{"gene":"IKBIP","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2004,"finding":"IKIP (IKBIP) is a p53 target gene: its expression is upregulated by X-irradiation in a p53-dependent manner, and overexpression of IKIP promotes apoptosis in endothelial cells. IKIP is co-regulated with APAF1 from a shared 488 bp bidirectional promoter.","method":"Promoter analysis, X-irradiation experiments, p53-dependence assays, transfection-induced apoptosis in endothelial cells","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — functional overexpression phenotype and promoter mapping in a single study; moderate evidence","pmids":["15389287"],"is_preprint":false},{"year":2019,"finding":"IKIP (IKBIP) negatively regulates NF-κB activation by physically interacting with IKKα/β and blocking their association with NEMO, thereby inhibiting IKKα/β phosphorylation. IKIP-deficient macrophages show enhanced and prolonged IKKα/β, IκB, and p65 phosphorylation upon LPS, TNF-α, and IL-1β stimulation, and 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/mice, LPS/TNF-α/IL-1β stimulation, Western blot for phosphorylation, in vivo septic shock and colitis models","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP defining binding partner and mechanism, combined with KO cell and animal phenotypes across multiple stimuli, replicated across assays in single study","pmids":["31826938"],"is_preprint":false},{"year":2022,"finding":"IKBIP binds directly to CDK4 and prevents its ubiquitination-mediated proteasomal degradation, thereby sustaining CDK4 protein levels and promoting G1/S progression via the Cyclin D1/CDK4/CDK6/CDK2 pathway in glioblastoma cells. IKBIP knockdown induces G1/S arrest and suppresses tumor growth in a mouse xenograft model.","method":"Co-immunoprecipitation (IKBIP–CDK4 interaction), ubiquitination assay, IKBIP knockdown with flow cytometry cell-cycle analysis, Western blot for Cyclin D1/CDK4/CDK6/CDK2, in vivo xenograft mouse model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP plus ubiquitination assay plus in vivo data from a single lab; moderate evidence","pmids":["36244542"],"is_preprint":false},{"year":2024,"finding":"IKIP (IKBIP) inhibits migration and invasion of glioblastoma cells by downregulating THBS1 mRNA and suppressing THBS1/FAK signaling; conversely, IKIP overexpression in intracranially injected GBM cells promotes tumor growth but inhibits invasion of surrounding tissue.","method":"Transcriptomic comparison (IKIP overexpression vs. knockdown), transwell and wound-healing migration assays, Western blot/mRNA quantification of THBS1/FAK pathway, in vivo mouse brain tumor model","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2/3 — transcriptomic pathway identification combined with functional assays and in vivo model from a single lab","pmids":["38948026"],"is_preprint":false},{"year":2024,"finding":"IKBIP promotes proliferation and migration of esophageal squamous cell carcinoma cells through activation of the AKT signaling pathway; IKBIP overexpression increases AKT phosphorylation, and the AKT inhibitor LY-294002 reverses this effect. IKBIP knockdown induces apoptosis and G1/S arrest in ESCC cells.","method":"IKBIP knockdown/overexpression in ESCC cell lines, Western blot for AKT signaling, LY-294002 pharmacological inhibition, flow cytometry for apoptosis and cell cycle, xenograft mouse model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2/3 — pathway validation with pharmacological inhibitor plus KD/OE phenotypes and in vivo confirmation from a single lab","pmids":["38914958"],"is_preprint":false},{"year":2026,"finding":"Transcription factor SP1 binds to the IKBIP promoter and drives its expression; IKBIP in turn activates Wnt/β-catenin/EMT signaling in glioma cells by reducing phosphorylated β-catenin while increasing total β-catenin, leading to upregulation of ZEB1, ZEB2, and N-cadherin and downregulation of E-cadherin, thereby promoting glioma cell proliferation and invasion.","method":"ChIP/promoter-binding assay (SP1 binding to IKBIP promoter), IKBIP knockdown and overexpression in U251/U87 glioma lines, Western blot for β-catenin/p-β-catenin/ZEB1/ZEB2/N-cadherin/E-cadherin, in vitro invasion assays, in vivo tumor model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2/3 — promoter binding plus pathway protein quantification plus functional assays from a single lab","pmids":["42004064"],"is_preprint":false}],"current_model":"IKBIP (IKIP) is a p53-induced, proapoptotic protein that negatively regulates NF-κB by binding IKKα/β and blocking their association with NEMO (thereby inhibiting IKK phosphorylation), stabilizes CDK4 by preventing its ubiquitin-mediated degradation to drive cell-cycle progression, suppresses glioblastoma cell migration/invasion via THBS1/FAK downregulation, and activates AKT and Wnt/β-catenin/EMT signaling in cancer contexts, with its own transcription driven by SP1."},"narrative":{"teleology":[{"year":2004,"claim":"Identification of IKIP as a p53-inducible proapoptotic gene sharing a bidirectional promoter with APAF1 established it as a stress-responsive effector within the p53 apoptotic network.","evidence":"Promoter mapping and X-irradiation of endothelial cells showing p53-dependent upregulation and overexpression-induced apoptosis","pmids":["15389287"],"confidence":"Medium","gaps":["Endogenous proapoptotic mechanism and relevant protein interactions were not defined","Whether the bidirectional promoter coordinates IKIP and APAF1 functionally was not tested","No loss-of-function data provided"]},{"year":2019,"claim":"Demonstration that IKIP binds IKKα/β and prevents their association with NEMO resolved its molecular mechanism as a negative regulator of NF-κB, explaining its role in restraining inflammatory responses in vivo.","evidence":"Reciprocal Co-IP for IKIP–IKKα/β interaction, IKIP-knockout macrophages and mice challenged with LPS, TNF-α, IL-1β, and in vivo septic shock and colitis models","pmids":["31826938"],"confidence":"High","gaps":["Structural basis of IKIP–IKK binding and whether IKIP competes for the same NEMO-binding site is unknown","Tissue-specific regulation of IKIP expression in inflammatory contexts was not explored"]},{"year":2022,"claim":"Discovery that IKBIP directly binds CDK4 and protects it from ubiquitin-mediated degradation revealed a second, NF-κB-independent mechanism through which IKBIP promotes G1/S cell-cycle progression in glioblastoma.","evidence":"Co-IP of IKBIP–CDK4, ubiquitination assay, IKBIP knockdown causing G1 arrest, and in vivo xenograft suppression","pmids":["36244542"],"confidence":"Medium","gaps":["The E3 ligase whose activity IKBIP antagonizes to stabilize CDK4 was not identified","Whether CDK4 stabilization is linked to or independent of the NF-κB inhibitory function is unresolved","Single-lab finding awaiting independent confirmation"]},{"year":2024,"claim":"Linking IKBIP to THBS1/FAK suppression and AKT activation expanded its oncogenic signaling repertoire and revealed context-dependent effects: IKBIP promotes tumor growth but suppresses invasion in glioblastoma while promoting both proliferation and migration in esophageal carcinoma.","evidence":"Transcriptomic profiling plus transwell/wound-healing assays in GBM cells (THBS1/FAK); IKBIP KD/OE with AKT phosphorylation readout and LY-294002 rescue in ESCC cells; both with xenograft models","pmids":["38948026","38914958"],"confidence":"Medium","gaps":["Direct binding partners mediating AKT activation by IKBIP are unknown","Mechanism by which IKBIP downregulates THBS1 mRNA is not defined","Each pathway was characterized in a single tumor type by a single lab"]},{"year":2026,"claim":"Identification of SP1 as a transcriptional driver of IKBIP and of Wnt/β-catenin/EMT as a downstream effector pathway established a transcriptional circuit (SP1→IKBIP→β-catenin stabilization→EMT) operative in glioma.","evidence":"ChIP demonstrating SP1 binding to IKBIP promoter, IKBIP KD/OE in glioma lines with Western blot for β-catenin/p-β-catenin/ZEB1/ZEB2/N-cadherin/E-cadherin, invasion assays, in vivo model","pmids":["42004064"],"confidence":"Medium","gaps":["How IKBIP reduces β-catenin phosphorylation—whether by direct interaction with destruction complex components—is unknown","Relationship between the Wnt/β-catenin and NF-κB regulatory functions of IKBIP is unexplored","Single-lab finding in glioma cell lines"]},{"year":null,"claim":"A unifying model integrating IKBIP's NF-κB inhibitory, CDK4-stabilizing, AKT-activating, and Wnt/β-catenin-activating functions—and whether these reflect independent or interconnected mechanisms—remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural information exists for IKBIP or its complexes with IKKα/β or CDK4","Tissue-specific and stimulus-specific expression regulation beyond p53 and SP1 is uncharacterized","Whether IKBIP's proapoptotic activity in normal cells and pro-proliferative activity in cancer cells reflect the same or distinct molecular interactions is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["CHUK","IKBKB","CDK4"],"other_free_text":[]},"mechanistic_narrative":"IKBIP (also called IKIP) is a p53-inducible transmembrane protein that functions as a negative regulator of NF-κB signaling by physically binding IKKα/β and blocking their association with NEMO, thereby suppressing IKK phosphorylation and downstream inflammatory responses; IKBIP-deficient mice exhibit exacerbated LPS-induced septic shock and DSS-induced colitis [PMID:31826938]. Beyond its immune-regulatory role, IKBIP stabilizes CDK4 by preventing its ubiquitin-mediated proteasomal degradation, promoting G1/S cell-cycle progression in glioblastoma cells [PMID:36244542], and activates AKT and Wnt/β-catenin/EMT signaling to drive proliferation and invasion in glioma and esophageal squamous cell carcinoma [PMID:38914958, PMID:42004064]. IKBIP expression is transcriptionally induced by p53 from a bidirectional promoter shared with APAF1 and by SP1 binding to its own promoter, and its overexpression promotes apoptosis in endothelial cells [PMID:15389287, PMID:42004064]."},"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":41,"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":35,"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":33,"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":"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":"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":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":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":6567,"output_tokens":1804,"usd":0.02338},"stage2":{"model":"claude-opus-4-6","input_tokens":5143,"output_tokens":1942,"usd":0.111397},"total_usd":0.134777,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","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 upregulated by X-irradiation in a p53-dependent manner, and overexpression of IKIP promotes apoptosis in endothelial cells. IKIP is co-regulated with APAF1 from a shared 488 bp bidirectional promoter.\",\n      \"method\": \"Promoter analysis, X-irradiation experiments, p53-dependence assays, transfection-induced apoptosis in endothelial cells\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional overexpression phenotype and promoter mapping in a single study; moderate evidence\",\n      \"pmids\": [\"15389287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IKIP (IKBIP) negatively regulates NF-κB activation by physically interacting with IKKα/β and blocking their association with NEMO, thereby inhibiting IKKα/β phosphorylation. IKIP-deficient macrophages show enhanced and prolonged IKKα/β, IκB, and p65 phosphorylation upon LPS, TNF-α, and IL-1β stimulation, and 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/mice, LPS/TNF-α/IL-1β stimulation, Western blot for phosphorylation, in vivo septic shock and colitis models\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP defining binding partner and mechanism, combined with KO cell and animal phenotypes across multiple stimuli, replicated across assays in single study\",\n      \"pmids\": [\"31826938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IKBIP binds directly to CDK4 and prevents its ubiquitination-mediated proteasomal degradation, thereby sustaining CDK4 protein levels and promoting G1/S progression via the Cyclin D1/CDK4/CDK6/CDK2 pathway in glioblastoma cells. IKBIP knockdown induces G1/S arrest and suppresses tumor growth in a mouse xenograft model.\",\n      \"method\": \"Co-immunoprecipitation (IKBIP–CDK4 interaction), ubiquitination assay, IKBIP knockdown with flow cytometry cell-cycle analysis, Western blot for Cyclin D1/CDK4/CDK6/CDK2, in vivo xenograft mouse model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP plus ubiquitination assay plus in vivo data from a single lab; moderate evidence\",\n      \"pmids\": [\"36244542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IKIP (IKBIP) inhibits migration and invasion of glioblastoma cells by downregulating THBS1 mRNA and suppressing THBS1/FAK signaling; conversely, IKIP overexpression in intracranially injected GBM cells promotes tumor growth but inhibits invasion of surrounding tissue.\",\n      \"method\": \"Transcriptomic comparison (IKIP overexpression vs. knockdown), transwell and wound-healing migration assays, Western blot/mRNA quantification of THBS1/FAK pathway, in vivo mouse brain tumor model\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — transcriptomic pathway identification combined with functional assays and in vivo model from a single lab\",\n      \"pmids\": [\"38948026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IKBIP promotes proliferation and migration of esophageal squamous cell carcinoma cells through activation of the AKT signaling pathway; IKBIP overexpression increases AKT phosphorylation, and the AKT inhibitor LY-294002 reverses this effect. IKBIP knockdown induces apoptosis and G1/S arrest in ESCC cells.\",\n      \"method\": \"IKBIP knockdown/overexpression in ESCC cell lines, Western blot for AKT signaling, LY-294002 pharmacological inhibition, flow cytometry for apoptosis and cell cycle, xenograft mouse model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — pathway validation with pharmacological inhibitor plus KD/OE phenotypes and in vivo confirmation from a single lab\",\n      \"pmids\": [\"38914958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Transcription factor SP1 binds to the IKBIP promoter and drives its expression; IKBIP in turn activates Wnt/β-catenin/EMT signaling in glioma cells by reducing phosphorylated β-catenin while increasing total β-catenin, leading to upregulation of ZEB1, ZEB2, and N-cadherin and downregulation of E-cadherin, thereby promoting glioma cell proliferation and invasion.\",\n      \"method\": \"ChIP/promoter-binding assay (SP1 binding to IKBIP promoter), IKBIP knockdown and overexpression in U251/U87 glioma lines, Western blot for β-catenin/p-β-catenin/ZEB1/ZEB2/N-cadherin/E-cadherin, in vitro invasion assays, in vivo tumor model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — promoter binding plus pathway protein quantification plus functional assays from a single lab\",\n      \"pmids\": [\"42004064\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IKBIP (IKIP) is a p53-induced, proapoptotic protein that negatively regulates NF-κB by binding IKKα/β and blocking their association with NEMO (thereby inhibiting IKK phosphorylation), stabilizes CDK4 by preventing its ubiquitin-mediated degradation to drive cell-cycle progression, suppresses glioblastoma cell migration/invasion via THBS1/FAK downregulation, and activates AKT and Wnt/β-catenin/EMT signaling in cancer contexts, with its own transcription driven by SP1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IKBIP (also called IKIP) is a p53-inducible transmembrane protein that functions as a negative regulator of NF-κB signaling by physically binding IKKα/β and blocking their association with NEMO, thereby suppressing IKK phosphorylation and downstream inflammatory responses; IKBIP-deficient mice exhibit exacerbated LPS-induced septic shock and DSS-induced colitis [PMID:31826938]. Beyond its immune-regulatory role, IKBIP stabilizes CDK4 by preventing its ubiquitin-mediated proteasomal degradation, promoting G1/S cell-cycle progression in glioblastoma cells [PMID:36244542], and activates AKT and Wnt/β-catenin/EMT signaling to drive proliferation and invasion in glioma and esophageal squamous cell carcinoma [PMID:38914958, PMID:42004064]. IKBIP expression is transcriptionally induced by p53 from a bidirectional promoter shared with APAF1 and by SP1 binding to its own promoter, and its overexpression promotes apoptosis in endothelial cells [PMID:15389287, PMID:42004064].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of IKIP as a p53-inducible proapoptotic gene sharing a bidirectional promoter with APAF1 established it as a stress-responsive effector within the p53 apoptotic network.\",\n      \"evidence\": \"Promoter mapping and X-irradiation of endothelial cells showing p53-dependent upregulation and overexpression-induced apoptosis\",\n      \"pmids\": [\"15389287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous proapoptotic mechanism and relevant protein interactions were not defined\",\n        \"Whether the bidirectional promoter coordinates IKIP and APAF1 functionally was not tested\",\n        \"No loss-of-function data provided\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that IKIP binds IKKα/β and prevents their association with NEMO resolved its molecular mechanism as a negative regulator of NF-κB, explaining its role in restraining inflammatory responses in vivo.\",\n      \"evidence\": \"Reciprocal Co-IP for IKIP–IKKα/β interaction, IKIP-knockout macrophages and mice challenged with LPS, TNF-α, IL-1β, and in vivo septic shock and colitis models\",\n      \"pmids\": [\"31826938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of IKIP–IKK binding and whether IKIP competes for the same NEMO-binding site is unknown\",\n        \"Tissue-specific regulation of IKIP expression in inflammatory contexts was not explored\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that IKBIP directly binds CDK4 and protects it from ubiquitin-mediated degradation revealed a second, NF-κB-independent mechanism through which IKBIP promotes G1/S cell-cycle progression in glioblastoma.\",\n      \"evidence\": \"Co-IP of IKBIP–CDK4, ubiquitination assay, IKBIP knockdown causing G1 arrest, and in vivo xenograft suppression\",\n      \"pmids\": [\"36244542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The E3 ligase whose activity IKBIP antagonizes to stabilize CDK4 was not identified\",\n        \"Whether CDK4 stabilization is linked to or independent of the NF-κB inhibitory function is unresolved\",\n        \"Single-lab finding awaiting independent confirmation\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking IKBIP to THBS1/FAK suppression and AKT activation expanded its oncogenic signaling repertoire and revealed context-dependent effects: IKBIP promotes tumor growth but suppresses invasion in glioblastoma while promoting both proliferation and migration in esophageal carcinoma.\",\n      \"evidence\": \"Transcriptomic profiling plus transwell/wound-healing assays in GBM cells (THBS1/FAK); IKBIP KD/OE with AKT phosphorylation readout and LY-294002 rescue in ESCC cells; both with xenograft models\",\n      \"pmids\": [\"38948026\", \"38914958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding partners mediating AKT activation by IKBIP are unknown\",\n        \"Mechanism by which IKBIP downregulates THBS1 mRNA is not defined\",\n        \"Each pathway was characterized in a single tumor type by a single lab\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of SP1 as a transcriptional driver of IKBIP and of Wnt/β-catenin/EMT as a downstream effector pathway established a transcriptional circuit (SP1→IKBIP→β-catenin stabilization→EMT) operative in glioma.\",\n      \"evidence\": \"ChIP demonstrating SP1 binding to IKBIP promoter, IKBIP KD/OE in glioma lines with Western blot for β-catenin/p-β-catenin/ZEB1/ZEB2/N-cadherin/E-cadherin, invasion assays, in vivo model\",\n      \"pmids\": [\"42004064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How IKBIP reduces β-catenin phosphorylation—whether by direct interaction with destruction complex components—is unknown\",\n        \"Relationship between the Wnt/β-catenin and NF-κB regulatory functions of IKBIP is unexplored\",\n        \"Single-lab finding in glioma cell lines\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying model integrating IKBIP's NF-κB inhibitory, CDK4-stabilizing, AKT-activating, and Wnt/β-catenin-activating functions—and whether these reflect independent or interconnected mechanisms—remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural information exists for IKBIP or its complexes with IKKα/β or CDK4\",\n        \"Tissue-specific and stimulus-specific expression regulation beyond p53 and SP1 is uncharacterized\",\n        \"Whether IKBIP's proapoptotic activity in normal cells and pro-proliferative activity in cancer cells reflect the same or distinct molecular interactions is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CHUK\", \"IKBKB\", \"CDK4\"],\n    \"other_free_text\": []\n  }\n}\n```"}