction [PMID:26317789, PMID:39901723].","teleology":[{"year":1999,"claim":"Established the basic identity of LDOC1 as a nuclear protein with a leucine-zipper-like motif and an SH3-binding-like proline-rich region, framing it as a candidate signaling/regulatory protein.","evidence":"EGFP fusion localization, Northern blot and chromosomal mapping","pmids":["10403563"],"confidence":"Medium","gaps":["No molecular partners or enzymatic activity defined","Functional role unknown at this stage"]},{"year":2003,"claim":"Answered what pathway LDOC1 acts on by showing it specifically inhibits NF-κB transcriptional activity, defining its first signaling role.","evidence":"NF-κB luciferase reporter assays with pathway-specificity controls and stable transfection","pmids":["12712434"],"confidence":"Medium","gaps":["Did not identify the molecular step in NF-κB inhibited","Single lab, reporter-based"]},{"year":2005,"claim":"Connected LDOC1 to programmed cell death and identified its first physical partner, showing LDOC1 induces apoptosis via mitochondrial membrane potential loss enhanced by MZF-1.","evidence":"Apoptosis assays, mitochondrial membrane potential measurement, caspase-3 assay, Co-IP","pmids":["15670815"],"confidence":"Medium","gaps":["Mechanism linking LDOC1 to mitochondrial depolarization unresolved","MZF-1 interaction not reciprocally mapped to domains"]},{"year":2005,"claim":"Identified WAVE3 as a negative regulator that controls LDOC1 localization, establishing that nuclear retention is required for LDOC1's pro-apoptotic function.","evidence":"Direct pulldown binding to the WAVE3 V-domain, fluorescence localization, apoptosis and p53 protein/mRNA analysis","pmids":["16272576"],"confidence":"Medium","gaps":["How cytoplasmic relocalization inactivates LDOC1 not defined","p53 stabilization mechanism inferred, not directly shown"]},{"year":2013,"claim":"Demonstrated tumor-suppressive function in vivo by showing LDOC1 restoration suppresses NF-κB (p50/p65) and inhibits tumor growth in oral cancer.","evidence":"Ectopic expression, western blot for p50/p65, in vivo tumor model","pmids":["23362108"],"confidence":"Medium","gaps":["Did not distinguish direct vs indirect NF-κB suppression","Co-effect with BEX1 not separated"]},{"year":2014,"claim":"Defined a physiological, non-cancer role by showing LDOC1 controls placental trophoblast giant cell maturation and parturition timing through progesterone/lactogen output.","evidence":"Knockout mouse with hormonal assays and placental histology","pmids":["25468940"],"confidence":"High","gaps":["Molecular pathway linking LDOC1 to TGC differentiation unknown","Relationship to LDOC1's NF-κB role not addressed"]},{"year":2015,"claim":"Explained how LDOC1 becomes silenced in disease, showing cigarette smoke condensate drives DNMT1/DNMT3A-mediated promoter hypermethylation and that knockdown confers proliferative/clonogenic capacity.","evidence":"Methylation-specific PCR, CSC treatment, DNMT immunofluorescence, clonogenicity assay","pmids":["26317789"],"confidence":"Medium","gaps":["Direct DNMT recruitment to LDOC1 locus not shown","Reversibility of silencing untested"]},{"year":2015,"claim":"Extended the NF-κB-suppressive tumor suppressor role to papillary thyroid cancer and linked it to restored TGF-β1 responsiveness.","evidence":"Lentiviral expression, NF-κB reporter, western blot panel, flow cytometry","pmids":["26637328"],"confidence":"Medium","gaps":["Mechanistic link to TGF-β1 pathway not defined"]},{"year":2016,"claim":"Identified GNL3L as a physical partner whose destabilization underlies part of LDOC1's NF-κB suppression, connecting LDOC1 to a nucleolar GTPase.","evidence":"Reciprocal Co-IP, ectopic expression/knockdown, NF-κB reporter, proliferation assays","pmids":["27764577"],"confidence":"Medium","gaps":["Mechanism of GNL3L destabilization unknown","Whether GNL3L is the dominant NF-κB route unclear"]},{"year":2017,"claim":"Linked LDOC1 to anti-metastatic activity, showing it lowers Wnt5a and reduces migration, invasion, and lung metastasis.","evidence":"Stable expression, transwell assays, metastasis gene qRT-PCR array, xenograft with micro-CT","pmids":["28240050"],"confidence":"Medium","gaps":["Direct vs indirect Wnt5a regulation not established"]},{"year":2019,"claim":"Revealed a degradative mechanism by showing LDOC1 assembles with pJAK2 and the E3 ligase LNX1 to drive pJAK2 ubiquitination, suppressing STAT3 activation.","evidence":"Co-IP, confocal colocalization, in vivo xenograft with phosphorylation analysis","pmids":["30634502"],"confidence":"Medium","gaps":["Ubiquitin linkage type and LDOC1's adaptor role not structurally defined","Direct vs scaffold function unclear"]},{"year":2019,"claim":"Placed LDOC1 in normal hematopoiesis as a target of AML exosomal miR-4532, whose loss activates JAK2/STAT3 and DKK1 to suppress hematopoiesis.","evidence":"miRNA target validation, gain/loss in CD34+ HSCs, exosome co-culture, CFU assays, western blot","pmids":["31842997"],"confidence":"Medium","gaps":["Direct miR-4532/LDOC1 binding only implied","Mechanism overlapping with LNX1 axis not integrated"]},{"year":2019,"claim":"Showed LDOC1 also restrains Wnt/β-catenin signaling in colorectal cancer, broadening its anti-proliferative reach beyond NF-κB.","evidence":"Lentiviral expression, western blot, β-catenin immunofluorescence, Transwell/Matrigel, flow cytometry","pmids":["31002361"],"confidence":"Medium","gaps":["Mechanism of β-catenin regulation undefined"]},{"year":2020,"claim":"Positioned LDOC1 upstream of the PI3K/Akt/GSK-3β axis controlling IL-1β during Candida albicans stimulation, extending its role to innate inflammatory output.","evidence":"Gain/loss-of-function, western blot for pAkt/pGSK-3β, PI3K/Akt inhibitors, GSK-3β S9A rescue","pmids":["33120999"],"confidence":"Medium","gaps":["Direct molecular target of LDOC1 in this axis not identified"]},{"year":2020,"claim":"Confirmed that nuclear-to-cytoplasmic translocation inactivates LDOC1 in thyroid cancer and that its NF-κB suppression is functionally responsible for its anti-tumor phenotype via inhibitor epistasis.","evidence":"Subcellular fractionation/IF, lentiviral KD/OE, NF-κB reporter, NF-κB inhibitor epistasis","pmids":["31889386"],"confidence":"Medium","gaps":["Trigger for mislocalization in tumors not defined"]},{"year":2024,"claim":"Added an upstream regulatory layer in which LINC01270 sponges miR-326 to sustain LDOC1 and limit NF-κB activity.","evidence":"siRNA knockdown, luciferase reporter, RIP, synthetic RNA perturbation","pmids":["39682774"],"confidence":"Low","gaps":["LDOC1 is a downstream effector; direct mechanism on LDOC1 protein not addressed","Single lab, ceRNA-centric"]},{"year":2025,"claim":"Established an epigenetic mode of LDOC1 silencing in ependymoma (H3K27me3 compaction) and showed LDOC1 loss is required for tumor growth via NF-κB and IL-6.","evidence":"ChIP for H3K27me3, lentiviral restoration, NF-κB analysis, IL-6 ELISA, in vivo competition assay","pmids":["39901723"],"confidence":"Medium","gaps":["Direct PRC2 recruitment to LDOC1 not shown","Link between NF-κB and IL-6 mechanistically incomplete"]},{"year":2026,"claim":"Defined LDOC1's chromatin mechanism, showing it interacts with H2B/H2Bub1, PSMA1, and THAP12 to drive proteasomal turnover of H2Bub1, controlling chromatin accessibility and EMT/metastasis programs.","evidence":"Co-IP, PLA, ChIP-seq, ATAC-seq, MNase digestion, transcriptomics, migration/adhesion assays","pmids":["41484780"],"confidence":"High","gaps":["Whether H2Bub1 regulation is direct catalytic targeting or adaptor-mediated unresolved","Integration with NF-κB and JAK2 roles not established"]},{"year":2026,"claim":"Reported a paradoxical bidirectional effect of LDOC1 on STAT1 transcription and phosphorylation, hinting at a role in pro-inflammatory signaling.","evidence":"Gain/loss-of-function, RT-qPCR, western blot for pSTAT1, target gene analysis","pmids":["41828328"],"confidence":"Low","gaps":["Paradoxical bidirectional result not mechanistically clarified","Single lab, single method set"]},{"year":null,"claim":"It remains unresolved how LDOC1's distinct activities — NF-κB suppression, pJAK2/LNX1-mediated degradation, and H2Bub1 chromatin control — are mechanistically unified, and whether they reflect a single biochemical function or independent scaffolding roles.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of LDOC1 or its complexes","No defined catalytic activity","Relationship between developmental placental role and tumor-suppressor activity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[10,17]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[17]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,6,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,14]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,10,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,13,16]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[17]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5]}],"complexes":[],"partners":["GNL3L","LNX1","JAK2","MZF-1","WAVE3","PSMA1","THAP12","H2B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95751","full_name":"Protein LDOC1","aliases":["Leucine zipper protein down-regulated in cancer cells"],"length_aa":146,"mass_kda":17.0,"function":"May have an important role in the development and/or progression of some cancers","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O95751/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LDOC1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LDOC1","total_profiled":1310},"omim":[{"mim_id":"300402","title":"LEUCINE ZIPPER, DOWNREGULATED IN CANCER 1; LDOC1","url":"https://www.omim.org/entry/300402"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":54.7}],"url":"https://www.proteinatlas.org/search/LDOC1"},"hgnc":{"alias_symbol":["Mar7","Mart7","SIRH7","RTL7"],"prev_symbol":["BCUR1"]},"alphafold":{"accession":"O95751","domains":[{"cath_id":"1.20.5","chopping":"2-45","consensus_level":"medium","plddt":94.107,"start":2,"end":45},{"cath_id":"1.10.1200","chopping":"62-130","consensus_level":"high","plddt":96.7025,"start":62,"end":130}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95751","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95751-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95751-F1-predicted_aligned_error_v6.png","plddt_mean":90.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LDOC1","jax_strain_url":"https://www.jax.org/strain/search?query=LDOC1"},"sequence":{"accession":"O95751","fasta_url":"https://rest.uniprot.org/uniprotkb/O95751.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95751/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95751"}},"corpus_meta":[{"pmid":"23362108","id":"PMC_23362108","title":"Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma.","date":"2013","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23362108","citation_count":79,"is_preprint":false},{"pmid":"12712434","id":"PMC_12712434","title":"Leucine-zipper protein, LDOC1, inhibits NF-kappaB activation and sensitizes pancreatic cancer cells to apoptosis.","date":"2003","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12712434","citation_count":65,"is_preprint":false},{"pmid":"10403563","id":"PMC_10403563","title":"Identification of a novel gene, LDOC1, down-regulated in cancer cell lines.","date":"1999","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/10403563","citation_count":64,"is_preprint":false},{"pmid":"25468940","id":"PMC_25468940","title":"Sirh7/Ldoc1 knockout mice exhibit placental P4 overproduction and delayed parturition.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25468940","citation_count":56,"is_preprint":false},{"pmid":"31842997","id":"PMC_31842997","title":"Acute myeloid leukemia cells secrete microRNA-4532-containing exosomes to mediate normal hematopoiesis in hematopoietic stem cells by activating the LDOC1-dependent STAT3 signaling pathway.","date":"2019","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31842997","citation_count":39,"is_preprint":false},{"pmid":"15670815","id":"PMC_15670815","title":"LDOC1, a novel MZF-1-interacting protein, induces apoptosis.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15670815","citation_count":38,"is_preprint":false},{"pmid":"26637328","id":"PMC_26637328","title":"LDOC1 inhibits proliferation and promotes apoptosis by repressing NF-κB activation in papillary thyroid carcinoma.","date":"2015","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/26637328","citation_count":35,"is_preprint":false},{"pmid":"31889905","id":"PMC_31889905","title":"HAND2-AS1 inhibits invasion and metastasis of cervical cancer cells via microRNA-330-5p-mediated LDOC1.","date":"2019","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31889905","citation_count":30,"is_preprint":false},{"pmid":"27764577","id":"PMC_27764577","title":"Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation.","date":"2016","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/27764577","citation_count":28,"is_preprint":false},{"pmid":"30634502","id":"PMC_30634502","title":"Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/30634502","citation_count":22,"is_preprint":false},{"pmid":"28510691","id":"PMC_28510691","title":"NF-κB upregulation through epigenetic silencing of LDOC1 drives tumor biology and specific immunophenotype in Group A ependymoma.","date":"2017","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28510691","citation_count":20,"is_preprint":false},{"pmid":"26317789","id":"PMC_26317789","title":"LDOC1 silenced by cigarette exposure and involved in oral neoplastic transformation.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26317789","citation_count":19,"is_preprint":false},{"pmid":"24125169","id":"PMC_24125169","title":"Loss of LDOC1 expression by promoter methylation in cervical cancer cells.","date":"2013","source":"Cancer investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24125169","citation_count":18,"is_preprint":false},{"pmid":"16272576","id":"PMC_16272576","title":"WAVE3 functions as a negative regulator of LDOC1.","date":"2005","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16272576","citation_count":18,"is_preprint":false},{"pmid":"24554348","id":"PMC_24554348","title":"Epigenetic silencing of the LDOC1 tumor suppressor gene in ovarian cancer cells.","date":"2014","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/24554348","citation_count":13,"is_preprint":false},{"pmid":"33120999","id":"PMC_33120999","title":"LDOC1 Suppresses Microbe-Induced Production of IL-1β in Human Normal and Cancerous Oral Cells through the PI3K/Akt/GSK-3β Axis.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33120999","citation_count":12,"is_preprint":false},{"pmid":"28240050","id":"PMC_28240050","title":"LDOC1 regulates Wnt5a expression and osteosarcoma cell metastasis and is correlated with the survival of osteosarcoma patients.","date":"2017","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28240050","citation_count":6,"is_preprint":false},{"pmid":"30993049","id":"PMC_30993049","title":"Salivary LDOC1 is a gender-difference biomarker of oral squamous cell carcinoma.","date":"2019","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/30993049","citation_count":6,"is_preprint":false},{"pmid":"23942005","id":"PMC_23942005","title":"Overexpression of LDOC1 in human biliary epithelial cells inhibits apoptosis through NF-κB signaling.","date":"2013","source":"Journal of pediatric gastroenterology and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/23942005","citation_count":6,"is_preprint":false},{"pmid":"37635478","id":"PMC_37635478","title":"Calycosin inhibits gemcitabine-resistant lung cancer cells proliferation through modulation of the LDOC1/GNL3L/NFκB.","date":"2023","source":"The Chinese journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37635478","citation_count":6,"is_preprint":false},{"pmid":"31002361","id":"PMC_31002361","title":"Effects of LDOC1 on colorectal cancer cells via downregulation of the Wnt/β-catenin signaling pathway.","date":"2019","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31002361","citation_count":5,"is_preprint":false},{"pmid":"39682774","id":"PMC_39682774","title":"LINC01270 Regulates the NF-κB-Mediated Pro-Inflammatory Response via the miR-326/LDOC1 Axis in THP-1 Cells.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/39682774","citation_count":3,"is_preprint":false},{"pmid":"31889386","id":"PMC_31889386","title":"LDOC1 is differentially expressed in thyroid cancer and display tumor-suppressive function in papillary thyroid carcinoma.","date":"2020","source":"Cell biology 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41828328","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16149,"output_tokens":4650,"usd":0.059098,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12765,"output_tokens":5607,"usd":0.102,"stage2_stop_reason":"end_turn"},"total_usd":0.161098,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"LDOC1 encodes a nuclear protein with a leucine zipper-like motif at the N-terminal region and a proline-rich region similar to an SH3-binding domain; EGFP-LDOC1 fusion protein localizes to the nucleus.\",\n      \"method\": \"EGFP fusion protein localization assay, Northern blot, chromosomal mapping\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment with functional implication, single lab, single method\",\n      \"pmids\": [\"10403563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LDOC1 inhibits NF-κB transcriptional activity; transient LDOC1 expression blocked NF-κB reporter activity driven by MEKK1, TNF-α, or PMA in a dose-dependent manner, without affecting p53, AP-1, or CRE-dependent reporter expression.\",\n      \"method\": \"NF-κB luciferase reporter assay, stable transfection, cell viability assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple reporter assays with pathway specificity controls, single lab\",\n      \"pmids\": [\"12712434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LDOC1 overexpression induces apoptosis via loss of mitochondrial membrane potential, leading to both caspase-3-dependent and -independent pathways; transcription factor MZF-1 physically interacts with LDOC1 and enhances its pro-apoptotic activity.\",\n      \"method\": \"Phosphatidylserine externalization assay, mitochondrial membrane potential measurement, caspase-3 activity assay, co-immunoprecipitation (MZF-1/LDOC1 interaction)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (apoptosis assays + Co-IP), single lab\",\n      \"pmids\": [\"15670815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LDOC1 binds directly to the verprolin homology (V) domain of WAVE3; WAVE3 expression induces translocation of LDOC1 from the nucleus to the cytoplasm, inhibiting LDOC1-induced apoptosis; LDOC1-induced apoptosis is accompanied by increased p53 protein (not transcription), suggesting LDOC1 inhibits p53 degradation.\",\n      \"method\": \"Direct binding assay (pulldown), subcellular localization (fluorescence microscopy), apoptosis assay, p53 protein/mRNA analysis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated plus functional localization consequence, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16272576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Restored expression of BEX1 and LDOC1 in OSCC cells suppresses NF-κB signaling, specifically decreasing p50 and p65 expression, and exerts growth inhibitory effects in vitro and in vivo.\",\n      \"method\": \"Ectopic expression, NF-κB pathway analysis (western blot for p50/p65), in vivo tumor model\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional experiments with defined molecular readouts, single lab\",\n      \"pmids\": [\"23362108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sirh7/Ldoc1 knockout mice show abnormal placental trophoblast giant cell (TGC) differentiation/maturation, leading to overproduction of placental progesterone (P4) and placental lactogen 1 (PL1), and delayed parturition with low pup weaning rate.\",\n      \"method\": \"Knockout mouse model, hormonal assays (P4, PL1 measurement), histological analysis of placenta\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific endocrine and cellular phenotypic readouts, multiple orthogonal methods\",\n      \"pmids\": [\"25468940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LDOC1 physically interacts with GNL3L (a nucleolar GTPase); ectopic LDOC1 expression destabilizes endogenous GNL3L and down-modulates GNL3L-induced cell proliferation; GNL3L upregulates NF-κB-dependent transcriptional activity via p65, which is reversed by co-expression of LDOC1.\",\n      \"method\": \"Co-immunoprecipitation (protein-protein interaction assays), ectopic expression/knockdown, NF-κB reporter assay, cell proliferation assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction assays plus functional reporter and proliferation assays, single lab\",\n      \"pmids\": [\"27764577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LDOC1 promoter is hypermethylated by cigarette smoke condensate (CSC) exposure via increased nuclear DNMT1 and DNMT3A accumulation; LDOC1 knockdown confers proliferative and clonogenic capacity on untransformed oral cells.\",\n      \"method\": \"Quantitative methylation-specific PCR, CSC treatment, DNMT immunofluorescence, loss-of-function knockdown with clonogenicity assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link between CSC exposure, DNMT accumulation, and LDOC1 silencing with functional consequence, single lab\",\n      \"pmids\": [\"26317789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LDOC1 overexpression in PTC cells suppresses proliferation and induces apoptosis by inhibiting NF-κB activation; LDOC1-overexpressing cells recover responsiveness to TGF-β1 antiproliferative signaling.\",\n      \"method\": \"Lentiviral ectopic expression, NF-κB luciferase reporter assay, western blot (p65, IκBα, c-Myc, Bax, Bcl-xL), flow cytometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26637328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LDOC1 expression decreases Wnt5a levels in osteosarcoma cells and suppresses osteosarcoma cell migration and invasion in vitro; in a xenograft model, LDOC1 expression is associated with reduced lung metastasis.\",\n      \"method\": \"Lentiviral stable expression, transwell migration/invasion assay, qRT-PCR array for metastasis genes, xenograft model with micro-CT imaging\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo assays with a specific downstream target (Wnt5a), single lab\",\n      \"pmids\": [\"28240050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LDOC1 forms protein complexes with phospho-JAK2 (pJAK2) and E3 ubiquitin ligase LNX1, targeting pJAK2 for ubiquitin-dependent proteasomal degradation; LDOC1 deficiency reduces LNX1-pJAK2 interaction, leading to ineffective pJAK2 ubiquitination and consequent STAT3 activation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescent confocal microscopy, in vivo xenograft with phosphorylation analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus confocal colocalization and in vivo functional validation, single lab\",\n      \"pmids\": [\"30634502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AML cell-derived exosomes deliver miR-4532 into hematopoietic stem cells (CD34+), where miR-4532 targets LDOC1 mRNA; loss of LDOC1 activates JAK2/STAT3 phosphorylation and increases DKK1, suppressing normal hematopoiesis; ectopic LDOC1 expression or JAK2 inhibition reverses these effects.\",\n      \"method\": \"miRNA target validation (luciferase/binding assay implied), gain- and loss-of-function in CD34+ HSCs, exosome co-culture, colony-forming unit assays, western blot for pJAK2/pSTAT3\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional gain/loss experiments with pathway readouts, multiple methods, single lab\",\n      \"pmids\": [\"31842997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LDOC1 overexpression in colorectal cancer cells inhibits Wnt/β-catenin signaling, reducing nuclear β-catenin levels and suppressing proliferation, migration, and invasion while promoting apoptosis.\",\n      \"method\": \"Lentiviral ectopic expression, western blot, cellular immunofluorescence for β-catenin localization, Transwell and Matrigel assays, flow cytometry\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional and molecular assays, single lab\",\n      \"pmids\": [\"31002361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LDOC1 deficiency increases Akt phosphorylation and subsequent inhibitory phosphorylation of GSK-3β (Ser9) upon Candida albicans stimulation, leading to increased IL-1β production; PI3K/Akt inhibitors or constitutively active GSK-3β (S9A mutant) reduce IL-1β in LDOC1-deficient cells, placing LDOC1 upstream of the PI3K/Akt/GSK-3β axis.\",\n      \"method\": \"Gain/loss-of-function (ectopic expression and knockdown), western blot for pAkt and pGSK-3β, pharmacological inhibitors (PI3K/Akt), active mutant GSK-3β (S9A) rescue experiment\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via active mutant plus inhibitor validation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33120999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LDOC1 is translocated from the nucleus to the cytoplasm in human thyroid cancer; LDOC1 ablation in PTC cells facilitates nuclear p65 expression and NF-κB activity; NF-κB inhibition reverses the effects of LDOC1 ablation on proliferation, apoptosis, migration, and invasion.\",\n      \"method\": \"Subcellular fractionation/immunofluorescence, lentiviral KD and OE, NF-κB luciferase reporter, NF-κB inhibitor epistasis experiment\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with NF-κB inhibitor plus localization and functional assays, single lab\",\n      \"pmids\": [\"31889386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LINC01270 acts as a competing endogenous RNA (ceRNA) for miR-326, maintaining LDOC1 expression; knockdown of LINC01270 downregulates LDOC1 and enhances NF-κB activity; luciferase reporter assay confirmed the LINC01270/miR-326/LDOC1 regulatory axis in NF-κB modulation.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay, RNA immunoprecipitation (RIP), synthetic RNA perturbation experiments\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, largely ceRNA mechanism with LDOC1 as downstream effector; mechanistic detail on LDOC1 itself is indirect\",\n      \"pmids\": [\"39682774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LDOC1 loss in PFA1 ependymoma results from H3K27me3-mediated chromatin compaction at the LDOC1 locus; restoration of LDOC1 reduces proliferation, NF-κB signaling, and IL-6 secretion; in vivo competition assay showed LDOC1-transduced tumor cells were outcompeted, indicating loss of LDOC1 is required for PFA tumor growth.\",\n      \"method\": \"ChIP (H3K27me3), lentiviral LDOC1 restoration, NF-κB pathway analysis, IL-6 ELISA, in vivo tumor competition model\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including ChIP and in vivo competition assay, single lab\",\n      \"pmids\": [\"39901723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LDOC1 physically interacts with histone H2B, H2Bub1, PSMA1, and THAP12; LDOC1 promotes proteasomal degradation of H2B and H2Bub1 via PSMA1, limiting global H2Bub1 levels; LDOC1 knockdown causes loss of chromatin-bound H2Bub1 and enhanced chromatin compaction partly through THAP12; the LDOC1-H2Bub1 axis regulates metastasis-related genes (cytoskeletal remodeling, cell adhesion, EMT); LDOC1 loss enhances TGF-β-induced epithelial-mesenchymal plasticity and promotes a hybrid E/M phenotype.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, ChIP-seq, ATAC-seq, MNase digestion, transcriptomic profiling, immunofluorescence, flow cytometry, functional migration/adhesion assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple rigorous orthogonal methods (Co-IP, PLA, ChIP-seq, ATAC-seq, MNase, transcriptomics) in one study establishing a mechanistic epigenetic role\",\n      \"pmids\": [\"41484780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LDOC1 regulates STAT1 transcription and phosphorylation in an unexpected bidirectional manner: both gain- and loss-of-function of LDOC1 upregulate STAT1 transcription, revealing a novel role for LDOC1 in modulating STAT1-dependent pro-inflammatory signaling.\",\n      \"method\": \"Gain- and loss-of-function (siRNA and overexpression), RT-qPCR, western blot for pSTAT1, downstream target gene analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single set of methods, paradoxical bidirectional result not yet clarified mechanistically\",\n      \"pmids\": [\"41828328\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LDOC1 is a nuclear leucine-zipper protein that acts as a tumor suppressor by (1) inhibiting NF-κB signaling through interaction with GNL3L and suppression of p65 activity; (2) targeting phospho-JAK2 for ubiquitin-dependent proteasomal degradation via a complex with E3 ligase LNX1, thereby suppressing the IL-6/JAK2/STAT3 loop; (3) regulating histone H2Bub1 levels through interaction with PSMA1 and THAP12, controlling chromatin accessibility and metastatic transcriptional programs including EMT; (4) interacting with MZF-1 to promote apoptosis via mitochondrial membrane potential loss; (5) being negatively regulated by WAVE3, which binds its V-domain and relocalizes it from nucleus to cytoplasm; and (6) controlling placental progesterone and lactogen production to regulate parturition timing in mammals.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LDOC1 is a nuclear leucine-zipper protein that functions as a tumor suppressor by restraining inflammatory and proliferative signaling and by shaping chromatin state [#0, #1, #17]. A core activity is inhibition of NF-\\u03baB transcription: LDOC1 blocks NF-\\u03baB reporter activity downstream of MEKK1, TNF-\\u03b1, and PMA without affecting p53, AP-1, or CRE outputs, and its restoration lowers p50/p65 levels and suppresses tumor growth across oral, thyroid, and ependymoma models [#1, #4, #14, #16]. LDOC1 also interacts with the nucleolar GTPase GNL3L, destabilizing it and reversing GNL3L-driven p65 activation [#6]. In parallel, LDOC1 nucleates a complex with phospho-JAK2 and the E3 ligase LNX1 that drives ubiquitin-dependent proteasomal degradation of pJAK2, thereby damping the IL-6/JAK2/STAT3 axis; loss of LDOC1 weakens LNX1-pJAK2 engagement and unleashes STAT3 activation [#10, #16]. At the chromatin level, LDOC1 binds histone H2B, H2Bub1, PSMA1, and THAP12 and promotes proteasomal turnover of H2B/H2Bub1, limiting global H2Bub1 and controlling chromatin accessibility over metastasis genes; its loss enhances TGF-\\u03b2-induced epithelial-mesenchymal plasticity [#17]. LDOC1 additionally promotes apoptosis through MZF-1-enhanced loss of mitochondrial membrane potential, and is negatively regulated by WAVE3, which binds its V-domain and relocalizes it from nucleus to cytoplasm [#2, #3]. A genetic knockout establishes a developmental role in which LDOC1 controls placental trophoblast giant cell maturation and progesterone/lactogen output to time parturition [#5]. Across cancers LDOC1 is silenced epigenetically, by cigarette-smoke-induced DNMT-mediated promoter hypermethylation and by H3K27me3 chromatin compaction [#7, #16].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the basic identity of LDOC1 as a nuclear protein with a leucine-zipper-like motif and an SH3-binding-like proline-rich region, framing it as a candidate signaling/regulatory protein.\",\n      \"evidence\": \"EGFP fusion localization, Northern blot and chromosomal mapping\",\n      \"pmids\": [\"10403563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partners or enzymatic activity defined\", \"Functional role unknown at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Answered what pathway LDOC1 acts on by showing it specifically inhibits NF-\\u03baB transcriptional activity, defining its first signaling role.\",\n      \"evidence\": \"NF-\\u03baB luciferase reporter assays with pathway-specificity controls and stable transfection\",\n      \"pmids\": [\"12712434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the molecular step in NF-\\u03baB inhibited\", \"Single lab, reporter-based\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected LDOC1 to programmed cell death and identified its first physical partner, showing LDOC1 induces apoptosis via mitochondrial membrane potential loss enhanced by MZF-1.\",\n      \"evidence\": \"Apoptosis assays, mitochondrial membrane potential measurement, caspase-3 assay, Co-IP\",\n      \"pmids\": [\"15670815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking LDOC1 to mitochondrial depolarization unresolved\", \"MZF-1 interaction not reciprocally mapped to domains\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified WAVE3 as a negative regulator that controls LDOC1 localization, establishing that nuclear retention is required for LDOC1's pro-apoptotic function.\",\n      \"evidence\": \"Direct pulldown binding to the WAVE3 V-domain, fluorescence localization, apoptosis and p53 protein/mRNA analysis\",\n      \"pmids\": [\"16272576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How cytoplasmic relocalization inactivates LDOC1 not defined\", \"p53 stabilization mechanism inferred, not directly shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated tumor-suppressive function in vivo by showing LDOC1 restoration suppresses NF-\\u03baB (p50/p65) and inhibits tumor growth in oral cancer.\",\n      \"evidence\": \"Ectopic expression, western blot for p50/p65, in vivo tumor model\",\n      \"pmids\": [\"23362108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not distinguish direct vs indirect NF-\\u03baB suppression\", \"Co-effect with BEX1 not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a physiological, non-cancer role by showing LDOC1 controls placental trophoblast giant cell maturation and parturition timing through progesterone/lactogen output.\",\n      \"evidence\": \"Knockout mouse with hormonal assays and placental histology\",\n      \"pmids\": [\"25468940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway linking LDOC1 to TGC differentiation unknown\", \"Relationship to LDOC1's NF-\\u03baB role not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Explained how LDOC1 becomes silenced in disease, showing cigarette smoke condensate drives DNMT1/DNMT3A-mediated promoter hypermethylation and that knockdown confers proliferative/clonogenic capacity.\",\n      \"evidence\": \"Methylation-specific PCR, CSC treatment, DNMT immunofluorescence, clonogenicity assay\",\n      \"pmids\": [\"26317789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNMT recruitment to LDOC1 locus not shown\", \"Reversibility of silencing untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the NF-\\u03baB-suppressive tumor suppressor role to papillary thyroid cancer and linked it to restored TGF-\\u03b21 responsiveness.\",\n      \"evidence\": \"Lentiviral expression, NF-\\u03baB reporter, western blot panel, flow cytometry\",\n      \"pmids\": [\"26637328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link to TGF-\\u03b21 pathway not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified GNL3L as a physical partner whose destabilization underlies part of LDOC1's NF-\\u03baB suppression, connecting LDOC1 to a nucleolar GTPase.\",\n      \"evidence\": \"Reciprocal Co-IP, ectopic expression/knockdown, NF-\\u03baB reporter, proliferation assays\",\n      \"pmids\": [\"27764577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of GNL3L destabilization unknown\", \"Whether GNL3L is the dominant NF-\\u03baB route unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked LDOC1 to anti-metastatic activity, showing it lowers Wnt5a and reduces migration, invasion, and lung metastasis.\",\n      \"evidence\": \"Stable expression, transwell assays, metastasis gene qRT-PCR array, xenograft with micro-CT\",\n      \"pmids\": [\"28240050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect Wnt5a regulation not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a degradative mechanism by showing LDOC1 assembles with pJAK2 and the E3 ligase LNX1 to drive pJAK2 ubiquitination, suppressing STAT3 activation.\",\n      \"evidence\": \"Co-IP, confocal colocalization, in vivo xenograft with phosphorylation analysis\",\n      \"pmids\": [\"30634502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type and LDOC1's adaptor role not structurally defined\", \"Direct vs scaffold function unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed LDOC1 in normal hematopoiesis as a target of AML exosomal miR-4532, whose loss activates JAK2/STAT3 and DKK1 to suppress hematopoiesis.\",\n      \"evidence\": \"miRNA target validation, gain/loss in CD34+ HSCs, exosome co-culture, CFU assays, western blot\",\n      \"pmids\": [\"31842997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miR-4532/LDOC1 binding only implied\", \"Mechanism overlapping with LNX1 axis not integrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed LDOC1 also restrains Wnt/\\u03b2-catenin signaling in colorectal cancer, broadening its anti-proliferative reach beyond NF-\\u03baB.\",\n      \"evidence\": \"Lentiviral expression, western blot, \\u03b2-catenin immunofluorescence, Transwell/Matrigel, flow cytometry\",\n      \"pmids\": [\"31002361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of \\u03b2-catenin regulation undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned LDOC1 upstream of the PI3K/Akt/GSK-3\\u03b2 axis controlling IL-1\\u03b2 during Candida albicans stimulation, extending its role to innate inflammatory output.\",\n      \"evidence\": \"Gain/loss-of-function, western blot for pAkt/pGSK-3\\u03b2, PI3K/Akt inhibitors, GSK-3\\u03b2 S9A rescue\",\n      \"pmids\": [\"33120999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of LDOC1 in this axis not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed that nuclear-to-cytoplasmic translocation inactivates LDOC1 in thyroid cancer and that its NF-\\u03baB suppression is functionally responsible for its anti-tumor phenotype via inhibitor epistasis.\",\n      \"evidence\": \"Subcellular fractionation/IF, lentiviral KD/OE, NF-\\u03baB reporter, NF-\\u03baB inhibitor epistasis\",\n      \"pmids\": [\"31889386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger for mislocalization in tumors not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added an upstream regulatory layer in which LINC01270 sponges miR-326 to sustain LDOC1 and limit NF-\\u03baB activity.\",\n      \"evidence\": \"siRNA knockdown, luciferase reporter, RIP, synthetic RNA perturbation\",\n      \"pmids\": [\"39682774\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"LDOC1 is a downstream effector; direct mechanism on LDOC1 protein not addressed\", \"Single lab, ceRNA-centric\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established an epigenetic mode of LDOC1 silencing in ependymoma (H3K27me3 compaction) and showed LDOC1 loss is required for tumor growth via NF-\\u03baB and IL-6.\",\n      \"evidence\": \"ChIP for H3K27me3, lentiviral restoration, NF-\\u03baB analysis, IL-6 ELISA, in vivo competition assay\",\n      \"pmids\": [\"39901723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PRC2 recruitment to LDOC1 not shown\", \"Link between NF-\\u03baB and IL-6 mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined LDOC1's chromatin mechanism, showing it interacts with H2B/H2Bub1, PSMA1, and THAP12 to drive proteasomal turnover of H2Bub1, controlling chromatin accessibility and EMT/metastasis programs.\",\n      \"evidence\": \"Co-IP, PLA, ChIP-seq, ATAC-seq, MNase digestion, transcriptomics, migration/adhesion assays\",\n      \"pmids\": [\"41484780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H2Bub1 regulation is direct catalytic targeting or adaptor-mediated unresolved\", \"Integration with NF-\\u03baB and JAK2 roles not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reported a paradoxical bidirectional effect of LDOC1 on STAT1 transcription and phosphorylation, hinting at a role in pro-inflammatory signaling.\",\n      \"evidence\": \"Gain/loss-of-function, RT-qPCR, western blot for pSTAT1, target gene analysis\",\n      \"pmids\": [\"41828328\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Paradoxical bidirectional result not mechanistically clarified\", \"Single lab, single method set\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how LDOC1's distinct activities — NF-\\u03baB suppression, pJAK2/LNX1-mediated degradation, and H2Bub1 chromatin control — are mechanistically unified, and whether they reflect a single biochemical function or independent scaffolding roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of LDOC1 or its complexes\", \"No defined catalytic activity\", \"Relationship between developmental placental role and tumor-suppressor activity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [10, 17]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 6, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 10, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 13, 16]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GNL3L\", \"LNX1\", \"JAK2\", \"MZF-1\", \"WAVE3\", \"PSMA1\", \"THAP12\", \"H2B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}