{"gene":"GABPB1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2023,"finding":"HOMER3 cooperates with platelet-activating factor acetylhydrolase 1b catalytic subunit 3 to upregulate GABPB1 protein levels; GABPB1 in turn acts as a key transcription factor for mitochondrial biogenesis, controlling mitochondrial inner membrane genes and mitochondrial function in non-small cell lung cancer cells. Loss of HOMER3 reduced GABPB1 levels, causing mitochondrial dysfunction and suppressed proliferation and invasion.","method":"shRNA knockdown of HOMER3 in NSCLC cells with in vitro and in vivo functional assays; mechanistic follow-up linking HOMER3–PAFAH1B3 complex to GABPB1 upregulation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, mechanistic link established by KD with defined phenotype, but no direct binding assay or reconstitution for HOMER3–GABPB1 relationship","pmids":["38081871"],"is_preprint":false},{"year":2022,"finding":"GABPB1 knockdown in thyroid cancer cells with mutated TERT promoter led to diminished TERT expression, consistent with GABPB1 (as part of the GABP complex) being required for mutant TERT promoter-driven transcription and telomerase activation. Paradoxically, GABPB1 knockdown increased invasive and metastatic potential in vitro and in a zebrafish xenograft model, indicating GABPB1 also functions as a tumor suppressor in thyroid cancer progression. GABPB1 promoter hypermethylation silences its expression, and DNA methylation inhibitors restored GABPB1 expression.","method":"shRNA knockdown in TC-derived cell lines; invasion assays in vitro; zebrafish xenograft metastasis model; methylation-specific analysis and DNA methylation inhibitor treatment","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal methods (KD + in vivo model + epigenetic intervention), but not independently replicated","pmids":["35326537"],"is_preprint":false},{"year":2022,"finding":"GABPB1 silencing in GBM cells reduced TERT expression, GSH levels (via decreased pentose phosphate pathway flux and glucose-6-phosphate dehydrogenase activity and NADPH), and lactate production (via reduced glycolytic flux and decreased GLUT1, monocarboxylate transporters, and lactate dehydrogenase A expression/activity), placing GABPB1 upstream of TERT and metabolic reprogramming in GBM.","method":"shRNA silencing of GABPB1 in GBM cells; 1H-MRS and hyperpolarized 13C-MRS metabolic flux analysis; enzymatic activity assays; in vivo tumor models","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MRS, enzymatic assays, in vivo), single lab","pmids":["35460557"],"is_preprint":false},{"year":2023,"finding":"GABPB1 silencing in GBM reduced flux through the pentose phosphate pathway, as measured by reduced hyperpolarized 6-phosphogluconolactone production from hyperpolarized δ-[1-13C]gluconolactone, linking GABPB1 to PPP regulation downstream of mutant TERT promoter activation.","method":"Stable shRNA lines and doxycycline-inducible shRNA; hyperpolarized 13C MRS on live cells and in vivo tumors","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal model systems (stable and inducible KD), in vivo and in vitro MRS, single lab","pmids":["36997627"],"is_preprint":false},{"year":2019,"finding":"GABPB1 protein transcriptionally regulates the PRDX5 (Peroxiredoxin-5) peroxidase gene; downregulation of GABPB1 protein (mediated by the antisense lncRNA GABPB1-AS1 blocking its translation) suppresses PRDX5 expression, reducing cellular antioxidant capacity and enabling erastin-induced ferroptosis in HepG2 cells.","method":"Overexpression and knockdown experiments in HepG2 cells; Western blot for GABPB1 protein; measurement of PRDX5 mRNA and protein; ferroptosis cell viability assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, functional link between GABPB1 and PRDX5 demonstrated by KD/OE with defined readout; mechanism of lncRNA-mediated translational blockade of GABPB1 inferred but not fully reconstituted","pmids":["31700067"],"is_preprint":false},{"year":2024,"finding":"BAIAP2L2 physically interacts with GABPB1, inhibiting its ubiquitin-mediated proteasomal degradation and promoting its nuclear translocation. GABPB1 in turn regulates reactive oxygen species (ROS) levels in hepatocellular carcinoma cells, with the NFκB1–BAIAP2L2–GABPB1 axis promoting cancer properties and reducing sensitivity to lenvatinib.","method":"Co-immunoprecipitation of BAIAP2L2 and GABPB1; ubiquitination assays; subcellular fractionation/nuclear translocation assays; ROS measurements; NFκB1 promoter-binding assays","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for protein interaction, ubiquitination assay, nuclear translocation assay, ROS functional readout; single lab","pmids":["39496939"],"is_preprint":false},{"year":2023,"finding":"Gabpb1 knockout in mice (by CRISPR/Cas9) caused early preimplantation developmental arrest with increased apoptosis. In nuclear-transfer (cloned) embryos, Gabpb1 was found to be silenced due to H3K9me3-mediated repression (partly through suppression of Klf16), and supplementing Gabpb1 mRNA supported efficient preimplantation development of cloned embryos.","method":"CRISPR/Cas9 knockout in mouse embryos; siRNA screening of H3K9me3-repressed genes; mRNA supplementation rescue experiments; apoptosis assays","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR KO with specific developmental phenotype, siRNA screen, mRNA rescue, and epigenetic mechanism, multiple orthogonal approaches in a single rigorous study","pmids":["37640449"],"is_preprint":false},{"year":2024,"finding":"shRNA-mediated suppression of GABPB1 in A549 and H1299 NSCLC cells decreased cell growth, colony formation, and increased apoptosis rate, establishing a cancer-promoting role for GABPB1 in NSCLC.","method":"shRNA knockdown; cell proliferation assays; colony formation assay; apoptosis analysis","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell-based approach, no defined molecular pathway for GABPB1 action in NSCLC","pmids":["38466508"],"is_preprint":false}],"current_model":"GABPB1 (GABPβ1) is the beta subunit of the GA-binding protein (GABP/NRF2) transcription factor complex; it is required for mutant TERT promoter-driven TERT expression and telomerase activation, regulates mitochondrial biogenesis and inner membrane gene expression, controls the pentose phosphate pathway and glycolytic flux (affecting NADPH, GSH, and lactate), transcriptionally activates antioxidant genes such as PRDX5, and its protein stability is regulated by BAIAP2L2-mediated inhibition of ubiquitin-dependent degradation and subsequent nuclear translocation; loss of GABPB1 in mouse embryos causes preimplantation apoptotic arrest, establishing it as an essential developmental gene."},"narrative":{"mechanistic_narrative":"GABPB1 is a transcription factor subunit that couples promoter-driven gene expression to telomerase activation, mitochondrial biogenesis, and redox/metabolic control [PMID:35460557, PMID:38081871, PMID:39496939]. In cancers carrying mutant TERT promoters, GABPB1 is required for TERT expression and telomerase activation, and through this axis it drives metabolic reprogramming — sustaining pentose phosphate pathway flux (glucose-6-phosphate dehydrogenase activity, NADPH, and GSH) and glycolytic output (GLUT1, monocarboxylate transporters, and lactate dehydrogenase A) [PMID:35460557, PMID:36997627]. GABPB1 also acts as a transcriptional regulator of mitochondrial inner-membrane genes, controlling mitochondrial function and proliferation [PMID:38081871], and transcriptionally activates the antioxidant gene PRDX5 to set cellular antioxidant capacity and resistance to ferroptosis [PMID:31700067]. Its abundance and nuclear localization are post-translationally controlled: BAIAP2L2 binds GABPB1 and blocks its ubiquitin-dependent proteasomal degradation while promoting nuclear translocation, an axis that modulates ROS levels [PMID:39496939]. GABPB1 is essential for development: its loss in mouse embryos causes preimplantation apoptotic arrest [PMID:37640449]. Its functional output in cancer is context-dependent, behaving as a tumor-promoting factor in lung cancer yet restraining invasion and metastasis in thyroid cancer where its expression is silenced by promoter hypermethylation [PMID:38466508, PMID:35326537].","teleology":[{"year":2019,"claim":"Established a direct transcriptional target of GABPB1 in redox homeostasis, showing it activates the antioxidant peroxidase PRDX5 to govern ferroptosis sensitivity.","evidence":"knockdown/overexpression in HepG2 cells with PRDX5 mRNA/protein and ferroptosis viability readouts","pmids":["31700067"],"confidence":"Medium","gaps":["lncRNA-mediated translational blockade of GABPB1 inferred but not reconstituted","direct binding of GABPB1 to the PRDX5 promoter not demonstrated"]},{"year":2022,"claim":"Placed GABPB1 upstream of mutant TERT promoter activity and metabolic reprogramming, linking the transcription factor to telomerase, PPP/NADPH/GSH, and glycolytic lactate output.","evidence":"shRNA silencing in glioblastoma cells with MRS flux analysis, enzymatic assays, and in vivo tumor models","pmids":["35460557"],"confidence":"Medium","gaps":["whether metabolic effects are fully mediated through TERT versus direct metabolic gene regulation not separated","single lab"]},{"year":2022,"claim":"Revealed context-dependent and dual roles in cancer: required for mutant-TERT transcription yet acting as an epigenetically silenced tumor suppressor restraining thyroid cancer invasion.","evidence":"shRNA knockdown, invasion assays, zebrafish xenograft metastasis model, and DNA methylation inhibitor treatment in thyroid cancer cells","pmids":["35326537"],"confidence":"Medium","gaps":["mechanism reconciling reduced TERT with increased invasion unresolved","not independently replicated"]},{"year":2023,"claim":"Confirmed GABPB1 control of pentose phosphate pathway flux as a downstream consequence of mutant TERT promoter activation.","evidence":"stable and doxycycline-inducible shRNA lines with hyperpolarized 13C MRS in cells and in vivo tumors","pmids":["36997627"],"confidence":"Medium","gaps":["direct transcriptional targets in the PPP not identified","single lab"]},{"year":2023,"claim":"Identified GABPB1 as a key driver of mitochondrial biogenesis controlled upstream by a HOMER3-PAFAH1B3 complex regulating its protein levels.","evidence":"shRNA knockdown of HOMER3 in NSCLC cells with in vitro/in vivo functional assays and mechanistic follow-up","pmids":["38081871"],"confidence":"Medium","gaps":["no direct binding assay for the HOMER3-GABPB1 relationship","specific mitochondrial inner-membrane target genes not enumerated"]},{"year":2023,"claim":"Demonstrated GABPB1 is an essential developmental gene and an H3K9me3-repressed barrier to embryo reprogramming, whose mRNA supplementation rescues cloned embryo development.","evidence":"CRISPR/Cas9 knockout in mouse embryos, siRNA screen of H3K9me3-repressed genes, and mRNA supplementation rescue with apoptosis assays","pmids":["37640449"],"confidence":"High","gaps":["downstream effector genes mediating the apoptotic arrest not defined","relationship to its transcriptional targets in development unmapped"]},{"year":2024,"claim":"Defined post-translational control of GABPB1, showing BAIAP2L2 stabilizes it against ubiquitin-dependent degradation and drives nuclear translocation within an NFkB1-BAIAP2L2-GABPB1 axis regulating ROS and drug resistance.","evidence":"Co-IP, ubiquitination assays, subcellular fractionation, ROS measurements, and promoter-binding assays in hepatocellular carcinoma cells","pmids":["39496939"],"confidence":"Medium","gaps":["E3 ligase mediating GABPB1 ubiquitination not identified","single Co-IP-based interaction without reciprocal structural validation"]},{"year":2024,"claim":"Reinforced a cancer-promoting role in lung cancer at the cellular level.","evidence":"shRNA knockdown with proliferation, colony formation, and apoptosis assays in A549 and H1299 NSCLC cells","pmids":["38466508"],"confidence":"Low","gaps":["no defined molecular pathway for GABPB1 action in this context","single cell-based approach, single lab"]},{"year":null,"claim":"The direct genome-wide transcriptional targets of GABPB1 and the structural basis of its assembly into the GABP complex remain uncharacterized in this corpus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no genome-wide binding map of GABPB1 in the timeline","molecular partner within the GABP complex (the alpha subunit) not characterized here","mechanistic basis for tumor-suppressor versus oncogenic switch unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3]}],"complexes":["GABP/NRF2 transcription factor complex"],"partners":["BAIAP2L2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q06547","full_name":"GA-binding protein subunit beta-1","aliases":["GABP subunit beta-2","GABPB-2","Nuclear respiratory factor 2","Transcription factor E4TF1-47","Transcription factor E4TF1-53"],"length_aa":395,"mass_kda":42.5,"function":"Transcription factor capable of interacting with purine rich repeats (GA repeats) (PubMed:10675337, PubMed:8441384, PubMed:8816484). Acts as a master regulator of nuclear-encoded mitochondrial genes (By similarity) (Microbial infection) Necessary for the expression of the Adenovirus E4 gene","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q06547/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GABPB1","classification":"Not Classified","n_dependent_lines":606,"n_total_lines":1208,"dependency_fraction":0.5016556291390728},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GABPB1","total_profiled":1310},"omim":[{"mim_id":"621284","title":"GA-BINDING PROTEIN TRANSCRIPTION FACTOR, SUBUNIT BETA-2; GABPB2","url":"https://www.omim.org/entry/621284"},{"mim_id":"620845","title":"TRANSMEMBRANE 4 L6 FAMILY, MEMBER 19; TM4SF19","url":"https://www.omim.org/entry/620845"},{"mim_id":"600610","title":"GA-BINDING PROTEIN TRANSCRIPTION FACTOR, SUBUNIT BETA-1; GABPB1","url":"https://www.omim.org/entry/600610"},{"mim_id":"600609","title":"GA-BINDING PROTEIN TRANSCRIPTION FACTOR, ALPHA SUBUNIT; GABPA","url":"https://www.omim.org/entry/600609"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytoplasmic bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GABPB1"},"hgnc":{"alias_symbol":["E4TF1-47","GABPB"],"prev_symbol":["GABPB2"]},"alphafold":{"accession":"Q06547","domains":[{"cath_id":"1.25.40.20","chopping":"2-164","consensus_level":"high","plddt":94.5498,"start":2,"end":164}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06547","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q06547-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q06547-F1-predicted_aligned_error_v6.png","plddt_mean":68.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GABPB1","jax_strain_url":"https://www.jax.org/strain/search?query=GABPB1"},"sequence":{"accession":"Q06547","fasta_url":"https://rest.uniprot.org/uniprotkb/Q06547.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q06547/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06547"}},"corpus_meta":[{"pmid":"31700067","id":"PMC_31700067","title":"LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31700067","citation_count":197,"is_preprint":false},{"pmid":"32844486","id":"PMC_32844486","title":"HPV16 E6 oncoprotein-induced upregulation of lncRNA GABPB1-AS1 facilitates cervical cancer progression by regulating miR-519e-5p/Notch2 axis.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32844486","citation_count":21,"is_preprint":false},{"pmid":"35460557","id":"PMC_35460557","title":"Imaging biomarkers of TERT or GABPB1 silencing in TERT-positive glioblastoma.","date":"2022","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35460557","citation_count":17,"is_preprint":false},{"pmid":"38081871","id":"PMC_38081871","title":"HOMER3 promotes non-small cell lung cancer growth and metastasis primarily through GABPB1-mediated mitochondrial metabolism.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38081871","citation_count":17,"is_preprint":false},{"pmid":"34276213","id":"PMC_34276213","title":"Long Non-Coding RNA GABPB1-AS1 Augments Malignancy of Glioma Cells by Sequestering MicroRNA-330 and Reinforcing the ZNF367/Cell Cycle Signaling Pathway.","date":"2021","source":"Neuropsychiatric disease and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/34276213","citation_count":16,"is_preprint":false},{"pmid":"37121382","id":"PMC_37121382","title":"LncRNA FTX Inhibits Ferroptosis of Hippocampal Neurons Displaying Epileptiform Discharges In vitro Through the miR-142-5p/GABPB1 Axis.","date":"2023","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37121382","citation_count":10,"is_preprint":false},{"pmid":"23486860","id":"PMC_23486860","title":"The GABPB1 gene A/G polymorphism in Polish rowers.","date":"2012","source":"Journal of human kinetics","url":"https://pubmed.ncbi.nlm.nih.gov/23486860","citation_count":9,"is_preprint":false},{"pmid":"35326537","id":"PMC_35326537","title":"Downregulation and Hypermethylation of GABPB1 Is Associated with Aggressive Thyroid Cancer Features.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/35326537","citation_count":8,"is_preprint":false},{"pmid":"35342417","id":"PMC_35342417","title":"GABPB1-AS1 Promotes the Development of Osteosarcoma by Targeting SP1 and Activating the Wnt/β-Catenin Pathway.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35342417","citation_count":8,"is_preprint":false},{"pmid":"36756790","id":"PMC_36756790","title":"LncRNA GABPB1-IT1 inhibits the tumorigenesis of renal cancer via the miR-21/PTEN axis.","date":"2023","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/36756790","citation_count":8,"is_preprint":false},{"pmid":"37640449","id":"PMC_37640449","title":"Incomplete activation of Alyref and Gabpb1 leads to preimplantation arrest in cloned mouse embryos.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/37640449","citation_count":7,"is_preprint":false},{"pmid":"37304650","id":"PMC_37304650","title":"GABPB1-AS1 acts as a tumor suppressor and inhibits non-small cell lung cancer progression by targeting miRNA-566/F-box protein 47.","date":"2022","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/37304650","citation_count":7,"is_preprint":false},{"pmid":"36997627","id":"PMC_36997627","title":"Hyperpolarized δ-[1- 13C]gluconolactone imaging visualizes response to TERT or GABPB1 targeting therapy for glioblastoma.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36997627","citation_count":5,"is_preprint":false},{"pmid":"30904536","id":"PMC_30904536","title":"Association of SNP rs7181866 in the nuclear respiratory factor-2 beta subunit encoding GABPB1 gene with obesity and type-2 diabetes mellitus in South Indian population.","date":"2019","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/30904536","citation_count":5,"is_preprint":false},{"pmid":"33346691","id":"PMC_33346691","title":"Association study of performance-related polymorphisms in Brazilian combat-sport athletes highlights variants in the GABPB1 gene.","date":"2020","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33346691","citation_count":4,"is_preprint":false},{"pmid":"38466508","id":"PMC_38466508","title":"GABPB1 plays a cancer-promoting role in non-small cell lung cancer.","date":"2024","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38466508","citation_count":3,"is_preprint":false},{"pmid":"40972828","id":"PMC_40972828","title":"Isoflurane aggravates cognitive deficits in aged rats via lncRNA GABPB1-AS1/miR-361-3p-mediated NLRP3 inflammasome activation.","date":"2025","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40972828","citation_count":2,"is_preprint":false},{"pmid":"39004908","id":"PMC_39004908","title":"LncRNA GABPB1-AS1 is a potential target for the diagnosis of prostate cancer.","date":"2024","source":"Nucleosides, nucleotides & nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/39004908","citation_count":2,"is_preprint":false},{"pmid":"39496939","id":"PMC_39496939","title":"BAIAP2L2 promotes the malignancy of hepatocellular carcinoma via GABPB1-mediated reactive oxygen species imbalance.","date":"2024","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39496939","citation_count":2,"is_preprint":false},{"pmid":"39114718","id":"PMC_39114718","title":"Silencing lncRNA GABPB1-AS1 alleviates cerebral ischemia reperfusion injury through the miR-641/NUCKS1 axis.","date":"2024","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/39114718","citation_count":1,"is_preprint":false},{"pmid":"33664823","id":"PMC_33664823","title":"lncRNA GABPB1 intronic transcript 1 upregulates pigment epithelium-derived factor via miR-93 to suppress cell proliferation in hepatocellular carcinoma.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/33664823","citation_count":1,"is_preprint":false},{"pmid":"38824919","id":"PMC_38824919","title":"LncRNA GABPB1-IT1 Is Upregulated in Ischemia-Induced Acute Kidney Injury and Downregulates miR-204-5p to Promote Hypoxia-Induced Human Renal Proximal Tubular Epithelial Cell Apoptosis.","date":"2024","source":"Kidney & blood pressure research","url":"https://pubmed.ncbi.nlm.nih.gov/38824919","citation_count":0,"is_preprint":false},{"pmid":"35343317","id":"PMC_35343317","title":"Association of single nucleotide polymorphisms in the nuclear respiratory factor-2 beta subunit-encoding the GABPB1 gene within the occupational environment.","date":"2022","source":"Toxicology and industrial health","url":"https://pubmed.ncbi.nlm.nih.gov/35343317","citation_count":0,"is_preprint":false},{"pmid":"40388723","id":"PMC_40388723","title":"Genetic biomarkers of skiers from the Oğlağo Tribe in Muş Province, Turkey: An analysis of ACTN3, VEGF-A, and GABPB1 polymorphisms.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40388723","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14922,"output_tokens":2347,"usd":0.039986,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9446,"output_tokens":2784,"usd":0.058415,"stage2_stop_reason":"end_turn"},"total_usd":0.098401,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"HOMER3 cooperates with platelet-activating factor acetylhydrolase 1b catalytic subunit 3 to upregulate GABPB1 protein levels; GABPB1 in turn acts as a key transcription factor for mitochondrial biogenesis, controlling mitochondrial inner membrane genes and mitochondrial function in non-small cell lung cancer cells. Loss of HOMER3 reduced GABPB1 levels, causing mitochondrial dysfunction and suppressed proliferation and invasion.\",\n      \"method\": \"shRNA knockdown of HOMER3 in NSCLC cells with in vitro and in vivo functional assays; mechanistic follow-up linking HOMER3–PAFAH1B3 complex to GABPB1 upregulation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, mechanistic link established by KD with defined phenotype, but no direct binding assay or reconstitution for HOMER3–GABPB1 relationship\",\n      \"pmids\": [\"38081871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GABPB1 knockdown in thyroid cancer cells with mutated TERT promoter led to diminished TERT expression, consistent with GABPB1 (as part of the GABP complex) being required for mutant TERT promoter-driven transcription and telomerase activation. Paradoxically, GABPB1 knockdown increased invasive and metastatic potential in vitro and in a zebrafish xenograft model, indicating GABPB1 also functions as a tumor suppressor in thyroid cancer progression. GABPB1 promoter hypermethylation silences its expression, and DNA methylation inhibitors restored GABPB1 expression.\",\n      \"method\": \"shRNA knockdown in TC-derived cell lines; invasion assays in vitro; zebrafish xenograft metastasis model; methylation-specific analysis and DNA methylation inhibitor treatment\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal methods (KD + in vivo model + epigenetic intervention), but not independently replicated\",\n      \"pmids\": [\"35326537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GABPB1 silencing in GBM cells reduced TERT expression, GSH levels (via decreased pentose phosphate pathway flux and glucose-6-phosphate dehydrogenase activity and NADPH), and lactate production (via reduced glycolytic flux and decreased GLUT1, monocarboxylate transporters, and lactate dehydrogenase A expression/activity), placing GABPB1 upstream of TERT and metabolic reprogramming in GBM.\",\n      \"method\": \"shRNA silencing of GABPB1 in GBM cells; 1H-MRS and hyperpolarized 13C-MRS metabolic flux analysis; enzymatic activity assays; in vivo tumor models\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MRS, enzymatic assays, in vivo), single lab\",\n      \"pmids\": [\"35460557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GABPB1 silencing in GBM reduced flux through the pentose phosphate pathway, as measured by reduced hyperpolarized 6-phosphogluconolactone production from hyperpolarized δ-[1-13C]gluconolactone, linking GABPB1 to PPP regulation downstream of mutant TERT promoter activation.\",\n      \"method\": \"Stable shRNA lines and doxycycline-inducible shRNA; hyperpolarized 13C MRS on live cells and in vivo tumors\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal model systems (stable and inducible KD), in vivo and in vitro MRS, single lab\",\n      \"pmids\": [\"36997627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GABPB1 protein transcriptionally regulates the PRDX5 (Peroxiredoxin-5) peroxidase gene; downregulation of GABPB1 protein (mediated by the antisense lncRNA GABPB1-AS1 blocking its translation) suppresses PRDX5 expression, reducing cellular antioxidant capacity and enabling erastin-induced ferroptosis in HepG2 cells.\",\n      \"method\": \"Overexpression and knockdown experiments in HepG2 cells; Western blot for GABPB1 protein; measurement of PRDX5 mRNA and protein; ferroptosis cell viability assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, functional link between GABPB1 and PRDX5 demonstrated by KD/OE with defined readout; mechanism of lncRNA-mediated translational blockade of GABPB1 inferred but not fully reconstituted\",\n      \"pmids\": [\"31700067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAIAP2L2 physically interacts with GABPB1, inhibiting its ubiquitin-mediated proteasomal degradation and promoting its nuclear translocation. GABPB1 in turn regulates reactive oxygen species (ROS) levels in hepatocellular carcinoma cells, with the NFκB1–BAIAP2L2–GABPB1 axis promoting cancer properties and reducing sensitivity to lenvatinib.\",\n      \"method\": \"Co-immunoprecipitation of BAIAP2L2 and GABPB1; ubiquitination assays; subcellular fractionation/nuclear translocation assays; ROS measurements; NFκB1 promoter-binding assays\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for protein interaction, ubiquitination assay, nuclear translocation assay, ROS functional readout; single lab\",\n      \"pmids\": [\"39496939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Gabpb1 knockout in mice (by CRISPR/Cas9) caused early preimplantation developmental arrest with increased apoptosis. In nuclear-transfer (cloned) embryos, Gabpb1 was found to be silenced due to H3K9me3-mediated repression (partly through suppression of Klf16), and supplementing Gabpb1 mRNA supported efficient preimplantation development of cloned embryos.\",\n      \"method\": \"CRISPR/Cas9 knockout in mouse embryos; siRNA screening of H3K9me3-repressed genes; mRNA supplementation rescue experiments; apoptosis assays\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR KO with specific developmental phenotype, siRNA screen, mRNA rescue, and epigenetic mechanism, multiple orthogonal approaches in a single rigorous study\",\n      \"pmids\": [\"37640449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"shRNA-mediated suppression of GABPB1 in A549 and H1299 NSCLC cells decreased cell growth, colony formation, and increased apoptosis rate, establishing a cancer-promoting role for GABPB1 in NSCLC.\",\n      \"method\": \"shRNA knockdown; cell proliferation assays; colony formation assay; apoptosis analysis\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell-based approach, no defined molecular pathway for GABPB1 action in NSCLC\",\n      \"pmids\": [\"38466508\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GABPB1 (GABPβ1) is the beta subunit of the GA-binding protein (GABP/NRF2) transcription factor complex; it is required for mutant TERT promoter-driven TERT expression and telomerase activation, regulates mitochondrial biogenesis and inner membrane gene expression, controls the pentose phosphate pathway and glycolytic flux (affecting NADPH, GSH, and lactate), transcriptionally activates antioxidant genes such as PRDX5, and its protein stability is regulated by BAIAP2L2-mediated inhibition of ubiquitin-dependent degradation and subsequent nuclear translocation; loss of GABPB1 in mouse embryos causes preimplantation apoptotic arrest, establishing it as an essential developmental gene.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GABPB1 is a transcription factor subunit that couples promoter-driven gene expression to telomerase activation, mitochondrial biogenesis, and redox/metabolic control [#2, #0, #5]. In cancers carrying mutant TERT promoters, GABPB1 is required for TERT expression and telomerase activation, and through this axis it drives metabolic reprogramming — sustaining pentose phosphate pathway flux (glucose-6-phosphate dehydrogenase activity, NADPH, and GSH) and glycolytic output (GLUT1, monocarboxylate transporters, and lactate dehydrogenase A) [#2, #3]. GABPB1 also acts as a transcriptional regulator of mitochondrial inner-membrane genes, controlling mitochondrial function and proliferation [#0], and transcriptionally activates the antioxidant gene PRDX5 to set cellular antioxidant capacity and resistance to ferroptosis [#4]. Its abundance and nuclear localization are post-translationally controlled: BAIAP2L2 binds GABPB1 and blocks its ubiquitin-dependent proteasomal degradation while promoting nuclear translocation, an axis that modulates ROS levels [#5]. GABPB1 is essential for development: its loss in mouse embryos causes preimplantation apoptotic arrest [#6]. Its functional output in cancer is context-dependent, behaving as a tumor-promoting factor in lung cancer yet restraining invasion and metastasis in thyroid cancer where its expression is silenced by promoter hypermethylation [#7, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a direct transcriptional target of GABPB1 in redox homeostasis, showing it activates the antioxidant peroxidase PRDX5 to govern ferroptosis sensitivity.\",\n      \"evidence\": \"knockdown/overexpression in HepG2 cells with PRDX5 mRNA/protein and ferroptosis viability readouts\",\n      \"pmids\": [\"31700067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"lncRNA-mediated translational blockade of GABPB1 inferred but not reconstituted\", \"direct binding of GABPB1 to the PRDX5 promoter not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed GABPB1 upstream of mutant TERT promoter activity and metabolic reprogramming, linking the transcription factor to telomerase, PPP/NADPH/GSH, and glycolytic lactate output.\",\n      \"evidence\": \"shRNA silencing in glioblastoma cells with MRS flux analysis, enzymatic assays, and in vivo tumor models\",\n      \"pmids\": [\"35460557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether metabolic effects are fully mediated through TERT versus direct metabolic gene regulation not separated\", \"single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed context-dependent and dual roles in cancer: required for mutant-TERT transcription yet acting as an epigenetically silenced tumor suppressor restraining thyroid cancer invasion.\",\n      \"evidence\": \"shRNA knockdown, invasion assays, zebrafish xenograft metastasis model, and DNA methylation inhibitor treatment in thyroid cancer cells\",\n      \"pmids\": [\"35326537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism reconciling reduced TERT with increased invasion unresolved\", \"not independently replicated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed GABPB1 control of pentose phosphate pathway flux as a downstream consequence of mutant TERT promoter activation.\",\n      \"evidence\": \"stable and doxycycline-inducible shRNA lines with hyperpolarized 13C MRS in cells and in vivo tumors\",\n      \"pmids\": [\"36997627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct transcriptional targets in the PPP not identified\", \"single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified GABPB1 as a key driver of mitochondrial biogenesis controlled upstream by a HOMER3-PAFAH1B3 complex regulating its protein levels.\",\n      \"evidence\": \"shRNA knockdown of HOMER3 in NSCLC cells with in vitro/in vivo functional assays and mechanistic follow-up\",\n      \"pmids\": [\"38081871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no direct binding assay for the HOMER3-GABPB1 relationship\", \"specific mitochondrial inner-membrane target genes not enumerated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated GABPB1 is an essential developmental gene and an H3K9me3-repressed barrier to embryo reprogramming, whose mRNA supplementation rescues cloned embryo development.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in mouse embryos, siRNA screen of H3K9me3-repressed genes, and mRNA supplementation rescue with apoptosis assays\",\n      \"pmids\": [\"37640449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"downstream effector genes mediating the apoptotic arrest not defined\", \"relationship to its transcriptional targets in development unmapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined post-translational control of GABPB1, showing BAIAP2L2 stabilizes it against ubiquitin-dependent degradation and drives nuclear translocation within an NFkB1-BAIAP2L2-GABPB1 axis regulating ROS and drug resistance.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, subcellular fractionation, ROS measurements, and promoter-binding assays in hepatocellular carcinoma cells\",\n      \"pmids\": [\"39496939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating GABPB1 ubiquitination not identified\", \"single Co-IP-based interaction without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reinforced a cancer-promoting role in lung cancer at the cellular level.\",\n      \"evidence\": \"shRNA knockdown with proliferation, colony formation, and apoptosis assays in A549 and H1299 NSCLC cells\",\n      \"pmids\": [\"38466508\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no defined molecular pathway for GABPB1 action in this context\", \"single cell-based approach, single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct genome-wide transcriptional targets of GABPB1 and the structural basis of its assembly into the GABP complex remain uncharacterized in this corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no genome-wide binding map of GABPB1 in the timeline\", \"molecular partner within the GABP complex (the alpha subunit) not characterized here\", \"mechanistic basis for tumor-suppressor versus oncogenic switch unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\"GABP/NRF2 transcription factor complex\"],\n    \"partners\": [\"BAIAP2L2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}