{"gene":"EIF1AX","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1997,"finding":"EIF1A (eIF-4C) is essential for transfer of the initiator Met-tRNAf (as Met-tRNAf·eIF2·GTP ternary complex) to 40S ribosomal subunits in the absence of mRNA to form the 40S preinitiation complex; it acts catalytically in this reaction and is absent from the resulting complex, indicating it does not stabilize Met-tRNAf binding. EIF1A plays no role in the subunit joining reaction or in generating ribosomal subunits from 80S ribosomes.","method":"In vitro translation initiation assay with purified mammalian components; functional reconstitution with eIF5-dependent 80S complex formation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro reconstitution assay with purified factors, catalytic activity demonstrated, negative results explicitly stated; single lab but multiple orthogonal functional readouts","pmids":["9065455"],"is_preprint":false},{"year":1980,"finding":"eIF-4C (EIF1AX) stimulates initiation complex formation by acting accessory to eIF-3 in dissociating native 80S ribosomes into subunits, preventing premature 40S–60S association, and dissociating inactive 40S dimers into active monomers.","method":"In vitro ribosome dissociation and initiation complex formation assay with native and washed ribosomal subunits","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical reconstitution, single lab, single study; foundational but not independently replicated within this corpus","pmids":["6901506"],"is_preprint":false},{"year":1994,"finding":"EIF1AX (eIF-4C) protein has a distinctive dipole structure: basic N-terminus and acidic C-terminus, conserved between mammalian and wheat germ proteins (68% identity), suggesting the polarity enables interaction with ribosomes (via rRNA) and other translation initiation factors. Wheat germ and rabbit eIF-4C are functionally interchangeable in heterologous in vitro assays.","method":"Chemical peptide sequencing, cDNA cloning, PCR, heterologous in vitro translation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — sequence determination plus functional cross-species reconstitution; single lab but multiple methods","pmids":["8106356"],"is_preprint":false},{"year":1995,"finding":"EIF1AX (eIF-1A) is an RNA-binding protein, as demonstrated by Northwestern blotting with mRNA fragments. Its abundance in HeLa cells is 0.2 molecules per ribosome, and overexpression of eIF-1A fails to stimulate translation rates in transiently transfected COS-1 cells, indicating it is not limiting for protein synthesis.","method":"Northwestern blotting; Western immunoblotting; polysome profile analysis; transient transfection with overexpression; E. coli overexpression and purification","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA binding, abundance quantification, overexpression functional test), single lab","pmids":["7890705"],"is_preprint":false},{"year":1993,"finding":"Wheat germ eIF-4C (EIF1AX ortholog) functions as a single polypeptide and is not involved in mRNA binding to 40S ribosomal subunits, as concentrations required for translation are similar across different mRNA species whereas eIF-4A and eIF-4F show mRNA-specific differences.","method":"Purification from wheat germ, gel filtration, in vitro translation assay with satellite tobacco necrosis virus RNA, alfalfa mosaic virus RNA 4, and barley alpha-amylase mRNA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution assay, plant ortholog, single lab; negative finding for mRNA binding role is explicit","pmids":["8227048"],"is_preprint":false},{"year":2018,"finding":"The C-terminal EIF1AX-A113splice mutation (most prevalent in advanced thyroid cancer) stabilizes the 43S preinitiation complex (PIC) and induces ATF4, which suppresses EIF2α phosphorylation, enabling a general increase in protein synthesis. Co-occurring RAS mutations stabilize c-MYC (augmented by EIF1AX-A113splice). ATF4 and c-MYC together induce amino acid transporters and sensitize mTOR to amino acid supply, cooperating with RAS to drive tumorigenesis.","method":"Isogenic cell lines expressing mutant EIF1AX, mouse tumorigenesis models, ribosome/PIC assembly assays, phosphorylation assays (EIF2α), gene expression analysis, mTOR sensitivity assays, pharmacological inhibition (MEK, BRD4, mTOR inhibitors)","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal mechanistic methods (PIC stabilization, phosphorylation assay, mouse model, isogenic cell lines, inhibitor studies) in a single rigorous study; mechanistic pathway fully delineated","pmids":["30305285"],"is_preprint":false},{"year":2017,"finding":"Missense EIF1AX mutations clustered at the N-terminus (region associated with translational initiation fidelity) co-occur significantly with NRAS mutations in low-grade serous ovarian carcinoma; coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells.","method":"Exome and whole genome sequencing; coexpression of mutant proteins in LGSC cell lines; proliferation and clonogenic survival assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assays with defined mutant constructs plus genomic co-occurrence analysis; single lab","pmids":["28646021"],"is_preprint":false},{"year":2014,"finding":"EIF1AX interacts with 14-3-3γ and RPS7 in bovine mammary epithelial cells, forming a molecular network that regulates protein translation and cell proliferation; these interactions were confirmed by co-immunoprecipitation, MALDI-TOF/TOF peptide mass fingerprinting, colocalization, and FRET analysis. Overexpression of EIF1AX promotes protein translation and cell proliferation.","method":"Co-immunoprecipitation, MALDI-TOF/TOF mass spectrometry, FRET, colocalization, overexpression and inhibition experiments","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by multiple orthogonal methods (Co-IP, MS, FRET, colocalization), single lab; bovine cell model","pmids":["25281768"],"is_preprint":false},{"year":2020,"finding":"EIF1AX promotes breast cancer cell proliferation by driving G1/S cell cycle transition through transcriptional repression of p21 (CDKN1A) in a p53-independent manner, as demonstrated by ChIP and luciferase reporter assays.","method":"Colony formation and xenograft assays, RNA-Seq, flow cytometry (cell cycle), ChIP assay, luciferase reporter assay, shRNA knockdown","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assays directly demonstrate transcriptional repression of p21; multiple methods in single lab","pmids":["32926483"],"is_preprint":false},{"year":2022,"finding":"Cytoplasmic localization of EIF1AX (mediated by exportin 1/XPO1) promotes tumor cell migration, invasion, and epithelial-mesenchymal transition in endometrial carcinoma; nuclear import of EIF1AX (via SV40NLS) suppresses these phenotypes. XPO1-dependent nuclear export of EIF1AX was confirmed by leptomycin B treatment and mutation of the EIF1AX nuclear export sequence.","method":"shRNA knockdown, SV40NLS-forced nuclear import, leptomycin B treatment, nuclear export sequence mutagenesis, migration/invasion assays, in vivo lung metastasis model, subcellular fractionation/immunofluorescence","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (pharmacological, genetic, mutagenesis) linking XPO1-mediated cytoplasmic localization to functional cancer phenotypes; single lab","pmids":["36589683"],"is_preprint":false},{"year":2022,"finding":"EIF1AX interacts with EIF1AX mRNA and PCBP1 to promote EIF1AX mRNA degradation; additionally, EIF1AX promotes c-Myc translation through the internal ribosome entry site (IRES) pathway via interaction with YBX-1, forming a feed-forward loop that sustains EC cell proliferation.","method":"RNA immunoprecipitation, co-immunoprecipitation, in vitro and in vivo proliferation/apoptosis assays, RNA sequencing; the paper primarily describes the lncRNA EIF1AX-AS1 but mechanistically links it to EIF1AX protein function","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic findings about EIF1AX protein (IRES-mediated c-Myc translation, YBX-1 interaction) are secondary results in a paper primarily focused on the lncRNA; single lab, single methods per finding","pmids":["35080085"],"is_preprint":false},{"year":2025,"finding":"EIF1AX undergoes nucleolar translocation upon treatment with 2,5-MeC in endometrial cancer cells; this translocation promotes cellular senescence by recruiting DDX21 to form nucleolar aggregates that suppress rDNA transcription, as shown by co-immunoprecipitation mass spectrometry and CUT&TAG sequencing.","method":"Compound library screen, CRISPR library screen, co-immunoprecipitation mass spectrometry, CUT&TAG sequencing, RNA sequencing, antibody array, in vivo tumor growth assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP MS identifies DDX21 as binding partner; CUT&TAG links EIF1AX nucleolar aggregates to rDNA transcription suppression; multiple orthogonal methods; single lab","pmids":["41405406"],"is_preprint":false},{"year":1996,"finding":"eIF-4C (EIF1AX) mRNA is transiently increased at the 2-cell stage of mouse preimplantation embryo development (zygotic gene activation); this increase requires the first round of DNA replication (blocked by aphidicolin) and is reversed by a mechanism requiring chromatin remodeling via histone deacetylation (blocked by trapoxin), but does not require cytokinesis or mitosis.","method":"mRNA differential display, RT-PCR, two-dimensional gel electrophoresis (protein synthesis rate), aphidicolin/cytochalasin D/nocodazole/trapoxin pharmacological treatments in mouse embryos","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological perturbations with defined readouts linking DNA replication and chromatin state to EIF1AX expression; single lab, mouse embryo model","pmids":["8631492"],"is_preprint":false},{"year":2013,"finding":"Recurrent somatic EIF1AX mutations in uveal melanoma all cause in-frame changes specifically affecting the N-terminus of the protein, identified by exome sequencing and confirmed by targeted resequencing; these mutations occur predominantly in tumors with disomy 3 and are mutually exclusive with SF3B1 mutations.","method":"Exome sequencing, targeted resequencing of 31 disomy-3 and 35 monosomy-3 uveal melanomas","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — robust sequencing with large cohort establishes mutation clustering at N-terminus and mutual exclusivity; no direct functional experiment on mechanism","pmids":["23793026"],"is_preprint":false}],"current_model":"EIF1AX is a eukaryotic translation initiation factor that acts catalytically to transfer the Met-tRNAf·eIF2·GTP ternary complex to 40S ribosomal subunits to form the 43S preinitiation complex (PIC), prevents premature 60S joining and 40S dimerization, and does not remain stably associated with the PIC after assembly; cancer-associated mutations (especially the A113splice variant) stabilize the PIC, induce ATF4 to suppress EIF2α phosphorylation and globally increase protein synthesis, and cooperate with RAS/c-MYC to activate mTOR signaling, while the protein also represses p21 transcription to drive G1/S cell cycle progression, and its subcellular localization (nuclear vs. cytoplasmic, regulated by XPO1-mediated export) determines its oncogenic activity in endometrial cancer."},"narrative":{"mechanistic_narrative":"EIF1AX (historically eIF-4C/eIF-1A) is a eukaryotic translation initiation factor that acts catalytically to transfer the initiator Met-tRNAf (as the Met-tRNAf·eIF2·GTP ternary complex) to 40S ribosomal subunits, forming the 40S preinitiation complex without itself remaining stably associated with the assembled complex [PMID:9065455]. It functions accessory to eIF-3 in dissociating native 80S ribosomes into subunits, preventing premature 40S–60S association, and resolving inactive 40S dimers into active monomers [PMID:6901506], and it is an RNA-binding protein whose basic N-terminus/acidic C-terminus dipole architecture is conserved across species and mediates ribosome and factor contacts [PMID:8106356, PMID:7890705]. Beyond its core initiation role, EIF1AX drives proliferation: its overexpression promotes protein synthesis and cell growth [PMID:25281768], and it accelerates G1/S transition through p53-independent transcriptional repression of p21/CDKN1A [PMID:32926483]. Cancer-associated mutations cluster regionally — N-terminal missense changes recur in uveal melanoma and co-occur with NRAS in low-grade serous ovarian carcinoma to promote proliferation [PMID:23793026, PMID:28646021], while the C-terminal A113splice variant stabilizes the 43S preinitiation complex and induces ATF4 to suppress eIF2α phosphorylation, globally elevating protein synthesis and cooperating with RAS/c-MYC to sensitize mTOR to amino acid supply [PMID:30305285]. In endometrial carcinoma, XPO1-mediated cytoplasmic localization of EIF1AX promotes migration, invasion, and EMT, whereas forced nuclear import suppresses these phenotypes [PMID:36589683].","teleology":[{"year":1980,"claim":"Established that EIF1AX (eIF-4C) acts at the ribosome-dissociation step of initiation rather than as a passive cofactor, defining its role in generating and maintaining the active 40S subunit pool.","evidence":"In vitro ribosome dissociation and initiation complex formation with native/washed subunits","pmids":["6901506"],"confidence":"Medium","gaps":["Single lab, not independently replicated in this corpus","Structural basis of anti-association activity not defined"]},{"year":1993,"claim":"Distinguished EIF1AX function from mRNA-binding initiation factors by showing the wheat germ ortholog acts as a single polypeptide with no mRNA-specific concentration requirement, ruling out a direct role in mRNA recruitment.","evidence":"Purification and in vitro translation with multiple mRNA species (plant ortholog)","pmids":["8227048"],"confidence":"Medium","gaps":["Plant ortholog model","Negative finding for mRNA binding role"]},{"year":1994,"claim":"Defined the conserved basic-N-terminus/acidic-C-terminus dipole architecture and demonstrated functional interchangeability across species, framing the structural basis for ribosome and factor interactions.","evidence":"Peptide sequencing, cDNA cloning, heterologous in vitro translation","pmids":["8106356"],"confidence":"Medium","gaps":["No high-resolution structure","Specific rRNA/factor contacts not mapped"]},{"year":1995,"claim":"Characterized EIF1AX as an RNA-binding protein present at sub-stoichiometric levels relative to ribosomes and showed it is not rate-limiting for translation, refining its catalytic (not stoichiometric) role.","evidence":"Northwestern blotting, abundance quantification, overexpression in COS-1 cells","pmids":["7890705"],"confidence":"Medium","gaps":["RNA targets not defined","Overexpression negative result in normal cells contrasts with later cancer findings"]},{"year":1996,"claim":"Linked EIF1AX expression to early developmental gene activation, showing its mRNA is transiently induced at zygotic gene activation in a DNA-replication- and chromatin-remodeling-dependent manner.","evidence":"Differential display, RT-PCR, pharmacological perturbation in mouse embryos","pmids":["8631492"],"confidence":"Medium","gaps":["Functional consequence of induction unclear","Mouse embryo-specific context"]},{"year":1997,"claim":"Resolved the catalytic mechanism: EIF1AX promotes Met-tRNAf ternary complex transfer to 40S subunits but is absent from the resulting complex, showing it acts catalytically and not by stabilizing tRNA binding.","evidence":"In vitro reconstitution with purified mammalian factors and eIF5-dependent 80S formation","pmids":["9065455"],"confidence":"High","gaps":["Kinetic mechanism of release not detailed","No structural snapshot of the catalytic intermediate"]},{"year":2013,"claim":"Identified EIF1AX as a recurrently mutated cancer gene, with in-frame N-terminal mutations clustering in disomy-3 uveal melanoma and mutual exclusivity with SF3B1, implicating the initiation-fidelity region in tumorigenesis.","evidence":"Exome and targeted resequencing of uveal melanoma cohorts","pmids":["23793026"],"confidence":"Medium","gaps":["No direct functional mechanism for N-terminal mutations","Effect on initiation fidelity not assayed"]},{"year":2014,"claim":"Placed EIF1AX in a physical interaction network with 14-3-3γ and RPS7 coupling it to translation and proliferation control beyond the canonical PIC.","evidence":"Co-IP, MALDI-TOF/TOF MS, FRET, colocalization, overexpression (bovine cells)","pmids":["25281768"],"confidence":"Medium","gaps":["Bovine cell model","Functional role of 14-3-3γ binding not dissected"]},{"year":2017,"claim":"Provided functional evidence that N-terminal EIF1AX mutants cooperate oncogenically with NRAS, showing co-occurrence and joint promotion of proliferation in ovarian carcinoma.","evidence":"Sequencing plus coexpression and clonogenic assays in LGSC cell lines","pmids":["28646021"],"confidence":"Medium","gaps":["Molecular basis of NRAS cooperation not resolved","Single lab"]},{"year":2018,"claim":"Delineated the oncogenic mechanism of the C-terminal A113splice variant: PIC stabilization induces ATF4, suppresses eIF2α phosphorylation, raises global translation, and cooperates with RAS/c-MYC to drive mTOR amino-acid sensitization.","evidence":"Isogenic cell lines, mouse tumorigenesis, PIC/phosphorylation assays, inhibitor studies","pmids":["30305285"],"confidence":"High","gaps":["Whether N-terminal mutants share this PIC-stabilizing mechanism unknown","Direct biophysical basis of PIC stabilization not shown"]},{"year":2020,"claim":"Identified a transcriptional, translation-independent oncogenic activity: EIF1AX represses p21/CDKN1A in a p53-independent manner to drive G1/S progression.","evidence":"ChIP, luciferase reporter, RNA-Seq, flow cytometry, xenograft with shRNA knockdown","pmids":["32926483"],"confidence":"Medium","gaps":["Mechanism of nuclear/chromatin recruitment to CDKN1A unclear","Relationship to canonical cytoplasmic initiation role unresolved"]},{"year":2022,"claim":"Showed that subcellular localization governs EIF1AX oncogenic output, with XPO1-mediated cytoplasmic localization driving migration/invasion/EMT and nuclear import suppressing them in endometrial carcinoma.","evidence":"shRNA, SV40NLS forced import, leptomycin B, NES mutagenesis, migration/metastasis assays","pmids":["36589683"],"confidence":"Medium","gaps":["Molecular effectors downstream of cytoplasmic localization not fully defined","Single lab"]},{"year":2022,"claim":"Proposed a feed-forward loop in which EIF1AX regulates its own mRNA via PCBP1 and promotes c-Myc IRES-dependent translation through YBX-1 to sustain proliferation.","evidence":"RIP, Co-IP, proliferation/apoptosis assays (findings secondary to an lncRNA study)","pmids":["35080085"],"confidence":"Low","gaps":["Mechanistic findings are secondary results in an lncRNA-focused paper","YBX-1 interaction and IRES activity not independently confirmed"]},{"year":2025,"claim":"Revealed a nucleolar, senescence-inducing function whereby drug-triggered EIF1AX translocation recruits DDX21 into nucleolar aggregates that suppress rDNA transcription.","evidence":"Compound/CRISPR screens, co-IP MS, CUT&TAG, in vivo tumor assays","pmids":["41405406"],"confidence":"Medium","gaps":["Endogenous trigger of nucleolar translocation unknown","Structural basis of DDX21 aggregate formation not defined"]},{"year":null,"claim":"How EIF1AX's canonical cytoplasmic translation-initiation activity mechanistically connects to its nuclear/nucleolar transcriptional and senescence functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking initiation activity to chromatin/rDNA regulation","N-terminal vs C-terminal mutation mechanisms not reconciled","Structural basis of mutation-driven PIC stabilization absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,9]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[11]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,13]}],"complexes":["43S preinitiation complex"],"partners":["RPS7","YWHAG","PCBP1","YBX1","DDX21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P47813","full_name":"Eukaryotic translation initiation factor 1A, X-chromosomal","aliases":["Eukaryotic translation initiation factor 4C","eIF-4C"],"length_aa":144,"mass_kda":16.5,"function":"Component of the 43S pre-initiation complex (43S PIC), which binds to the mRNA cap-proximal region, scans mRNA 5'-untranslated region, and locates the initiation codon (PubMed:9732867). This protein enhances formation of the cap-proximal complex (PubMed:9732867). Together with EIF1, facilitates scanning, start codon recognition, promotion of the assembly of 48S complex at the initiation codon (43S PIC becomes 48S PIC after the start codon is reached), and dissociation of aberrant complexes (PubMed:9732867). After start codon location, together with EIF5B orients the initiator methionine-tRNA in a conformation that allows 60S ribosomal subunit joining to form the 80S initiation complex (PubMed:35732735). Is released after 80S initiation complex formation, just after GTP hydrolysis by EIF5B, and before release of EIF5B (PubMed:35732735). Its globular part is located in the A site of the 40S ribosomal subunit (PubMed:35732735). Its interaction with EIF5 during scanning contribute to the maintenance of EIF1 within the open 43S PIC (PubMed:24319994). In contrast to yeast orthologs, does not bind EIF1 (PubMed:24319994)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P47813/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF1AX","classification":"Common Essential","n_dependent_lines":1108,"n_total_lines":1208,"dependency_fraction":0.9172185430463576},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EIF1AX","total_profiled":1310},"omim":[{"mim_id":"618473","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 1A DOMAIN-CONTAINING PROTEIN; EIF1AD","url":"https://www.omim.org/entry/618473"},{"mim_id":"618365","title":"ZINC FINGER- AND SCAN DOMAIN-CONTAINING PROTEIN 10; ZSCAN10","url":"https://www.omim.org/entry/618365"},{"mim_id":"612720","title":"DExH-BOX HELICASE; DHX29","url":"https://www.omim.org/entry/612720"},{"mim_id":"400014","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 1A, Y-LINKED; EIF1AY","url":"https://www.omim.org/entry/400014"},{"mim_id":"300186","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 1A, X-LINKED; EIF1AX","url":"https://www.omim.org/entry/300186"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF1AX"},"hgnc":{"alias_symbol":["eIF-1A","eIF-4C"],"prev_symbol":["EIF4C","EIF1A"]},"alphafold":{"accession":"P47813","domains":[{"cath_id":"2.40.50.140","chopping":"32-105","consensus_level":"high","plddt":92.2601,"start":32,"end":105}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P47813","model_url":"https://alphafold.ebi.ac.uk/files/AF-P47813-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P47813-F1-predicted_aligned_error_v6.png","plddt_mean":77.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF1AX","jax_strain_url":"https://www.jax.org/strain/search?query=EIF1AX"},"sequence":{"accession":"P47813","fasta_url":"https://rest.uniprot.org/uniprotkb/P47813.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P47813/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P47813"}},"corpus_meta":[{"pmid":"23793026","id":"PMC_23793026","title":"Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23793026","citation_count":420,"is_preprint":false},{"pmid":"24970262","id":"PMC_24970262","title":"Chromosome 3 status combined with BAP1 and EIF1AX mutation profiles are associated with metastasis in uveal melanoma.","date":"2014","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/24970262","citation_count":137,"is_preprint":false},{"pmid":"8631492","id":"PMC_8631492","title":"Transient expression of translation initiation factor eIF-4C during the 2-cell stage of the preimplantation mouse embryo: identification by mRNA differential display and the role of DNA replication in zygotic gene activation.","date":"1996","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/8631492","citation_count":135,"is_preprint":false},{"pmid":"24423917","id":"PMC_24423917","title":"Mutation frequencies of GNAQ, GNA11, BAP1, SF3B1, EIF1AX and TERT in uveal melanoma: detection of an activating mutation in the TERT gene promoter in a single case of uveal melanoma.","date":"2014","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24423917","citation_count":87,"is_preprint":false},{"pmid":"30305285","id":"PMC_30305285","title":"EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC.","date":"2018","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/30305285","citation_count":82,"is_preprint":false},{"pmid":"26911375","id":"PMC_26911375","title":"Prevalence and phenotypic correlations of EIF1AX mutations in thyroid nodules.","date":"2016","source":"Endocrine-related 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EIF1A plays no role in the subunit joining reaction or in generating ribosomal subunits from 80S ribosomes.\",\n      \"method\": \"In vitro translation initiation assay with purified mammalian components; functional reconstitution with eIF5-dependent 80S complex formation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro reconstitution assay with purified factors, catalytic activity demonstrated, negative results explicitly stated; single lab but multiple orthogonal functional readouts\",\n      \"pmids\": [\"9065455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1980,\n      \"finding\": \"eIF-4C (EIF1AX) stimulates initiation complex formation by acting accessory to eIF-3 in dissociating native 80S ribosomes into subunits, preventing premature 40S–60S association, and dissociating inactive 40S dimers into active monomers.\",\n      \"method\": \"In vitro ribosome dissociation and initiation complex formation assay with native and washed ribosomal subunits\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical reconstitution, single lab, single study; foundational but not independently replicated within this corpus\",\n      \"pmids\": [\"6901506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"EIF1AX (eIF-4C) protein has a distinctive dipole structure: basic N-terminus and acidic C-terminus, conserved between mammalian and wheat germ proteins (68% identity), suggesting the polarity enables interaction with ribosomes (via rRNA) and other translation initiation factors. Wheat germ and rabbit eIF-4C are functionally interchangeable in heterologous in vitro assays.\",\n      \"method\": \"Chemical peptide sequencing, cDNA cloning, PCR, heterologous in vitro translation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — sequence determination plus functional cross-species reconstitution; single lab but multiple methods\",\n      \"pmids\": [\"8106356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"EIF1AX (eIF-1A) is an RNA-binding protein, as demonstrated by Northwestern blotting with mRNA fragments. Its abundance in HeLa cells is 0.2 molecules per ribosome, and overexpression of eIF-1A fails to stimulate translation rates in transiently transfected COS-1 cells, indicating it is not limiting for protein synthesis.\",\n      \"method\": \"Northwestern blotting; Western immunoblotting; polysome profile analysis; transient transfection with overexpression; E. coli overexpression and purification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA binding, abundance quantification, overexpression functional test), single lab\",\n      \"pmids\": [\"7890705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Wheat germ eIF-4C (EIF1AX ortholog) functions as a single polypeptide and is not involved in mRNA binding to 40S ribosomal subunits, as concentrations required for translation are similar across different mRNA species whereas eIF-4A and eIF-4F show mRNA-specific differences.\",\n      \"method\": \"Purification from wheat germ, gel filtration, in vitro translation assay with satellite tobacco necrosis virus RNA, alfalfa mosaic virus RNA 4, and barley alpha-amylase mRNA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution assay, plant ortholog, single lab; negative finding for mRNA binding role is explicit\",\n      \"pmids\": [\"8227048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The C-terminal EIF1AX-A113splice mutation (most prevalent in advanced thyroid cancer) stabilizes the 43S preinitiation complex (PIC) and induces ATF4, which suppresses EIF2α phosphorylation, enabling a general increase in protein synthesis. Co-occurring RAS mutations stabilize c-MYC (augmented by EIF1AX-A113splice). ATF4 and c-MYC together induce amino acid transporters and sensitize mTOR to amino acid supply, cooperating with RAS to drive tumorigenesis.\",\n      \"method\": \"Isogenic cell lines expressing mutant EIF1AX, mouse tumorigenesis models, ribosome/PIC assembly assays, phosphorylation assays (EIF2α), gene expression analysis, mTOR sensitivity assays, pharmacological inhibition (MEK, BRD4, mTOR inhibitors)\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal mechanistic methods (PIC stabilization, phosphorylation assay, mouse model, isogenic cell lines, inhibitor studies) in a single rigorous study; mechanistic pathway fully delineated\",\n      \"pmids\": [\"30305285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Missense EIF1AX mutations clustered at the N-terminus (region associated with translational initiation fidelity) co-occur significantly with NRAS mutations in low-grade serous ovarian carcinoma; coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells.\",\n      \"method\": \"Exome and whole genome sequencing; coexpression of mutant proteins in LGSC cell lines; proliferation and clonogenic survival assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assays with defined mutant constructs plus genomic co-occurrence analysis; single lab\",\n      \"pmids\": [\"28646021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EIF1AX interacts with 14-3-3γ and RPS7 in bovine mammary epithelial cells, forming a molecular network that regulates protein translation and cell proliferation; these interactions were confirmed by co-immunoprecipitation, MALDI-TOF/TOF peptide mass fingerprinting, colocalization, and FRET analysis. Overexpression of EIF1AX promotes protein translation and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, MALDI-TOF/TOF mass spectrometry, FRET, colocalization, overexpression and inhibition experiments\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by multiple orthogonal methods (Co-IP, MS, FRET, colocalization), single lab; bovine cell model\",\n      \"pmids\": [\"25281768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EIF1AX promotes breast cancer cell proliferation by driving G1/S cell cycle transition through transcriptional repression of p21 (CDKN1A) in a p53-independent manner, as demonstrated by ChIP and luciferase reporter assays.\",\n      \"method\": \"Colony formation and xenograft assays, RNA-Seq, flow cytometry (cell cycle), ChIP assay, luciferase reporter assay, shRNA knockdown\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assays directly demonstrate transcriptional repression of p21; multiple methods in single lab\",\n      \"pmids\": [\"32926483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cytoplasmic localization of EIF1AX (mediated by exportin 1/XPO1) promotes tumor cell migration, invasion, and epithelial-mesenchymal transition in endometrial carcinoma; nuclear import of EIF1AX (via SV40NLS) suppresses these phenotypes. XPO1-dependent nuclear export of EIF1AX was confirmed by leptomycin B treatment and mutation of the EIF1AX nuclear export sequence.\",\n      \"method\": \"shRNA knockdown, SV40NLS-forced nuclear import, leptomycin B treatment, nuclear export sequence mutagenesis, migration/invasion assays, in vivo lung metastasis model, subcellular fractionation/immunofluorescence\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (pharmacological, genetic, mutagenesis) linking XPO1-mediated cytoplasmic localization to functional cancer phenotypes; single lab\",\n      \"pmids\": [\"36589683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EIF1AX interacts with EIF1AX mRNA and PCBP1 to promote EIF1AX mRNA degradation; additionally, EIF1AX promotes c-Myc translation through the internal ribosome entry site (IRES) pathway via interaction with YBX-1, forming a feed-forward loop that sustains EC cell proliferation.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, in vitro and in vivo proliferation/apoptosis assays, RNA sequencing; the paper primarily describes the lncRNA EIF1AX-AS1 but mechanistically links it to EIF1AX protein function\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic findings about EIF1AX protein (IRES-mediated c-Myc translation, YBX-1 interaction) are secondary results in a paper primarily focused on the lncRNA; single lab, single methods per finding\",\n      \"pmids\": [\"35080085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EIF1AX undergoes nucleolar translocation upon treatment with 2,5-MeC in endometrial cancer cells; this translocation promotes cellular senescence by recruiting DDX21 to form nucleolar aggregates that suppress rDNA transcription, as shown by co-immunoprecipitation mass spectrometry and CUT&TAG sequencing.\",\n      \"method\": \"Compound library screen, CRISPR library screen, co-immunoprecipitation mass spectrometry, CUT&TAG sequencing, RNA sequencing, antibody array, in vivo tumor growth assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP MS identifies DDX21 as binding partner; CUT&TAG links EIF1AX nucleolar aggregates to rDNA transcription suppression; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"41405406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"eIF-4C (EIF1AX) mRNA is transiently increased at the 2-cell stage of mouse preimplantation embryo development (zygotic gene activation); this increase requires the first round of DNA replication (blocked by aphidicolin) and is reversed by a mechanism requiring chromatin remodeling via histone deacetylation (blocked by trapoxin), but does not require cytokinesis or mitosis.\",\n      \"method\": \"mRNA differential display, RT-PCR, two-dimensional gel electrophoresis (protein synthesis rate), aphidicolin/cytochalasin D/nocodazole/trapoxin pharmacological treatments in mouse embryos\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological perturbations with defined readouts linking DNA replication and chromatin state to EIF1AX expression; single lab, mouse embryo model\",\n      \"pmids\": [\"8631492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Recurrent somatic EIF1AX mutations in uveal melanoma all cause in-frame changes specifically affecting the N-terminus of the protein, identified by exome sequencing and confirmed by targeted resequencing; these mutations occur predominantly in tumors with disomy 3 and are mutually exclusive with SF3B1 mutations.\",\n      \"method\": \"Exome sequencing, targeted resequencing of 31 disomy-3 and 35 monosomy-3 uveal melanomas\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — robust sequencing with large cohort establishes mutation clustering at N-terminus and mutual exclusivity; no direct functional experiment on mechanism\",\n      \"pmids\": [\"23793026\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF1AX is a eukaryotic translation initiation factor that acts catalytically to transfer the Met-tRNAf·eIF2·GTP ternary complex to 40S ribosomal subunits to form the 43S preinitiation complex (PIC), prevents premature 60S joining and 40S dimerization, and does not remain stably associated with the PIC after assembly; cancer-associated mutations (especially the A113splice variant) stabilize the PIC, induce ATF4 to suppress EIF2α phosphorylation and globally increase protein synthesis, and cooperate with RAS/c-MYC to activate mTOR signaling, while the protein also represses p21 transcription to drive G1/S cell cycle progression, and its subcellular localization (nuclear vs. cytoplasmic, regulated by XPO1-mediated export) determines its oncogenic activity in endometrial cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EIF1AX (historically eIF-4C/eIF-1A) is a eukaryotic translation initiation factor that acts catalytically to transfer the initiator Met-tRNAf (as the Met-tRNAf·eIF2·GTP ternary complex) to 40S ribosomal subunits, forming the 40S preinitiation complex without itself remaining stably associated with the assembled complex [#0]. It functions accessory to eIF-3 in dissociating native 80S ribosomes into subunits, preventing premature 40S–60S association, and resolving inactive 40S dimers into active monomers [#1], and it is an RNA-binding protein whose basic N-terminus/acidic C-terminus dipole architecture is conserved across species and mediates ribosome and factor contacts [#2, #3]. Beyond its core initiation role, EIF1AX drives proliferation: its overexpression promotes protein synthesis and cell growth [#7], and it accelerates G1/S transition through p53-independent transcriptional repression of p21/CDKN1A [#8]. Cancer-associated mutations cluster regionally — N-terminal missense changes recur in uveal melanoma and co-occur with NRAS in low-grade serous ovarian carcinoma to promote proliferation [#13, #6], while the C-terminal A113splice variant stabilizes the 43S preinitiation complex and induces ATF4 to suppress eIF2α phosphorylation, globally elevating protein synthesis and cooperating with RAS/c-MYC to sensitize mTOR to amino acid supply [#5]. In endometrial carcinoma, XPO1-mediated cytoplasmic localization of EIF1AX promotes migration, invasion, and EMT, whereas forced nuclear import suppresses these phenotypes [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1980,\n      \"claim\": \"Established that EIF1AX (eIF-4C) acts at the ribosome-dissociation step of initiation rather than as a passive cofactor, defining its role in generating and maintaining the active 40S subunit pool.\",\n      \"evidence\": \"In vitro ribosome dissociation and initiation complex formation with native/washed subunits\",\n      \"pmids\": [\"6901506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently replicated in this corpus\", \"Structural basis of anti-association activity not defined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Distinguished EIF1AX function from mRNA-binding initiation factors by showing the wheat germ ortholog acts as a single polypeptide with no mRNA-specific concentration requirement, ruling out a direct role in mRNA recruitment.\",\n      \"evidence\": \"Purification and in vitro translation with multiple mRNA species (plant ortholog)\",\n      \"pmids\": [\"8227048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Plant ortholog model\", \"Negative finding for mRNA binding role\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined the conserved basic-N-terminus/acidic-C-terminus dipole architecture and demonstrated functional interchangeability across species, framing the structural basis for ribosome and factor interactions.\",\n      \"evidence\": \"Peptide sequencing, cDNA cloning, heterologous in vitro translation\",\n      \"pmids\": [\"8106356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure\", \"Specific rRNA/factor contacts not mapped\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Characterized EIF1AX as an RNA-binding protein present at sub-stoichiometric levels relative to ribosomes and showed it is not rate-limiting for translation, refining its catalytic (not stoichiometric) role.\",\n      \"evidence\": \"Northwestern blotting, abundance quantification, overexpression in COS-1 cells\",\n      \"pmids\": [\"7890705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA targets not defined\", \"Overexpression negative result in normal cells contrasts with later cancer findings\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Linked EIF1AX expression to early developmental gene activation, showing its mRNA is transiently induced at zygotic gene activation in a DNA-replication- and chromatin-remodeling-dependent manner.\",\n      \"evidence\": \"Differential display, RT-PCR, pharmacological perturbation in mouse embryos\",\n      \"pmids\": [\"8631492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of induction unclear\", \"Mouse embryo-specific context\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved the catalytic mechanism: EIF1AX promotes Met-tRNAf ternary complex transfer to 40S subunits but is absent from the resulting complex, showing it acts catalytically and not by stabilizing tRNA binding.\",\n      \"evidence\": \"In vitro reconstitution with purified mammalian factors and eIF5-dependent 80S formation\",\n      \"pmids\": [\"9065455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetic mechanism of release not detailed\", \"No structural snapshot of the catalytic intermediate\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified EIF1AX as a recurrently mutated cancer gene, with in-frame N-terminal mutations clustering in disomy-3 uveal melanoma and mutual exclusivity with SF3B1, implicating the initiation-fidelity region in tumorigenesis.\",\n      \"evidence\": \"Exome and targeted resequencing of uveal melanoma cohorts\",\n      \"pmids\": [\"23793026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct functional mechanism for N-terminal mutations\", \"Effect on initiation fidelity not assayed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed EIF1AX in a physical interaction network with 14-3-3γ and RPS7 coupling it to translation and proliferation control beyond the canonical PIC.\",\n      \"evidence\": \"Co-IP, MALDI-TOF/TOF MS, FRET, colocalization, overexpression (bovine cells)\",\n      \"pmids\": [\"25281768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bovine cell model\", \"Functional role of 14-3-3γ binding not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided functional evidence that N-terminal EIF1AX mutants cooperate oncogenically with NRAS, showing co-occurrence and joint promotion of proliferation in ovarian carcinoma.\",\n      \"evidence\": \"Sequencing plus coexpression and clonogenic assays in LGSC cell lines\",\n      \"pmids\": [\"28646021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of NRAS cooperation not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Delineated the oncogenic mechanism of the C-terminal A113splice variant: PIC stabilization induces ATF4, suppresses eIF2α phosphorylation, raises global translation, and cooperates with RAS/c-MYC to drive mTOR amino-acid sensitization.\",\n      \"evidence\": \"Isogenic cell lines, mouse tumorigenesis, PIC/phosphorylation assays, inhibitor studies\",\n      \"pmids\": [\"30305285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether N-terminal mutants share this PIC-stabilizing mechanism unknown\", \"Direct biophysical basis of PIC stabilization not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a transcriptional, translation-independent oncogenic activity: EIF1AX represses p21/CDKN1A in a p53-independent manner to drive G1/S progression.\",\n      \"evidence\": \"ChIP, luciferase reporter, RNA-Seq, flow cytometry, xenograft with shRNA knockdown\",\n      \"pmids\": [\"32926483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear/chromatin recruitment to CDKN1A unclear\", \"Relationship to canonical cytoplasmic initiation role unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that subcellular localization governs EIF1AX oncogenic output, with XPO1-mediated cytoplasmic localization driving migration/invasion/EMT and nuclear import suppressing them in endometrial carcinoma.\",\n      \"evidence\": \"shRNA, SV40NLS forced import, leptomycin B, NES mutagenesis, migration/metastasis assays\",\n      \"pmids\": [\"36589683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors downstream of cytoplasmic localization not fully defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Proposed a feed-forward loop in which EIF1AX regulates its own mRNA via PCBP1 and promotes c-Myc IRES-dependent translation through YBX-1 to sustain proliferation.\",\n      \"evidence\": \"RIP, Co-IP, proliferation/apoptosis assays (findings secondary to an lncRNA study)\",\n      \"pmids\": [\"35080085\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic findings are secondary results in an lncRNA-focused paper\", \"YBX-1 interaction and IRES activity not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a nucleolar, senescence-inducing function whereby drug-triggered EIF1AX translocation recruits DDX21 into nucleolar aggregates that suppress rDNA transcription.\",\n      \"evidence\": \"Compound/CRISPR screens, co-IP MS, CUT&TAG, in vivo tumor assays\",\n      \"pmids\": [\"41405406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous trigger of nucleolar translocation unknown\", \"Structural basis of DDX21 aggregate formation not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EIF1AX's canonical cytoplasmic translation-initiation activity mechanistically connects to its nuclear/nucleolar transcriptional and senescence functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking initiation activity to chromatin/rDNA regulation\", \"N-terminal vs C-terminal mutation mechanisms not reconciled\", \"Structural basis of mutation-driven PIC stabilization absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72613\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 13]}\n    ],\n    \"complexes\": [\n      \"43S preinitiation complex\"\n    ],\n    \"partners\": [\n      \"RPS7\",\n      \"YWHAG\",\n      \"PCBP1\",\n      \"YBX1\",\n      \"DDX21\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}