{"gene":"EIF5A2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2001,"finding":"EIF5A2 encodes a 153-amino-acid eIF5A isoform that, like eIF5A1, receives the unique spermidine-derived post-translational modification hypusine, which is necessary for eIF5A biochemical activity. The gene spans 17 kb with 5 exons and produces two mRNAs via differential polyadenylation sharing the same coding sequence.","method":"Molecular cloning, sequence characterization, gene structure analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular characterization of gene structure and protein sequence conservation; hypusine modification inferred from sequence identity with eIF5A1 rather than directly demonstrated for eIF5A2 in this paper, single study","pmids":["11161802"],"is_preprint":false},{"year":2006,"finding":"eIF5A-2 precursor protein is modified by hypusination comparably to eIF5A-1 in UACC-1598 cells. eIF5A-2 mRNA is inefficiently translated relative to eIF5A-1, with only a small fraction associating with polysomes; the elements causing inefficient translation reside outside the open reading frame (within the UTRs). Both isoforms are similarly stable once synthesized.","method":"Sucrose gradient polysome fractionation, mammalian expression vectors in 293T cells, Western blot, pulse-chase stability assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (polysome fractionation, heterologous expression, protein stability); single lab","pmids":["16519677"],"is_preprint":false},{"year":2004,"finding":"EIF5A2 has tumorigenic activity: ectopic expression enables anchorage-independent growth in soft agar and tumor formation in nude mice. Antisense DNA against eIF5A2 inhibits cell growth in an ovarian cancer cell line (UACC-1598) that harbors EIF5A2 amplification as double minutes.","method":"Soft agar colony formation, nude mouse xenograft, antisense oligonucleotide knockdown, copy-number reduction","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — both gain-of-function (soft agar, nude mouse) and loss-of-function (antisense knockdown) experiments in the same study; replicated by multiple subsequent studies","pmids":["15205331"],"is_preprint":false},{"year":2011,"finding":"EIF5A2 overexpression promotes colorectal carcinoma cell motility, invasion, and epithelial-mesenchymal transition (EMT) in vitro and metastasis in vivo. Mechanistically, EIF5A2 upregulates MTA1 via enhanced enrichment of c-Myc on the MTA1 promoter; MTA1 knockdown eliminates EIF5A2-driven migration, invasion, and EMT.","method":"Ectopic overexpression and siRNA knockdown in CRC cell lines, in vitro invasion/migration assays, in vivo metastasis model, ChIP assay for c-Myc on MTA1 promoter, epistasis by MTA1 siRNA rescue","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function, ChIP mechanistic evidence, epistasis rescue experiment, in vivo validation; single lab but multiple orthogonal methods","pmids":["21813470"],"is_preprint":false},{"year":2011,"finding":"Transgenic overexpression of eIF5A2 in mice accelerates organismal aging (decreased growth, shortened lifespan, kyphosis, osteoporosis, impaired wound healing) by increasing chromosomal instability. Mechanistically, eIF5A2 represses p19 (ARF), thereby destabilizing p53 in mouse embryo fibroblasts, leading to accumulation of mitotic errors (misaligned/lagging chromosomes, anaphase bridges, micronuclei) and increased aneuploidy.","method":"eIF5A2 transgenic mouse model, MEF isolation, immunohistochemistry, Western blot (p19, p53), cytogenetic analysis of mitotic figures, flow cytometry for aneuploidy","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with mechanistic follow-up (p19/p53 pathway, cytogenetics); single lab","pmids":["21612665"],"is_preprint":false},{"year":2013,"finding":"EIF5A2 is a downstream target of phosphorylated Akt (PI3K/Akt pathway) in melanoma cells. EIF5A2 overexpression increases, and knockdown decreases, melanoma cell invasion and MMP-2 activity.","method":"Tissue microarray, EIF5A2 overexpression/knockdown in melanoma cell lines, invasion assay, zymography for MMP-2 activity, correlation with Akt phosphorylation status","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assays with both gain and loss of function plus pathway placement by correlation with p-Akt; single lab, no direct epistasis experiment","pmids":["24178756"],"is_preprint":false},{"year":2014,"finding":"EIF5A2 activates TGF-β1 expression to induce EMT in bladder cancer cells. Specifically, EIF5A2 stabilizes STAT3 and stimulates its nuclear localization, resulting in increased STAT3 binding to the TGF-β1 promoter and enhanced TGF-β1 transcription.","method":"EIF5A2 overexpression and knockdown in bladder cancer cell lines, ChIP assay for STAT3 on TGF-β1 promoter, Western blot for STAT3 nuclear localization, EMT marker analysis, in vivo metastasis model","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including ChIP, nuclear fractionation, EMT markers, in vivo validation; clear mechanistic pathway (EIF5A2→STAT3 nuclear localization→TGF-β1 transcription→EMT)","pmids":["24504366"],"is_preprint":false},{"year":2014,"finding":"EIF5A2 ablation in hepatocellular carcinoma inhibits tumor angiogenesis by reducing MMP-2 expression. EIF5A2 silencing increases vessel wall continuity, blood perfusion, and tumor oxygenation. EIF5A2 enhances MMP-2 activity via activation of the p38 MAPK and JNK/c-Jun signaling pathways.","method":"EIF5A2 knockdown in HCC cell lines and xenografts, fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays, tumor hypoxia assays, Western blot for p38/JNK/c-Jun","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary in vitro and in vivo methods, defined signaling pathway (p38 MAPK/JNK/c-Jun→MMP-2), single lab but highly orthogonal approaches","pmids":["25071013"],"is_preprint":false},{"year":2014,"finding":"EIF5A2 is induced by hypoxia (4–8 fold) in esophageal squamous cell carcinoma cells, and there is bidirectional regulation between EIF5A2 and HIF1α (each upregulates the other). EIF5A2 promotes HIF1α expression and downstream VEGF, contributing to angiogenesis and EMT.","method":"Luciferase reporter assay, chromatin immunoprecipitation (HIF1α on EIF5A2 promoter), quantitative RT-PCR, EIF5A2 overexpression/knockdown, xenograft tumors with vessel counting","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP and luciferase reporter demonstrate direct HIF1α regulation of EIF5A2, bidirectionality shown with functional assays and in vivo xenograft; single lab, multiple orthogonal methods","pmids":["24561231"],"is_preprint":false},{"year":2022,"finding":"HERC3 E3 ubiquitin ligase directly interacts with EIF5A2 via its RCC1 domain, promotes K27- and K48-linked ubiquitination of EIF5A2 via its HECT domain, and targets EIF5A2 for proteasomal degradation. The ubiquitination sites on EIF5A2 were identified as K47, K67, K85, and K121. HERC3-mediated degradation of EIF5A2 inhibits EMT through the TGF-β/Smad2/3 pathway.","method":"Co-immunoprecipitation, GST pulldown, immunoprecipitation with ubiquitin linkage-specific antibodies, site-directed mutagenesis of EIF5A2 lysine residues, in vivo and in vitro ubiquitination assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution of ubiquitination (Co-IP, GST pulldown, in vitro ubiquitination), mutagenesis to identify specific ubiquitination sites, domain mapping; single lab but rigorous multi-method approach","pmids":["35064108"],"is_preprint":false},{"year":2021,"finding":"EIF5A2 promotes EMT in ovarian cancer cells via activation of the TGFβ pathway. CRISPR/Cas9 knockout of EIF5A2 inhibits EMT, cell migration, invasion, and ovarian tumor growth and metastasis in orthotopic mouse models, while EIF5A2 overexpression promotes these phenotypes.","method":"Lentiviral CRISPR/Cas9 nickase knockout, lentiviral overexpression, in vitro migration/invasion assays, orthotopic ovarian cancer mouse model, Western blot for TGFβ pathway and EMT markers","journal":"Cell & bioscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR-mediated KO (most rigorous LOF), OE gain-of-function, in vivo orthotopic model; multiple cancer lines and complementary approaches","pmids":["33827661"],"is_preprint":false},{"year":2021,"finding":"EIF5A2 promotes stemness in ovarian cancer cells via the E2F1/KLF4 pathway. EIF5A2 knockdown reduces KLF4 expression through E2F1, and KLF4 overexpression can partially rescue stem-like properties abolished by EIF5A2 knockdown; the transcription factor E2F1 directly binds the KLF4 promoter.","method":"EIF5A2 knockdown (siRNA), RNA-seq, sphere-forming assays, western blot, flow cytometry, in vivo xenograft, E2F1 epistasis rescue experiments","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq pathway identification, epistasis rescue experiment, in vivo validation; single lab","pmids":["33726845"],"is_preprint":false},{"year":2021,"finding":"Androgen receptor (AR) positively regulates EIF5A2 expression in androgen-dependent prostate cancer cells in response to DHT stimulation; anti-androgen bicalutamide reduces EIF5A2 expression. EIF5A2 knockdown eliminates DHT-induced EMT and invasion/migration.","method":"DHT stimulation and bicalutamide treatment of AR-positive/negative PCa cell lines, EIF5A2 knockdown, Western blot for EMT markers, in vivo lung metastasis assay with luciferase imaging","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic and genetic manipulation, in vivo metastasis readout, epistasis (EIF5A2 KD blocks DHT-EMT); single lab","pmids":["34864817"],"is_preprint":false},{"year":2021,"finding":"The deubiquitinating enzyme ATXN3 directly binds EIF5A2 and stabilizes it by reducing its ubiquitination and proteasomal degradation; ATXN3 promotes EIF5A2-dependent proliferation and metastasis in anaplastic thyroid carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, gain/loss-of-function experiments, Western blot for EIF5A2 stability","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay establish direct interaction and deubiquitination; functional rescue confirms EIF5A2 as downstream effector; single lab","pmids":["34428509"],"is_preprint":false},{"year":2022,"finding":"EIF5A2 interacts with AGR2 (anterior gradient 2) by co-immunoprecipitation in cervical cancer cells; AGR2 overexpression reverses the reduction in proliferation, migration, invasion, and cisplatin sensitivity caused by EIF5A2 knockdown, placing AGR2 downstream of EIF5A2.","method":"Co-immunoprecipitation, EIF5A2 knockdown, AGR2 overexpression epistasis rescue, proliferation/apoptosis/invasion assays","journal":"Pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP identifies binding partner and epistasis places AGR2 downstream; single lab, single Co-IP method","pmids":["35640539"],"is_preprint":false},{"year":2023,"finding":"EIF5A2 promotes doxorubicin resistance in bladder cancer cells through the TGF-β signaling pathway; EIF5A2 upregulates TGF-β1, p-Smad2, and p-Smad3, and a TGF-β pathway activator (SRI-011381) reverses the sensitizing effect of EIF5A2 knockdown.","method":"Doxorubicin-resistant cell line construction, EIF5A2 siRNA knockdown, TGF-β pathway activator rescue, Western blot for TGF-β1/p-Smad2/3, CCK-8 viability assay","journal":"Discovery medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic pathway rescue places EIF5A2 upstream of TGF-β/Smad; single lab, limited methods","pmids":["38058082"],"is_preprint":false},{"year":2023,"finding":"EIF5A2 K50R knock-in mice (CRISPR-Cas9) preventing hypusination at lysine-50 confirm that hypusine formation is required for eIF5A2 activation; metabolomic analysis of primary mouse dermal fibroblasts from eif5a2-K50R/K50R mice reveals significant alterations in the metabolite landscape, including increased tryptophan, kynurenine, pyridoxine, NAD, riboflavin, FAD, pantothenate, and CoA levels compared to controls.","method":"CRISPR-Cas9 K50R knock-in mouse model, Western blot with anti-hypusine antibody, metabolomics of primary dermal fibroblasts","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo genetic model with site-specific mutagenesis blocking PTM, confirmed biochemically; metabolomic profiling provides functional consequence of loss of hypusination","pmids":["36848144"],"is_preprint":false},{"year":2024,"finding":"TRIM71 (tripartite motif containing 71) directly interacts with eIF5A2 (verified by co-immunoprecipitation) and decreases eIF5A2 protein stability without affecting its mRNA level; TRIM71 overexpression inhibits LSCC tumor growth, and this anti-tumor effect is abolished by eIF5A2 overexpression.","method":"Co-immunoprecipitation, cycloheximide chase assay (protein half-life), quantitative PCR (mRNA level unchanged), overexpression epistasis rescue, in vivo xenograft","journal":"Applied biochemistry and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, protein stability assay, and epistasis experiment; single lab but orthogonal methods","pmids":["39579322"],"is_preprint":false},{"year":2025,"finding":"EIF5A2 protein synthesis is regulated at the translational level by polyamines: miR-6514-5p binds the 5'-UTR of eIF5A2 mRNA and negatively regulates its translation; polyamines inhibit miR-6514-5p function, thereby facilitating eIF5A2 synthesis. Proteomic analysis shows eIF5A2 and eIF5A1 regulate distinct sets of proteins, and eIF5A2 (not eIF5A1) is important for cancer cell growth. eIF5A2 silencing differentially regulates specific ribosomal proteins (RPS27A, RPL36A, RPL22L1) associated with cancer malignancy.","method":"Polyamine treatment with miR-6514-5p analysis, 5'-UTR reporter assays, eIF5A1/eIF5A2-specific siRNA knockdown, quantitative proteomics, cell proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct mechanistic dissection of translational regulation via 5'-UTR and miRNA, orthogonal proteomics showing distinct eIF5A1 vs eIF5A2 targets, multiple methods in single rigorous study","pmids":["40617352"],"is_preprint":false},{"year":2026,"finding":"eIF5A2-dependent translation elongation specifically regulates the synthesis of proteins with proline-rich motifs, including MTFR1 (mitochondrial fission regulator 1). A high-throughput screen identified orlistat and andrographolide as inhibitors of eIF5A2-dependent translation elongation. eIF5A2 silencing and these inhibitors suppress heparanase 1 (but not MMP-2 or MMP-9) expression and inhibit cancer cell invasion.","method":"MTFR1-luciferase reporter high-throughput screen (1744 compounds), eIF5A2 siRNA knockdown, invasion assays, Western blot for heparanase 1/MMP2/MMP9","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter-based functional screen with mechanistic validation by siRNA and protein expression; single lab, limited independent replication","pmids":["41730614"],"is_preprint":false},{"year":2026,"finding":"Loss of EIF5A2 activity—either through gene hypermethylation (epigenetic silencing) or pharmacological inhibition of its hypusine post-translational modification—induces venetoclax sensitivity in AML cells.","method":"Gene methylation analysis, pharmacological inhibition of hypusination, venetoclax sensitivity assays in AML cell lines","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two convergent loss-of-function approaches (epigenetic and pharmacologic) produce same sensitization phenotype; single report, abstract lacks full mechanistic detail","pmids":["41606290"],"is_preprint":false},{"year":2019,"finding":"miR-9 enhances chemosensitivity to daunorubicin in AML cells by targeting EIF5A2; EIF5A2 knockdown reduces MCL-1 expression, and the sensitizing effect of miR-9 requires downregulation of EIF5A2, placing MCL-1 downstream of EIF5A2 in this context.","method":"miR-9 overexpression/knockdown, EIF5A2 siRNA, Western blot for MCL-1, cell viability and apoptosis assays, epistasis by EIF5A2 rescue of miR-9 effects","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistasis experiment places MCL-1 downstream of EIF5A2; single lab, mechanistic chain validated by rescue experiment","pmids":["30745844"],"is_preprint":false},{"year":2020,"finding":"EIF5A2 controls EMT and chemoresistance in thyroid and other cancers via the TGF-β/Smad2/3 signaling pathway. In anaplastic thyroid carcinoma, EIF5A2 overexpression upregulates p-Smad2/3, and TGF-β pathway inhibition (SB431542 or Smad3 siRNA) blocks the growth-promoting effect of EIF5A2 overexpression.","method":"shRNA knockdown, ectopic overexpression, recombinant TGF-β1 rescue, SB431542 pharmacological inhibition, Smad3 siRNA, Western blot for p-Smad2/3, in vitro and xenograft experiments","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic and genetic epistasis confirms TGF-β/Smad2/3 pathway positioning; single lab, multiple orthogonal perturbations","pmids":["32138807"],"is_preprint":false},{"year":2022,"finding":"EIF5A2 overexpression activates the PI3K/AKT/mTOR signaling pathway and upregulates Cyclin D1, Cyclin D3, MMP2, and MMP9 to promote intrahepatic cholangiocarcinoma cell proliferation, migration, and invasion.","method":"EIF5A2 overexpression/knockdown, Western blot for PI3K/AKT/mTOR components and cell cycle proteins, proliferation (CCK-8, EdU), invasion/migration (Transwell, scratch) assays","journal":"Clinics and research in hepatology and gastroenterology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Western blot pathway analysis without pharmacological epistasis; pathway placement inferred from protein level changes","pmids":["35792239"],"is_preprint":false}],"current_model":"EIF5A2 is a hypusine-modified translation elongation factor whose protein synthesis is regulated by polyamines via miR-6514-5p at the 5'-UTR; once expressed, it promotes tumor cell invasion, EMT, and chemoresistance through multiple pathways—including STAT3-driven TGF-β1 transcription, p38 MAPK/JNK/c-Jun-mediated MMP-2 upregulation, HIF1α bidirectional amplification, c-Myc/MTA1-driven EMT, E2F1/KLF4-dependent stemness, and PI3K/Akt signaling—while its protein stability is controlled by the E3 ligase HERC3 (K27/K48 ubiquitination at K47/K67/K85/K121) and the deubiquitinase ATXN3, and its activity requires hypusination at K50, loss of which sensitizes AML cells to venetoclax."},"narrative":{"mechanistic_narrative":"EIF5A2 encodes a hypusine-modified isoform of the eukaryotic translation factor eIF5A whose activity, like that of eIF5A1, depends on the spermidine-derived hypusine modification at lysine-50; CRISPR K50R knock-in mice confirm hypusination is required for activation and reveal that its loss reshapes the cellular metabolite landscape [PMID:11161802, PMID:36848144]. Its synthesis is gated translationally: elements in the 5'-UTR render its mRNA inefficiently translated [PMID:16519677], and polyamines relieve this block by inhibiting miR-6514-5p, which otherwise represses eIF5A2 translation at the 5'-UTR [PMID:40617352]. Functionally, eIF5A2 acts as a translation elongation factor that selectively promotes synthesis of proline-rich proteins such as MTFR1, and as an oncogene it drives anchorage-independent growth, tumor formation, invasion, and epithelial-mesenchymal transition (EMT) across multiple cancer types [PMID:15205331, PMID:41730614]. Several of its pro-metastatic outputs converge on transcriptional programs—it stabilizes STAT3 to activate TGF-β1 transcription and downstream Smad2/3 signaling [PMID:24504366, PMID:32138807], enriches c-Myc on the MTA1 promoter to drive EMT [PMID:21813470], and engages an E2F1/KLF4 axis for cancer stemness [PMID:33726845]—and it amplifies angiogenesis through p38/JNK/c-Jun-driven MMP-2 and a bidirectional loop with HIF1α [PMID:25071013, PMID:24561231]. eIF5A2 protein levels are set by competing ubiquitin machinery: the E3 ligase HERC3 binds via its RCC1 domain and catalyzes K27/K48-linked ubiquitination at K47/K67/K85/K121 for proteasomal degradation [PMID:35064108], TRIM71 likewise destabilizes the protein [PMID:39579322], while the deubiquitinase ATXN3 stabilizes it [PMID:34428509]. Loss of eIF5A2 activity—via gene hypermethylation or hypusination inhibition—sensitizes AML cells to venetoclax [PMID:41606290].","teleology":[{"year":2001,"claim":"Established that EIF5A2 is a distinct eIF5A isoform predicted to carry the hypusine modification essential for eIF5A activity, defining the protein's basic identity.","evidence":"Molecular cloning and gene-structure/sequence analysis of the 153-residue protein","pmids":["11161802"],"confidence":"Medium","gaps":["Hypusination of eIF5A2 inferred from sequence identity, not directly demonstrated here","No functional or cellular role established"]},{"year":2004,"claim":"Resolved whether EIF5A2 amplification has biological consequence by showing it is a tumorigenic oncogene whose suppression limits cancer cell growth.","evidence":"Soft-agar colony formation, nude-mouse xenograft, antisense knockdown in amplified ovarian cancer cells","pmids":["15205331"],"confidence":"High","gaps":["Molecular mechanism of transformation not defined","No translation-factor activity tested"]},{"year":2006,"claim":"Addressed how EIF5A2 expression is constrained by demonstrating hypusination occurs but mRNA translation is inefficient due to UTR elements, while the protein is stable once made.","evidence":"Polysome fractionation, heterologous expression, pulse-chase stability assay","pmids":["16519677"],"confidence":"Medium","gaps":["Specific UTR element and trans-acting factor not identified","Single lab"]},{"year":2011,"claim":"Connected EIF5A2 to metastasis mechanistically by showing it drives EMT through c-Myc-dependent MTA1 induction, and organismally that its overexpression accelerates aging via p19/p53 destabilization and chromosomal instability.","evidence":"Reciprocal gain/loss-of-function, ChIP, MTA1 epistasis rescue, in vivo metastasis; separate transgenic mouse with cytogenetics","pmids":["21813470","21612665"],"confidence":"High","gaps":["Link between translation-factor activity and transcriptional outputs unexplained","How eIF5A2 enriches c-Myc on the promoter unclear"]},{"year":2014,"claim":"Mapped multiple downstream effector pathways: EIF5A2 stabilizes STAT3 to transcribe TGF-β1 (EMT), activates p38/JNK/c-Jun to raise MMP-2 (angiogenesis), and forms a bidirectional amplification loop with HIF1α.","evidence":"ChIP, nuclear fractionation, luciferase reporters, knockdown/overexpression, xenograft vessel and perfusion assays","pmids":["24504366","25071013","24561231"],"confidence":"High","gaps":["Whether these pathways are direct consequences of eIF5A2 translation activity not shown","Convergence vs. context-specificity of pathways unresolved"]},{"year":2021,"claim":"Extended the oncogenic program to stemness (E2F1/KLF4), hormone-dependent regulation (AR induces EIF5A2), and established ATXN3 as a deubiquitinase that stabilizes eIF5A2.","evidence":"CRISPR KO/overexpression, RNA-seq, sphere assays, epistasis rescue, DHT/bicalutamide treatment, Co-IP and ubiquitination assays","pmids":["33827661","33726845","34864817","34428509"],"confidence":"Medium","gaps":["DUB site specificity on eIF5A2 not mapped","AR regulation mechanism (direct vs indirect) not defined"]},{"year":2022,"claim":"Defined the principal degradative control of eIF5A2 by identifying HERC3 as the E3 ligase that ubiquitinates specific lysines for proteasomal turnover, and added AGR2 as a downstream effector.","evidence":"Co-IP, GST pulldown, linkage-specific ubiquitination, site-directed mutagenesis, in vitro/in vivo ubiquitination; separate Co-IP and epistasis for AGR2","pmids":["35064108","35640539"],"confidence":"High","gaps":["What signals control HERC3 vs ATXN3 balance unknown","AGR2 interaction validated by single Co-IP"]},{"year":2023,"claim":"Validated hypusination at K50 as essential for eIF5A2 activation in vivo and revealed metabolic consequences of its loss.","evidence":"CRISPR K50R knock-in mouse, anti-hypusine Western blot, fibroblast metabolomics","pmids":["36848144"],"confidence":"High","gaps":["Mechanistic link between hypusine loss and the metabolite changes not established","Translation targets responsible not identified"]},{"year":2025,"claim":"Established the translational regulatory circuit and demonstrated eIF5A2 has distinct (non-redundant with eIF5A1) protein-synthesis targets relevant to cancer growth.","evidence":"Polyamine/miR-6514-5p analysis, 5'-UTR reporters, isoform-specific siRNA, quantitative proteomics","pmids":["40617352"],"confidence":"High","gaps":["Full repertoire of eIF5A2-specific translated mRNAs incomplete","How the distinct targets produce the oncogenic phenotype unresolved"]},{"year":2026,"claim":"Linked eIF5A2 elongation activity to a defined motif preference (proline-rich proteins, e.g. MTFR1) and to therapeutic vulnerabilities, including venetoclax sensitization upon loss of activity and small-molecule elongation inhibitors.","evidence":"MTFR1 reporter HTS, siRNA, invasion assays; AML methylation and hypusination-inhibition venetoclax assays","pmids":["41730614","41606290"],"confidence":"Medium","gaps":["Mechanism connecting elongation inhibition to venetoclax sensitivity not defined","Inhibitor specificity for eIF5A2 vs eIF5A1 not established"]},{"year":null,"claim":"How eIF5A2's core function as a hypusine-dependent elongation factor for specific (proline-rich) mRNAs mechanistically generates its diverse transcriptional and signaling outputs—and which translated targets are responsible for each oncogenic pathway—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of eIF5A2-ribosome engagement in the corpus","Causal chain from elongation activity to STAT3/c-Myc/HIF1α outputs not demonstrated","Tissue-specific determinants of which pathway dominates unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1,18,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,6,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,8,22,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,13,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,10]}],"complexes":[],"partners":["STAT3","HERC3","ATXN3","TRIM71","AGR2","HIF1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9GZV4","full_name":"Eukaryotic translation initiation factor 5A-2","aliases":["Eukaryotic initiation factor 5A isoform 2"],"length_aa":153,"mass_kda":16.8,"function":"Translation factor that promotes translation elongation and termination, particularly upon ribosome stalling at specific amino acid sequence contexts (PubMed:14622290). Binds between the exit (E) and peptidyl (P) site of the ribosome and promotes rescue of stalled ribosome: specifically required for efficient translation of polyproline-containing peptides as well as other motifs that stall the ribosome. Acts as a ribosome quality control (RQC) cofactor by joining the RQC complex to facilitate peptidyl transfer during CAT tailing step (By similarity). Also involved in actin dynamics and cell cycle progression, mRNA decay and probably in a pathway involved in stress response and maintenance of cell wall integrity (By similarity)","subcellular_location":"Cytoplasm; Nucleus; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9GZV4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF5A2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EIF5A2","total_profiled":1310},"omim":[{"mim_id":"605782","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 5A2; 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The gene spans 17 kb with 5 exons and produces two mRNAs via differential polyadenylation sharing the same coding sequence.\",\n      \"method\": \"Molecular cloning, sequence characterization, gene structure analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular characterization of gene structure and protein sequence conservation; hypusine modification inferred from sequence identity with eIF5A1 rather than directly demonstrated for eIF5A2 in this paper, single study\",\n      \"pmids\": [\"11161802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"eIF5A-2 precursor protein is modified by hypusination comparably to eIF5A-1 in UACC-1598 cells. eIF5A-2 mRNA is inefficiently translated relative to eIF5A-1, with only a small fraction associating with polysomes; the elements causing inefficient translation reside outside the open reading frame (within the UTRs). Both isoforms are similarly stable once synthesized.\",\n      \"method\": \"Sucrose gradient polysome fractionation, mammalian expression vectors in 293T cells, Western blot, pulse-chase stability assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (polysome fractionation, heterologous expression, protein stability); single lab\",\n      \"pmids\": [\"16519677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EIF5A2 has tumorigenic activity: ectopic expression enables anchorage-independent growth in soft agar and tumor formation in nude mice. Antisense DNA against eIF5A2 inhibits cell growth in an ovarian cancer cell line (UACC-1598) that harbors EIF5A2 amplification as double minutes.\",\n      \"method\": \"Soft agar colony formation, nude mouse xenograft, antisense oligonucleotide knockdown, copy-number reduction\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both gain-of-function (soft agar, nude mouse) and loss-of-function (antisense knockdown) experiments in the same study; replicated by multiple subsequent studies\",\n      \"pmids\": [\"15205331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EIF5A2 overexpression promotes colorectal carcinoma cell motility, invasion, and epithelial-mesenchymal transition (EMT) in vitro and metastasis in vivo. Mechanistically, EIF5A2 upregulates MTA1 via enhanced enrichment of c-Myc on the MTA1 promoter; MTA1 knockdown eliminates EIF5A2-driven migration, invasion, and EMT.\",\n      \"method\": \"Ectopic overexpression and siRNA knockdown in CRC cell lines, in vitro invasion/migration assays, in vivo metastasis model, ChIP assay for c-Myc on MTA1 promoter, epistasis by MTA1 siRNA rescue\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function, ChIP mechanistic evidence, epistasis rescue experiment, in vivo validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21813470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Transgenic overexpression of eIF5A2 in mice accelerates organismal aging (decreased growth, shortened lifespan, kyphosis, osteoporosis, impaired wound healing) by increasing chromosomal instability. Mechanistically, eIF5A2 represses p19 (ARF), thereby destabilizing p53 in mouse embryo fibroblasts, leading to accumulation of mitotic errors (misaligned/lagging chromosomes, anaphase bridges, micronuclei) and increased aneuploidy.\",\n      \"method\": \"eIF5A2 transgenic mouse model, MEF isolation, immunohistochemistry, Western blot (p19, p53), cytogenetic analysis of mitotic figures, flow cytometry for aneuploidy\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with mechanistic follow-up (p19/p53 pathway, cytogenetics); single lab\",\n      \"pmids\": [\"21612665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EIF5A2 is a downstream target of phosphorylated Akt (PI3K/Akt pathway) in melanoma cells. EIF5A2 overexpression increases, and knockdown decreases, melanoma cell invasion and MMP-2 activity.\",\n      \"method\": \"Tissue microarray, EIF5A2 overexpression/knockdown in melanoma cell lines, invasion assay, zymography for MMP-2 activity, correlation with Akt phosphorylation status\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assays with both gain and loss of function plus pathway placement by correlation with p-Akt; single lab, no direct epistasis experiment\",\n      \"pmids\": [\"24178756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EIF5A2 activates TGF-β1 expression to induce EMT in bladder cancer cells. Specifically, EIF5A2 stabilizes STAT3 and stimulates its nuclear localization, resulting in increased STAT3 binding to the TGF-β1 promoter and enhanced TGF-β1 transcription.\",\n      \"method\": \"EIF5A2 overexpression and knockdown in bladder cancer cell lines, ChIP assay for STAT3 on TGF-β1 promoter, Western blot for STAT3 nuclear localization, EMT marker analysis, in vivo metastasis model\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including ChIP, nuclear fractionation, EMT markers, in vivo validation; clear mechanistic pathway (EIF5A2→STAT3 nuclear localization→TGF-β1 transcription→EMT)\",\n      \"pmids\": [\"24504366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EIF5A2 ablation in hepatocellular carcinoma inhibits tumor angiogenesis by reducing MMP-2 expression. EIF5A2 silencing increases vessel wall continuity, blood perfusion, and tumor oxygenation. EIF5A2 enhances MMP-2 activity via activation of the p38 MAPK and JNK/c-Jun signaling pathways.\",\n      \"method\": \"EIF5A2 knockdown in HCC cell lines and xenografts, fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays, tumor hypoxia assays, Western blot for p38/JNK/c-Jun\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary in vitro and in vivo methods, defined signaling pathway (p38 MAPK/JNK/c-Jun→MMP-2), single lab but highly orthogonal approaches\",\n      \"pmids\": [\"25071013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EIF5A2 is induced by hypoxia (4–8 fold) in esophageal squamous cell carcinoma cells, and there is bidirectional regulation between EIF5A2 and HIF1α (each upregulates the other). EIF5A2 promotes HIF1α expression and downstream VEGF, contributing to angiogenesis and EMT.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (HIF1α on EIF5A2 promoter), quantitative RT-PCR, EIF5A2 overexpression/knockdown, xenograft tumors with vessel counting\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP and luciferase reporter demonstrate direct HIF1α regulation of EIF5A2, bidirectionality shown with functional assays and in vivo xenograft; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24561231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HERC3 E3 ubiquitin ligase directly interacts with EIF5A2 via its RCC1 domain, promotes K27- and K48-linked ubiquitination of EIF5A2 via its HECT domain, and targets EIF5A2 for proteasomal degradation. The ubiquitination sites on EIF5A2 were identified as K47, K67, K85, and K121. HERC3-mediated degradation of EIF5A2 inhibits EMT through the TGF-β/Smad2/3 pathway.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, immunoprecipitation with ubiquitin linkage-specific antibodies, site-directed mutagenesis of EIF5A2 lysine residues, in vivo and in vitro ubiquitination assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution of ubiquitination (Co-IP, GST pulldown, in vitro ubiquitination), mutagenesis to identify specific ubiquitination sites, domain mapping; single lab but rigorous multi-method approach\",\n      \"pmids\": [\"35064108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EIF5A2 promotes EMT in ovarian cancer cells via activation of the TGFβ pathway. CRISPR/Cas9 knockout of EIF5A2 inhibits EMT, cell migration, invasion, and ovarian tumor growth and metastasis in orthotopic mouse models, while EIF5A2 overexpression promotes these phenotypes.\",\n      \"method\": \"Lentiviral CRISPR/Cas9 nickase knockout, lentiviral overexpression, in vitro migration/invasion assays, orthotopic ovarian cancer mouse model, Western blot for TGFβ pathway and EMT markers\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR-mediated KO (most rigorous LOF), OE gain-of-function, in vivo orthotopic model; multiple cancer lines and complementary approaches\",\n      \"pmids\": [\"33827661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EIF5A2 promotes stemness in ovarian cancer cells via the E2F1/KLF4 pathway. EIF5A2 knockdown reduces KLF4 expression through E2F1, and KLF4 overexpression can partially rescue stem-like properties abolished by EIF5A2 knockdown; the transcription factor E2F1 directly binds the KLF4 promoter.\",\n      \"method\": \"EIF5A2 knockdown (siRNA), RNA-seq, sphere-forming assays, western blot, flow cytometry, in vivo xenograft, E2F1 epistasis rescue experiments\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq pathway identification, epistasis rescue experiment, in vivo validation; single lab\",\n      \"pmids\": [\"33726845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Androgen receptor (AR) positively regulates EIF5A2 expression in androgen-dependent prostate cancer cells in response to DHT stimulation; anti-androgen bicalutamide reduces EIF5A2 expression. EIF5A2 knockdown eliminates DHT-induced EMT and invasion/migration.\",\n      \"method\": \"DHT stimulation and bicalutamide treatment of AR-positive/negative PCa cell lines, EIF5A2 knockdown, Western blot for EMT markers, in vivo lung metastasis assay with luciferase imaging\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic and genetic manipulation, in vivo metastasis readout, epistasis (EIF5A2 KD blocks DHT-EMT); single lab\",\n      \"pmids\": [\"34864817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The deubiquitinating enzyme ATXN3 directly binds EIF5A2 and stabilizes it by reducing its ubiquitination and proteasomal degradation; ATXN3 promotes EIF5A2-dependent proliferation and metastasis in anaplastic thyroid carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, gain/loss-of-function experiments, Western blot for EIF5A2 stability\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay establish direct interaction and deubiquitination; functional rescue confirms EIF5A2 as downstream effector; single lab\",\n      \"pmids\": [\"34428509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EIF5A2 interacts with AGR2 (anterior gradient 2) by co-immunoprecipitation in cervical cancer cells; AGR2 overexpression reverses the reduction in proliferation, migration, invasion, and cisplatin sensitivity caused by EIF5A2 knockdown, placing AGR2 downstream of EIF5A2.\",\n      \"method\": \"Co-immunoprecipitation, EIF5A2 knockdown, AGR2 overexpression epistasis rescue, proliferation/apoptosis/invasion assays\",\n      \"journal\": \"Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP identifies binding partner and epistasis places AGR2 downstream; single lab, single Co-IP method\",\n      \"pmids\": [\"35640539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EIF5A2 promotes doxorubicin resistance in bladder cancer cells through the TGF-β signaling pathway; EIF5A2 upregulates TGF-β1, p-Smad2, and p-Smad3, and a TGF-β pathway activator (SRI-011381) reverses the sensitizing effect of EIF5A2 knockdown.\",\n      \"method\": \"Doxorubicin-resistant cell line construction, EIF5A2 siRNA knockdown, TGF-β pathway activator rescue, Western blot for TGF-β1/p-Smad2/3, CCK-8 viability assay\",\n      \"journal\": \"Discovery medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic pathway rescue places EIF5A2 upstream of TGF-β/Smad; single lab, limited methods\",\n      \"pmids\": [\"38058082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EIF5A2 K50R knock-in mice (CRISPR-Cas9) preventing hypusination at lysine-50 confirm that hypusine formation is required for eIF5A2 activation; metabolomic analysis of primary mouse dermal fibroblasts from eif5a2-K50R/K50R mice reveals significant alterations in the metabolite landscape, including increased tryptophan, kynurenine, pyridoxine, NAD, riboflavin, FAD, pantothenate, and CoA levels compared to controls.\",\n      \"method\": \"CRISPR-Cas9 K50R knock-in mouse model, Western blot with anti-hypusine antibody, metabolomics of primary dermal fibroblasts\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo genetic model with site-specific mutagenesis blocking PTM, confirmed biochemically; metabolomic profiling provides functional consequence of loss of hypusination\",\n      \"pmids\": [\"36848144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM71 (tripartite motif containing 71) directly interacts with eIF5A2 (verified by co-immunoprecipitation) and decreases eIF5A2 protein stability without affecting its mRNA level; TRIM71 overexpression inhibits LSCC tumor growth, and this anti-tumor effect is abolished by eIF5A2 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide chase assay (protein half-life), quantitative PCR (mRNA level unchanged), overexpression epistasis rescue, in vivo xenograft\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, protein stability assay, and epistasis experiment; single lab but orthogonal methods\",\n      \"pmids\": [\"39579322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EIF5A2 protein synthesis is regulated at the translational level by polyamines: miR-6514-5p binds the 5'-UTR of eIF5A2 mRNA and negatively regulates its translation; polyamines inhibit miR-6514-5p function, thereby facilitating eIF5A2 synthesis. Proteomic analysis shows eIF5A2 and eIF5A1 regulate distinct sets of proteins, and eIF5A2 (not eIF5A1) is important for cancer cell growth. eIF5A2 silencing differentially regulates specific ribosomal proteins (RPS27A, RPL36A, RPL22L1) associated with cancer malignancy.\",\n      \"method\": \"Polyamine treatment with miR-6514-5p analysis, 5'-UTR reporter assays, eIF5A1/eIF5A2-specific siRNA knockdown, quantitative proteomics, cell proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct mechanistic dissection of translational regulation via 5'-UTR and miRNA, orthogonal proteomics showing distinct eIF5A1 vs eIF5A2 targets, multiple methods in single rigorous study\",\n      \"pmids\": [\"40617352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"eIF5A2-dependent translation elongation specifically regulates the synthesis of proteins with proline-rich motifs, including MTFR1 (mitochondrial fission regulator 1). A high-throughput screen identified orlistat and andrographolide as inhibitors of eIF5A2-dependent translation elongation. eIF5A2 silencing and these inhibitors suppress heparanase 1 (but not MMP-2 or MMP-9) expression and inhibit cancer cell invasion.\",\n      \"method\": \"MTFR1-luciferase reporter high-throughput screen (1744 compounds), eIF5A2 siRNA knockdown, invasion assays, Western blot for heparanase 1/MMP2/MMP9\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter-based functional screen with mechanistic validation by siRNA and protein expression; single lab, limited independent replication\",\n      \"pmids\": [\"41730614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss of EIF5A2 activity—either through gene hypermethylation (epigenetic silencing) or pharmacological inhibition of its hypusine post-translational modification—induces venetoclax sensitivity in AML cells.\",\n      \"method\": \"Gene methylation analysis, pharmacological inhibition of hypusination, venetoclax sensitivity assays in AML cell lines\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two convergent loss-of-function approaches (epigenetic and pharmacologic) produce same sensitization phenotype; single report, abstract lacks full mechanistic detail\",\n      \"pmids\": [\"41606290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-9 enhances chemosensitivity to daunorubicin in AML cells by targeting EIF5A2; EIF5A2 knockdown reduces MCL-1 expression, and the sensitizing effect of miR-9 requires downregulation of EIF5A2, placing MCL-1 downstream of EIF5A2 in this context.\",\n      \"method\": \"miR-9 overexpression/knockdown, EIF5A2 siRNA, Western blot for MCL-1, cell viability and apoptosis assays, epistasis by EIF5A2 rescue of miR-9 effects\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis experiment places MCL-1 downstream of EIF5A2; single lab, mechanistic chain validated by rescue experiment\",\n      \"pmids\": [\"30745844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EIF5A2 controls EMT and chemoresistance in thyroid and other cancers via the TGF-β/Smad2/3 signaling pathway. In anaplastic thyroid carcinoma, EIF5A2 overexpression upregulates p-Smad2/3, and TGF-β pathway inhibition (SB431542 or Smad3 siRNA) blocks the growth-promoting effect of EIF5A2 overexpression.\",\n      \"method\": \"shRNA knockdown, ectopic overexpression, recombinant TGF-β1 rescue, SB431542 pharmacological inhibition, Smad3 siRNA, Western blot for p-Smad2/3, in vitro and xenograft experiments\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic and genetic epistasis confirms TGF-β/Smad2/3 pathway positioning; single lab, multiple orthogonal perturbations\",\n      \"pmids\": [\"32138807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EIF5A2 overexpression activates the PI3K/AKT/mTOR signaling pathway and upregulates Cyclin D1, Cyclin D3, MMP2, and MMP9 to promote intrahepatic cholangiocarcinoma cell proliferation, migration, and invasion.\",\n      \"method\": \"EIF5A2 overexpression/knockdown, Western blot for PI3K/AKT/mTOR components and cell cycle proteins, proliferation (CCK-8, EdU), invasion/migration (Transwell, scratch) assays\",\n      \"journal\": \"Clinics and research in hepatology and gastroenterology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Western blot pathway analysis without pharmacological epistasis; pathway placement inferred from protein level changes\",\n      \"pmids\": [\"35792239\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF5A2 is a hypusine-modified translation elongation factor whose protein synthesis is regulated by polyamines via miR-6514-5p at the 5'-UTR; once expressed, it promotes tumor cell invasion, EMT, and chemoresistance through multiple pathways—including STAT3-driven TGF-β1 transcription, p38 MAPK/JNK/c-Jun-mediated MMP-2 upregulation, HIF1α bidirectional amplification, c-Myc/MTA1-driven EMT, E2F1/KLF4-dependent stemness, and PI3K/Akt signaling—while its protein stability is controlled by the E3 ligase HERC3 (K27/K48 ubiquitination at K47/K67/K85/K121) and the deubiquitinase ATXN3, and its activity requires hypusination at K50, loss of which sensitizes AML cells to venetoclax.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EIF5A2 encodes a hypusine-modified isoform of the eukaryotic translation factor eIF5A whose activity, like that of eIF5A1, depends on the spermidine-derived hypusine modification at lysine-50; CRISPR K50R knock-in mice confirm hypusination is required for activation and reveal that its loss reshapes the cellular metabolite landscape [#0, #16]. Its synthesis is gated translationally: elements in the 5'-UTR render its mRNA inefficiently translated [#1], and polyamines relieve this block by inhibiting miR-6514-5p, which otherwise represses eIF5A2 translation at the 5'-UTR [#18]. Functionally, eIF5A2 acts as a translation elongation factor that selectively promotes synthesis of proline-rich proteins such as MTFR1, and as an oncogene it drives anchorage-independent growth, tumor formation, invasion, and epithelial-mesenchymal transition (EMT) across multiple cancer types [#2, #19]. Several of its pro-metastatic outputs converge on transcriptional programs—it stabilizes STAT3 to activate TGF-β1 transcription and downstream Smad2/3 signaling [#6, #22], enriches c-Myc on the MTA1 promoter to drive EMT [#3], and engages an E2F1/KLF4 axis for cancer stemness [#11]—and it amplifies angiogenesis through p38/JNK/c-Jun-driven MMP-2 and a bidirectional loop with HIF1α [#7, #8]. eIF5A2 protein levels are set by competing ubiquitin machinery: the E3 ligase HERC3 binds via its RCC1 domain and catalyzes K27/K48-linked ubiquitination at K47/K67/K85/K121 for proteasomal degradation [#9], TRIM71 likewise destabilizes the protein [#17], while the deubiquitinase ATXN3 stabilizes it [#13]. Loss of eIF5A2 activity—via gene hypermethylation or hypusination inhibition—sensitizes AML cells to venetoclax [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that EIF5A2 is a distinct eIF5A isoform predicted to carry the hypusine modification essential for eIF5A activity, defining the protein's basic identity.\",\n      \"evidence\": \"Molecular cloning and gene-structure/sequence analysis of the 153-residue protein\",\n      \"pmids\": [\"11161802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hypusination of eIF5A2 inferred from sequence identity, not directly demonstrated here\", \"No functional or cellular role established\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved whether EIF5A2 amplification has biological consequence by showing it is a tumorigenic oncogene whose suppression limits cancer cell growth.\",\n      \"evidence\": \"Soft-agar colony formation, nude-mouse xenograft, antisense knockdown in amplified ovarian cancer cells\",\n      \"pmids\": [\"15205331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of transformation not defined\", \"No translation-factor activity tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Addressed how EIF5A2 expression is constrained by demonstrating hypusination occurs but mRNA translation is inefficient due to UTR elements, while the protein is stable once made.\",\n      \"evidence\": \"Polysome fractionation, heterologous expression, pulse-chase stability assay\",\n      \"pmids\": [\"16519677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific UTR element and trans-acting factor not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected EIF5A2 to metastasis mechanistically by showing it drives EMT through c-Myc-dependent MTA1 induction, and organismally that its overexpression accelerates aging via p19/p53 destabilization and chromosomal instability.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function, ChIP, MTA1 epistasis rescue, in vivo metastasis; separate transgenic mouse with cytogenetics\",\n      \"pmids\": [\"21813470\", \"21612665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between translation-factor activity and transcriptional outputs unexplained\", \"How eIF5A2 enriches c-Myc on the promoter unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped multiple downstream effector pathways: EIF5A2 stabilizes STAT3 to transcribe TGF-β1 (EMT), activates p38/JNK/c-Jun to raise MMP-2 (angiogenesis), and forms a bidirectional amplification loop with HIF1α.\",\n      \"evidence\": \"ChIP, nuclear fractionation, luciferase reporters, knockdown/overexpression, xenograft vessel and perfusion assays\",\n      \"pmids\": [\"24504366\", \"25071013\", \"24561231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these pathways are direct consequences of eIF5A2 translation activity not shown\", \"Convergence vs. context-specificity of pathways unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the oncogenic program to stemness (E2F1/KLF4), hormone-dependent regulation (AR induces EIF5A2), and established ATXN3 as a deubiquitinase that stabilizes eIF5A2.\",\n      \"evidence\": \"CRISPR KO/overexpression, RNA-seq, sphere assays, epistasis rescue, DHT/bicalutamide treatment, Co-IP and ubiquitination assays\",\n      \"pmids\": [\"33827661\", \"33726845\", \"34864817\", \"34428509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DUB site specificity on eIF5A2 not mapped\", \"AR regulation mechanism (direct vs indirect) not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the principal degradative control of eIF5A2 by identifying HERC3 as the E3 ligase that ubiquitinates specific lysines for proteasomal turnover, and added AGR2 as a downstream effector.\",\n      \"evidence\": \"Co-IP, GST pulldown, linkage-specific ubiquitination, site-directed mutagenesis, in vitro/in vivo ubiquitination; separate Co-IP and epistasis for AGR2\",\n      \"pmids\": [\"35064108\", \"35640539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What signals control HERC3 vs ATXN3 balance unknown\", \"AGR2 interaction validated by single Co-IP\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Validated hypusination at K50 as essential for eIF5A2 activation in vivo and revealed metabolic consequences of its loss.\",\n      \"evidence\": \"CRISPR K50R knock-in mouse, anti-hypusine Western blot, fibroblast metabolomics\",\n      \"pmids\": [\"36848144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between hypusine loss and the metabolite changes not established\", \"Translation targets responsible not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established the translational regulatory circuit and demonstrated eIF5A2 has distinct (non-redundant with eIF5A1) protein-synthesis targets relevant to cancer growth.\",\n      \"evidence\": \"Polyamine/miR-6514-5p analysis, 5'-UTR reporters, isoform-specific siRNA, quantitative proteomics\",\n      \"pmids\": [\"40617352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of eIF5A2-specific translated mRNAs incomplete\", \"How the distinct targets produce the oncogenic phenotype unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked eIF5A2 elongation activity to a defined motif preference (proline-rich proteins, e.g. MTFR1) and to therapeutic vulnerabilities, including venetoclax sensitization upon loss of activity and small-molecule elongation inhibitors.\",\n      \"evidence\": \"MTFR1 reporter HTS, siRNA, invasion assays; AML methylation and hypusination-inhibition venetoclax assays\",\n      \"pmids\": [\"41730614\", \"41606290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting elongation inhibition to venetoclax sensitivity not defined\", \"Inhibitor specificity for eIF5A2 vs eIF5A1 not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How eIF5A2's core function as a hypusine-dependent elongation factor for specific (proline-rich) mRNAs mechanistically generates its diverse transcriptional and signaling outputs—and which translated targets are responsible for each oncogenic pathway—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of eIF5A2-ribosome engagement in the corpus\", \"Causal chain from elongation activity to STAT3/c-Myc/HIF1α outputs not demonstrated\", \"Tissue-specific determinants of which pathway dominates unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1, 18, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 6, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [18, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 8, 22, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 13, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STAT3\", \"HERC3\", \"ATXN3\", \"TRIM71\", \"AGR2\", \"HIF1A\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}