{"gene":"IKBIP","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2004,"finding":"IKIP (IKBIP) is a p53 target gene: its expression is enhanced by X-irradiation in a p53-dependent manner, and IKIP promotes apoptosis when transfected into endothelial cells. IKIP and APAF1 share a common bidirectional 488 bp promoter.","method":"Reporter/transfection assays in endothelial cells, X-irradiation experiments, promoter analysis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression assay with apoptosis readout, promoter analysis, p53-dependence shown; single lab, multiple methods","pmids":["15389287"],"is_preprint":false},{"year":2019,"finding":"IKIP (IKBIP) negatively regulates NF-κB signaling by binding to IKKα/β and blocking their association with NEMO, thereby inhibiting IKKα/β phosphorylation and downstream IκB/p65 phosphorylation. IKIP-deficient macrophages show prolonged IKKα/β phosphorylation and enhanced NF-κB-responsive gene production. IKIP-deficient mice are more susceptible to LPS-induced septic shock and DSS-induced colitis.","method":"Co-immunoprecipitation (IKIP–IKKα/β interaction and disruption of IKK–NEMO association), IKIP-knockout macrophages and mice, LPS/TNF-α/IL-1β stimulation assays, Western blot for phosphorylation","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP defining mechanism, knockout cells and mice with multiple stimuli, in vivo disease models confirming function","pmids":["31826938"],"is_preprint":false},{"year":2022,"finding":"IKBIP directly binds CDK4 and prevents its ubiquitination-mediated proteasomal degradation in GBM cells, thereby maintaining CDK4 protein levels and sustaining Cyclin D1/CDK4/CDK6/CDK2-dependent G1/S cell cycle progression.","method":"Co-immunoprecipitation (IKBIP–CDK4 interaction), ubiquitination assay, IKBIP knockdown with cell cycle analysis (flow cytometry), in vivo mouse xenograft model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and in vivo model; single lab with multiple orthogonal methods","pmids":["36244542"],"is_preprint":false},{"year":2024,"finding":"IKIP overexpression in GBM cells inhibits migration and invasion by downregulating THBS1 mRNA and suppressing THBS1/FAK signaling, while IKIP knockdown has the opposite effect. In vivo, IKIP overexpression promoted tumor growth but inhibited tumor invasion of surrounding brain tissue.","method":"Transwell and wound healing migration/invasion assays, transcriptome comparison upon IKIP overexpression/knockdown, in vivo intracranial mouse model","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD/OE with defined pathway (THBS1/FAK) and in vivo validation; single lab, multiple orthogonal methods","pmids":["38948026"],"is_preprint":false},{"year":2024,"finding":"IKBIP knockdown in ESCC cells inhibits proliferation and migration and induces apoptosis and G1/S arrest; IKBIP overexpression activates the AKT signaling pathway, and this activation is blocked by the PI3K/AKT inhibitor LY-294002, placing IKBIP upstream of AKT in ESCC.","method":"IKBIP knockdown/overexpression in ESCC cells, Western blot for AKT pathway components, pharmacological inhibition with LY-294002, xenograft mouse model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD/OE with pathway placement via inhibitor validation and in vivo xenograft; single lab, multiple methods","pmids":["38914958"],"is_preprint":false},{"year":2026,"finding":"GULP1 directly interacts with IKIP (IKBIP) to relieve IKIP-mediated inhibition of IKKβ-dependent NF-κB activation, enhancing NF-κB signaling, upregulating OPA1 expression, restoring mitochondrial morphology, and improving fatty acid metabolism in diabetic cardiomyopathy hearts.","method":"Co-immunoprecipitation (GULP1–IKIP interaction), cardiac-specific GULP1 knockout and overexpression mice, electron microscopy, enzyme activity assays, ATP/fatty acid oxidation measurements, in vitro cardiomyocyte palmitic acid model","journal":"Cardiovascular diabetology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction (Co-IP), genetic KO/OE mouse models with multiple functional readouts; single lab, multiple orthogonal methods","pmids":["42015218"],"is_preprint":false},{"year":2026,"finding":"SP1 transcription factor binds the IKBIP promoter and transcriptionally upregulates IKBIP expression. IKBIP in turn promotes glioma proliferation and invasion through activation of the Wnt/β-catenin/EMT pathway, decreasing phospho-β-catenin while increasing total β-catenin and downstream EMT markers (ZEB1, ZEB2, N-cadherin), with reciprocal decrease in E-cadherin.","method":"Chromatin immunoprecipitation or promoter binding assay (SP1–IKBIP promoter), IKBIP knockdown/overexpression in glioma cell lines, Western blot for Wnt/β-catenin/EMT pathway components, in vitro invasion assays, in vivo mouse model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding assay plus functional KD/OE with defined pathway readout; single lab, multiple methods","pmids":["42004064"],"is_preprint":false}],"current_model":"IKBIP (IKIP) is a stress- and p53-inducible protein that acts as a negative regulator of canonical NF-κB signaling by binding IKKα/β and blocking their interaction with NEMO, thereby inhibiting IKK complex activation; it is itself subject to counter-regulation by GULP1 (which binds IKIP to relieve IKK inhibition), and in proliferating cancer cells it stabilizes CDK4 against ubiquitin-mediated degradation, activates AKT signaling, and modulates Wnt/β-catenin/EMT and THBS1/FAK pathways to control cell cycle progression, migration, and invasion."},"narrative":{"mechanistic_narrative":"IKBIP (IKIP) is a stress-responsive intracellular protein that functions both as a negative regulator of canonical NF-κB signaling and as a context-dependent driver of cancer cell proliferation and invasion [PMID:31826938, PMID:36244542]. It was first identified as a p53 target gene whose induction by X-irradiation promotes apoptosis in endothelial cells, sharing a bidirectional promoter with APAF1 [PMID:15389287]. Mechanistically, IKIP binds IKKα/β and blocks their association with NEMO, suppressing IKKα/β phosphorylation and downstream IκB/p65 phosphorylation; loss of IKIP prolongs IKK activation and sensitizes mice to LPS-induced septic shock and DSS-induced colitis [PMID:31826938]. This inhibitory function is itself relieved by GULP1, which binds IKIP to restore IKKβ-dependent NF-κB activation and downstream OPA1-linked mitochondrial and fatty-acid metabolic recovery in diabetic cardiomyopathy [PMID:42015218]. In proliferating tumor cells, IKBIP supports cell cycle progression and invasion through several effectors: it binds CDK4 and protects it from ubiquitin-mediated degradation to sustain Cyclin D1/CDK4-dependent G1/S transit [PMID:36244542], activates PI3K/AKT signaling in esophageal squamous carcinoma [PMID:38914958], drives the Wnt/β-catenin/EMT program in glioma downstream of SP1-mediated transcriptional upregulation [PMID:42004064], and suppresses migration via downregulation of THBS1/FAK signaling [PMID:38948026].","teleology":[{"year":2004,"claim":"Established IKBIP as a genuine stress-response gene by linking its expression to p53 and its function to apoptosis, situating it in the DNA-damage response.","evidence":"Reporter/transfection and X-irradiation assays in endothelial cells plus bidirectional promoter analysis with APAF1","pmids":["15389287"],"confidence":"Medium","gaps":["No molecular partner or biochemical activity identified","Mechanism connecting IKIP to the apoptotic machinery not defined","Single cell type tested"]},{"year":2019,"claim":"Defined IKBIP's core molecular mechanism as a brake on canonical NF-κB signaling, answering how it acts biochemically and demonstrating physiological relevance in inflammation.","evidence":"Reciprocal Co-IP of IKIP with IKKα/β and disruption of IKK–NEMO, knockout macrophages and mice in septic shock and colitis models","pmids":["31826938"],"confidence":"High","gaps":["Binding interface/domain on IKK not mapped","Relationship between NF-κB inhibition and earlier apoptotic role unresolved","Upstream regulators of IKIP not identified here"]},{"year":2022,"claim":"Revealed a pro-proliferative function distinct from NF-κB inhibition by showing IKBIP stabilizes CDK4, explaining how it sustains cell cycle progression in cancer.","evidence":"Co-IP of IKBIP with CDK4, ubiquitination assay, knockdown cell cycle analysis, and xenograft model in GBM","pmids":["36244542"],"confidence":"Medium","gaps":["E3 ligase that IKBIP antagonizes not identified","Reconciliation of pro-tumor role with apoptotic/p53 role unclear","Whether CDK4 stabilization depends on NF-κB activity untested"]},{"year":2024,"claim":"Extended IKBIP's tumor functions to motility control via THBS1/FAK and to a separate PI3K/AKT-dependent proliferation axis in esophageal carcinoma, showing pathway-specific and tissue-specific outputs.","evidence":"Knockdown/overexpression with migration/invasion assays and transcriptomics (GBM, THBS1/FAK) and LY-294002 epistasis with xenografts (ESCC, AKT)","pmids":["38948026","38914958"],"confidence":"Medium","gaps":["Direct molecular link between IKBIP and THBS1 transcription or AKT activation not established","Opposing effects on growth versus invasion not mechanistically reconciled","Whether these axes intersect with NF-κB unknown"]},{"year":2026,"claim":"Placed IKBIP within regulatory circuits by identifying both an upstream activator (SP1) driving a Wnt/β-catenin/EMT program in glioma and a counter-regulator (GULP1) that relieves its NF-κB inhibition with metabolic consequences.","evidence":"SP1–promoter binding plus KD/OE Wnt/EMT readouts (glioma); GULP1–IKIP Co-IP with cardiac KO/OE mice and mitochondrial/metabolic assays (diabetic cardiomyopathy)","pmids":["42004064","42015218"],"confidence":"Medium","gaps":["How GULP1 binding sterically relieves IKK inhibition not defined","Connection between Wnt/EMT activation and the established IKK-binding function unclear","Whether SP1 and GULP1 regulation co-occur in the same tissues untested"]},{"year":null,"claim":"How a single protein integrates its NF-κB-inhibitory, p53/apoptotic, and pro-proliferative (CDK4/AKT/Wnt) activities into a coherent context-dependent program remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model or domain map for IKBIP","Determinants of tumor-suppressive versus oncogenic output unknown","Whether the IKK-binding and CDK4-binding functions are mutually exclusive untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6]}],"complexes":[],"partners":["IKKΑ","IKKΒ","NEMO","CDK4","GULP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q70UQ0","full_name":"Inhibitor of nuclear factor kappa-B kinase-interacting protein","aliases":[],"length_aa":350,"mass_kda":39.3,"function":"Target of p53/TP53 with pro-apoptotic function","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q70UQ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IKBIP","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"SNX2","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IKBIP","total_profiled":1310},"omim":[{"mim_id":"609861","title":"I-KAPPA-B KINASE-INTERACTING PROTEIN; IKBIP","url":"https://www.omim.org/entry/609861"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nucleoli rim","reliability":"Additional"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IKBIP"},"hgnc":{"alias_symbol":["FLJ31051","IKIP"],"prev_symbol":[]},"alphafold":{"accession":"Q70UQ0","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q70UQ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q70UQ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q70UQ0-F1-predicted_aligned_error_v6.png","plddt_mean":82.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IKBIP","jax_strain_url":"https://www.jax.org/strain/search?query=IKBIP"},"sequence":{"accession":"Q70UQ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q70UQ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q70UQ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q70UQ0"}},"corpus_meta":[{"pmid":"15389287","id":"PMC_15389287","title":"A highly conserved proapoptotic gene, IKIP, located next to the APAF1 gene locus, is regulated by p53.","date":"2004","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/15389287","citation_count":42,"is_preprint":false},{"pmid":"35608653","id":"PMC_35608653","title":"In Vitro Kinase-to-Phosphosite Database (iKiP-DB) Predicts Kinase Activity in Phosphoproteomic Datasets.","date":"2022","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/35608653","citation_count":38,"is_preprint":false},{"pmid":"31826938","id":"PMC_31826938","title":"IKIP Negatively Regulates NF-κB Activation and Inflammation through Inhibition of IKKα/β Phosphorylation.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31826938","citation_count":36,"is_preprint":false},{"pmid":"36244542","id":"PMC_36244542","title":"IKBIP, a novel glioblastoma biomarker, maintains abnormal proliferation of tumor cells by inhibiting the ubiquitination and degradation of CDK4.","date":"2022","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/36244542","citation_count":10,"is_preprint":false},{"pmid":"34897031","id":"PMC_34897031","title":"hsa_circ_0072389, hsa_circ_0072386, hsa_circ_0008621, hsa_circ_0072387, and hsa_circ_0072391 aggravate glioma via miR-338-5p/IKBIP.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/34897031","citation_count":8,"is_preprint":false},{"pmid":"38914958","id":"PMC_38914958","title":"IKBIP promotes tumor development via the akt signaling pathway in esophageal squamous cell carcinoma.","date":"2024","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38914958","citation_count":5,"is_preprint":false},{"pmid":"37024442","id":"PMC_37024442","title":"IKBIP is a Predictive Biomarker Related to Immunosuppressive Microenvironment in Digestive System Malignancies.","date":"2023","source":"Discovery medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37024442","citation_count":5,"is_preprint":false},{"pmid":"37604283","id":"PMC_37604283","title":"V-ATPase subunit C 1 and IKBIP as tandem prospective biomarkers for diabetic nephropathy.","date":"2023","source":"Diabetes research and clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/37604283","citation_count":3,"is_preprint":false},{"pmid":"38948026","id":"PMC_38948026","title":"IKIP downregulates THBS1/FAK signaling to suppress migration and invasion by glioblastoma cells.","date":"2024","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/38948026","citation_count":2,"is_preprint":false},{"pmid":"42004064","id":"PMC_42004064","title":"SP1-IKBIP axis promotes the proliferation and invasion of glioma with Wnt/β-catenin associated epithelial-mesenchymal transition.","date":"2026","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/42004064","citation_count":0,"is_preprint":false},{"pmid":"42015218","id":"PMC_42015218","title":"GULP1 protects against diabetic cardiomyopathy through IKIP/NF-κB-dependent improvement of mitochondrial function.","date":"2026","source":"Cardiovascular diabetology","url":"https://pubmed.ncbi.nlm.nih.gov/42015218","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.06.18.599639","title":"Transcriptional pathobiology and multi-omics predictors for Parkinson’s disease","date":"2024-06-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.18.599639","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8129,"output_tokens":1986,"usd":0.027089,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9028,"output_tokens":2580,"usd":0.05482,"stage2_stop_reason":"end_turn"},"total_usd":0.081909,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"IKIP (IKBIP) is a p53 target gene: its expression is enhanced by X-irradiation in a p53-dependent manner, and IKIP promotes apoptosis when transfected into endothelial cells. IKIP and APAF1 share a common bidirectional 488 bp promoter.\",\n      \"method\": \"Reporter/transfection assays in endothelial cells, X-irradiation experiments, promoter analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression assay with apoptosis readout, promoter analysis, p53-dependence shown; single lab, multiple methods\",\n      \"pmids\": [\"15389287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IKIP (IKBIP) negatively regulates NF-κB signaling by binding to IKKα/β and blocking their association with NEMO, thereby inhibiting IKKα/β phosphorylation and downstream IκB/p65 phosphorylation. IKIP-deficient macrophages show prolonged IKKα/β phosphorylation and enhanced NF-κB-responsive gene production. IKIP-deficient mice are more susceptible to LPS-induced septic shock and DSS-induced colitis.\",\n      \"method\": \"Co-immunoprecipitation (IKIP–IKKα/β interaction and disruption of IKK–NEMO association), IKIP-knockout macrophages and mice, LPS/TNF-α/IL-1β stimulation assays, Western blot for phosphorylation\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP defining mechanism, knockout cells and mice with multiple stimuli, in vivo disease models confirming function\",\n      \"pmids\": [\"31826938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IKBIP directly binds CDK4 and prevents its ubiquitination-mediated proteasomal degradation in GBM cells, thereby maintaining CDK4 protein levels and sustaining Cyclin D1/CDK4/CDK6/CDK2-dependent G1/S cell cycle progression.\",\n      \"method\": \"Co-immunoprecipitation (IKBIP–CDK4 interaction), ubiquitination assay, IKBIP knockdown with cell cycle analysis (flow cytometry), in vivo mouse xenograft model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and in vivo model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36244542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IKIP overexpression in GBM cells inhibits migration and invasion by downregulating THBS1 mRNA and suppressing THBS1/FAK signaling, while IKIP knockdown has the opposite effect. In vivo, IKIP overexpression promoted tumor growth but inhibited tumor invasion of surrounding brain tissue.\",\n      \"method\": \"Transwell and wound healing migration/invasion assays, transcriptome comparison upon IKIP overexpression/knockdown, in vivo intracranial mouse model\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD/OE with defined pathway (THBS1/FAK) and in vivo validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38948026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IKBIP knockdown in ESCC cells inhibits proliferation and migration and induces apoptosis and G1/S arrest; IKBIP overexpression activates the AKT signaling pathway, and this activation is blocked by the PI3K/AKT inhibitor LY-294002, placing IKBIP upstream of AKT in ESCC.\",\n      \"method\": \"IKBIP knockdown/overexpression in ESCC cells, Western blot for AKT pathway components, pharmacological inhibition with LY-294002, xenograft mouse model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD/OE with pathway placement via inhibitor validation and in vivo xenograft; single lab, multiple methods\",\n      \"pmids\": [\"38914958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GULP1 directly interacts with IKIP (IKBIP) to relieve IKIP-mediated inhibition of IKKβ-dependent NF-κB activation, enhancing NF-κB signaling, upregulating OPA1 expression, restoring mitochondrial morphology, and improving fatty acid metabolism in diabetic cardiomyopathy hearts.\",\n      \"method\": \"Co-immunoprecipitation (GULP1–IKIP interaction), cardiac-specific GULP1 knockout and overexpression mice, electron microscopy, enzyme activity assays, ATP/fatty acid oxidation measurements, in vitro cardiomyocyte palmitic acid model\",\n      \"journal\": \"Cardiovascular diabetology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction (Co-IP), genetic KO/OE mouse models with multiple functional readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42015218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SP1 transcription factor binds the IKBIP promoter and transcriptionally upregulates IKBIP expression. IKBIP in turn promotes glioma proliferation and invasion through activation of the Wnt/β-catenin/EMT pathway, decreasing phospho-β-catenin while increasing total β-catenin and downstream EMT markers (ZEB1, ZEB2, N-cadherin), with reciprocal decrease in E-cadherin.\",\n      \"method\": \"Chromatin immunoprecipitation or promoter binding assay (SP1–IKBIP promoter), IKBIP knockdown/overexpression in glioma cell lines, Western blot for Wnt/β-catenin/EMT pathway components, in vitro invasion assays, in vivo mouse model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding assay plus functional KD/OE with defined pathway readout; single lab, multiple methods\",\n      \"pmids\": [\"42004064\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IKBIP (IKIP) is a stress- and p53-inducible protein that acts as a negative regulator of canonical NF-κB signaling by binding IKKα/β and blocking their interaction with NEMO, thereby inhibiting IKK complex activation; it is itself subject to counter-regulation by GULP1 (which binds IKIP to relieve IKK inhibition), and in proliferating cancer cells it stabilizes CDK4 against ubiquitin-mediated degradation, activates AKT signaling, and modulates Wnt/β-catenin/EMT and THBS1/FAK pathways to control cell cycle progression, migration, and invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IKBIP (IKIP) is a stress-responsive intracellular protein that functions both as a negative regulator of canonical NF-\\u03baB signaling and as a context-dependent driver of cancer cell proliferation and invasion [#1, #2]. It was first identified as a p53 target gene whose induction by X-irradiation promotes apoptosis in endothelial cells, sharing a bidirectional promoter with APAF1 [#0]. Mechanistically, IKIP binds IKK\\u03b1/\\u03b2 and blocks their association with NEMO, suppressing IKK\\u03b1/\\u03b2 phosphorylation and downstream I\\u03baB/p65 phosphorylation; loss of IKIP prolongs IKK activation and sensitizes mice to LPS-induced septic shock and DSS-induced colitis [#1]. This inhibitory function is itself relieved by GULP1, which binds IKIP to restore IKK\\u03b2-dependent NF-\\u03baB activation and downstream OPA1-linked mitochondrial and fatty-acid metabolic recovery in diabetic cardiomyopathy [#5]. In proliferating tumor cells, IKBIP supports cell cycle progression and invasion through several effectors: it binds CDK4 and protects it from ubiquitin-mediated degradation to sustain Cyclin D1/CDK4-dependent G1/S transit [#2], activates PI3K/AKT signaling in esophageal squamous carcinoma [#4], drives the Wnt/\\u03b2-catenin/EMT program in glioma downstream of SP1-mediated transcriptional upregulation [#6], and suppresses migration via downregulation of THBS1/FAK signaling [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established IKBIP as a genuine stress-response gene by linking its expression to p53 and its function to apoptosis, situating it in the DNA-damage response.\",\n      \"evidence\": \"Reporter/transfection and X-irradiation assays in endothelial cells plus bidirectional promoter analysis with APAF1\",\n      \"pmids\": [\"15389287\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No molecular partner or biochemical activity identified\", \"Mechanism connecting IKIP to the apoptotic machinery not defined\", \"Single cell type tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined IKBIP's core molecular mechanism as a brake on canonical NF-\\u03baB signaling, answering how it acts biochemically and demonstrating physiological relevance in inflammation.\",\n      \"evidence\": \"Reciprocal Co-IP of IKIP with IKK\\u03b1/\\u03b2 and disruption of IKK\\u2013NEMO, knockout macrophages and mice in septic shock and colitis models\",\n      \"pmids\": [\"31826938\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Binding interface/domain on IKK not mapped\", \"Relationship between NF-\\u03baB inhibition and earlier apoptotic role unresolved\", \"Upstream regulators of IKIP not identified here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a pro-proliferative function distinct from NF-\\u03baB inhibition by showing IKBIP stabilizes CDK4, explaining how it sustains cell cycle progression in cancer.\",\n      \"evidence\": \"Co-IP of IKBIP with CDK4, ubiquitination assay, knockdown cell cycle analysis, and xenograft model in GBM\",\n      \"pmids\": [\"36244542\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"E3 ligase that IKBIP antagonizes not identified\", \"Reconciliation of pro-tumor role with apoptotic/p53 role unclear\", \"Whether CDK4 stabilization depends on NF-\\u03baB activity untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended IKBIP's tumor functions to motility control via THBS1/FAK and to a separate PI3K/AKT-dependent proliferation axis in esophageal carcinoma, showing pathway-specific and tissue-specific outputs.\",\n      \"evidence\": \"Knockdown/overexpression with migration/invasion assays and transcriptomics (GBM, THBS1/FAK) and LY-294002 epistasis with xenografts (ESCC, AKT)\",\n      \"pmids\": [\"38948026\", \"38914958\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular link between IKBIP and THBS1 transcription or AKT activation not established\", \"Opposing effects on growth versus invasion not mechanistically reconciled\", \"Whether these axes intersect with NF-\\u03baB unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed IKBIP within regulatory circuits by identifying both an upstream activator (SP1) driving a Wnt/\\u03b2-catenin/EMT program in glioma and a counter-regulator (GULP1) that relieves its NF-\\u03baB inhibition with metabolic consequences.\",\n      \"evidence\": \"SP1\\u2013promoter binding plus KD/OE Wnt/EMT readouts (glioma); GULP1\\u2013IKIP Co-IP with cardiac KO/OE mice and mitochondrial/metabolic assays (diabetic cardiomyopathy)\",\n      \"pmids\": [\"42004064\", \"42015218\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How GULP1 binding sterically relieves IKK inhibition not defined\", \"Connection between Wnt/EMT activation and the established IKK-binding function unclear\", \"Whether SP1 and GULP1 regulation co-occur in the same tissues untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single protein integrates its NF-\\u03baB-inhibitory, p53/apoptotic, and pro-proliferative (CDK4/AKT/Wnt) activities into a coherent context-dependent program remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model or domain map for IKBIP\", \"Determinants of tumor-suppressive versus oncogenic output unknown\", \"Whether the IKK-binding and CDK4-binding functions are mutually exclusive untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IKK\\u03b1\", \"IKK\\u03b2\", \"NEMO\", \"CDK4\", \"GULP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}