{"gene":"ELOC","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2022,"finding":"ELOC (elongin C) encodes a key component of the VCB-CR E3 ubiquitin ligase complex (comprising pVHL, elongin C, elongin B, cullin 2, and ring box 1), which mediates oxygen sensing and degradation of hypoxia-inducible factors. A germline de novo pathogenic variant ELOC p.Tyr79Cys was shown to mimic the effects of pVHL deficiency on hypoxic signalling, and tumor analysis demonstrated chromosome 8 loss and expression of hypoxia-responsive proteins consistent with loss of VCB-CR complex activity.","method":"Whole-exome sequencing of proband trio, paired tumor/blood DNA analysis, bioinformatics analysis of RCC dataset, immunohistochemistry for hypoxia-responsive proteins","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal molecular and tumor analysis in a single study with orthogonal methods (WES, IHC, LOH analysis), single lab","pmids":["35323939"],"is_preprint":false},{"year":2025,"finding":"A germline ELOC p.E92G variant in a multigenerational family causes VHL disease manifestations (hemangioblastomas, ccRCC, pancreatic neuroendocrine tumors, pheochromocytomas). Tumor analysis demonstrated loss of heterozygosity at chromosome 8 (encoding ELOC), consistent with biallelic ELOC inactivation and loss of VCB-Cul2 E3-ubiquitin ligase complex activity. Treatment with belzutifan (a HIF-2α inhibitor) caused tumor regression, confirming that these tumors are driven by HIF pathway activation downstream of ELOC loss.","method":"Germline sequencing, tumor LOH analysis, chromosomal copy number analysis, clinical response to belzutifan (HIF-2α inhibitor)","journal":"Urologic oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — germline variant co-segregation, tumor LOH, pharmacological rescue with HIF-2α inhibitor, single family study","pmids":["41224595"],"is_preprint":false},{"year":2023,"finding":"ELOC mutations (especially Y79C) result in biallelic ELOC inactivation in RCC and are mutually exclusive with biallelic VHL aberrations. A novel ELOC duplication variant was modeled by High Ambiguity Driven biomolecular DOCKing to disrupt the ELOC-VHL interaction interface. Mass spectrometry (hyper reaction monitoring) showed that RCCs with biallelic ELOC alterations have significantly reduced ELOC expression but similar carbonic anhydrase 9 and VEGF-A expression compared with VHL-null ccRCC, indicating convergent HIF pathway activation.","method":"OncoScan copy number analysis, whole-exome sequencing, computational docking (HADDOCK), hyper reaction monitoring mass spectrometry","journal":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — molecular docking for structural claim (computational, not experimental structure), MS proteomics for expression; single lab, multiple orthogonal methods","pmids":["37088333"],"is_preprint":false},{"year":2019,"finding":"TCEB1 (ELOC) hotspot mutations in RCC (Y79C/S/F/N) were experimentally shown to always affect residues involved in hydrophobic interactions with VHL, and all tumors showed biallelic inactivation of the TCEB1 gene by combined somatic mutation and copy number alteration analysis, consistent with a tumor suppressor mechanism disrupting the VHL-elongin C interaction.","method":"Somatic mutation analysis, copy number alteration analysis, cancer cell fraction estimation (clonal analysis)","journal":"European urology focus","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biallelic inactivation confirmed across multiple tumors by orthogonal methods (sequencing + CNA), but mechanistic detail (hydrophobic interactions with VHL) is computationally inferred from mutation position, not directly assayed","pmids":["31813809"],"is_preprint":false},{"year":2009,"finding":"shRNA-mediated silencing of TCEB1 (ELOC) significantly decreased cellular invasion of prostate cancer cells (PC-3 and DU145) through Matrigel and reduced anchorage-independent growth of PC-3 cells. Transcriptional profiling of TCEB1-silenced cells revealed decreased expression of genes involved in invasion and metastasis. Overexpression of TCEB1 in NIH 3T3 cells increased growth rate.","method":"Lentivirus-mediated shRNA knockdown, Matrigel invasion assay, anchorage-independent growth assay, transcriptional profiling, lentiviral overexpression","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function experiments in multiple cell lines with defined cellular phenotypic readouts, single lab","pmids":["18844214"],"is_preprint":false},{"year":2025,"finding":"Fragment screening of the VHL-ELOB-ELOC (VBC) complex identified 7-hydroxycoumarin (7HC) derivatives that bind specifically to the ELOC component rather than VHL. The 7HC binding site on ELOC overlaps with the CUL2 binding interface but not the CUL5 binding interface, indicating that these compounds may selectively modulate CRL2 (but not CRL5) complex formation by competing with CUL2 for ELOC binding.","method":"Fragment screening, X-ray crystallography or binding assays (implied by binding site characterization), interface mapping","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — binding site characterization described but structural method not explicitly named in abstract; single lab, mechanistic inference from binding site overlap","pmids":["39881207"],"is_preprint":false},{"year":2014,"finding":"Computational modeling of HIV Vif showed that residues L146 and L149 of the BC-box motif bind to ELOC (EloC) by hydrophobic interactions, and residue P162 of the PPLP motif is important for EloB binding. Molecular dynamics simulation evaluated stability of the Vif-EloBC complex.","method":"Ab initio protein modeling (Rosetta), molecular docking, molecular dynamics simulation","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 / Weak — purely computational (ab initio modeling, docking, MD simulation), no experimental validation of the binding interface in this study","pmids":["24586532"],"is_preprint":false},{"year":2021,"finding":"STAU1 (Staufen1) was shown to bind SPRY4-IT1 lncRNA, which promotes STAU1 recruitment to the 3'-UTR of TCEB1 mRNA (via Alu element base-pairing between SPRY4-IT1 and TCEB1 3'-UTR), leading to STAU1-mediated mRNA decay (SMD) of TCEB1, reduced TCEB1 protein, and consequent upregulation of HIF-1α. STAU1 depletion abrogated TCEB1 SMD. NF-κB/p65 transactivates SPRY4-IT1 to initiate this cascade.","method":"RNA overexpression/knockdown, microarray, RNA pulldown/binding assays (STAU1-SPRY4-IT1 interaction), STAU1 depletion rescue, NF-κB reporter/ChIP (implied)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA binding, mRNA decay assay, rescue by STAU1 depletion), single lab; this concerns regulation of ELOC/TCEB1 mRNA stability, not direct protein mechanism","pmids":["34163032"],"is_preprint":false},{"year":2024,"finding":"The Vif-CBFβ-ELOB-ELOC-CUL5 (VβBCC) complex was shown by cryo-EM and SELEX to directly impede A3G-mediated DNA deamination independently of proteasomal degradation. RNA aptamers selected against the VβBCC complex restored A3G DNA deamination activity by inhibiting the complex, demonstrating that ELOC-containing VβBCC complex has a direct inhibitory function on A3G beyond promoting its ubiquitination.","method":"SELEX (aptamer selection), DNA deamination activity assay, cryo-EM (referenced from prior studies), functional inhibition assay","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional biochemical assays (DNA deamination activity) plus aptamer selection demonstrating direct complex inhibition of A3G, single lab","pmids":["38740386"],"is_preprint":false}],"current_model":"ELOC (elongin C, TCEB1) is an adaptor subunit of the VCB-CR (VHL-elongin C-elongin B-cullin 2-RBX1) E3 ubiquitin ligase complex, where it bridges VHL to the cullin scaffold via hydrophobic interactions at residues including Y79 and A100; hotspot mutations at these residues disrupt VHL binding, phenocopying VHL loss to cause HIF pathway activation and drive renal cell carcinoma through biallelic ELOC inactivation, while ELOC also participates in CRL5-containing complexes (e.g., Vif-CBFβ-ELOB-ELOC-CUL5) that ubiquitinate antiviral proteins, and ELOC expression promotes cancer cell invasion through transcriptional regulation of pro-invasive genes."},"narrative":{"mechanistic_narrative":"ELOC (elongin C, TCEB1) is an adaptor subunit of cullin-RING E3 ubiquitin ligase complexes, most prominently the VCB-CR/VBC complex (pVHL–elongin C–elongin B–cullin 2–RBX1) that mediates oxygen sensing and degradation of hypoxia-inducible factors [PMID:35323939]. Within this complex ELOC bridges VHL to the cullin scaffold through hydrophobic contacts, and germline and somatic hotspot mutations at residues such as Y79 and E92 disrupt the ELOC–VHL interface; combined with chromosome 8 loss of heterozygosity, biallelic ELOC inactivation phenocopies VHL loss, drives convergent HIF pathway activation, and causes renal cell carcinoma and a VHL-disease-like syndrome that regresses under HIF-2α inhibition [PMID:35323939, PMID:41224595, PMID:37088333, PMID:31813809]. ELOC additionally serves as an adaptor in CUL5-based complexes: as part of the HIV Vif–CBFβ–ELOB–ELOC–CUL5 assembly it directly impedes APOBEC3G DNA deamination independently of proteasomal degradation [PMID:38740386]. The ELOC binding surfaces for CUL2 and CUL5 are spatially distinct, allowing selective small-molecule modulation of CRL2 versus CRL5 assembly [PMID:39881207]. Beyond its E3 adaptor role, ELOC expression promotes cancer cell invasion and anchorage-independent growth through transcriptional regulation of pro-invasive genes [PMID:18844214], and its protein level is controlled post-transcriptionally by Staufen1-mediated decay of TCEB1 mRNA, which derepresses HIF-1α [PMID:34163032].","teleology":[{"year":2009,"claim":"Before its tumor-suppressor role was defined, ELOC was tested directly for a pro-tumorigenic cellular function, establishing that ELOC expression supports invasion and growth.","evidence":"shRNA knockdown and overexpression with Matrigel invasion, anchorage-independent growth, and transcriptional profiling in prostate cancer and NIH 3T3 cells","pmids":["18844214"],"confidence":"Medium","gaps":["Does not identify the molecular activity of ELOC mediating the invasive transcriptional program","No link to E3 ligase function established here"]},{"year":2014,"claim":"To explain how viral hijacking of ELOC occurs, the Vif binding mode was modeled, indicating that BC-box leucines engage ELOC by hydrophobic interactions.","evidence":"Ab initio modeling (Rosetta), docking, and molecular dynamics of the Vif-EloBC complex","pmids":["24586532"],"confidence":"Low","gaps":["Purely computational with no experimental validation of the interface","Does not assay complex function or ubiquitination activity"]},{"year":2019,"claim":"It was unknown whether ELOC mutations in RCC act as drivers; clonal and copy-number analysis established biallelic ELOC inactivation at the VHL-binding hotspot as a tumor-suppressor mechanism.","evidence":"Somatic mutation, copy number, and cancer cell fraction analysis of RCC tumors","pmids":["31813809"],"confidence":"Medium","gaps":["Hydrophobic interaction disruption inferred from mutation position, not directly assayed","No functional rescue or HIF readout in this study"]},{"year":2022,"claim":"Whether a germline ELOC variant could cause disease by mimicking VHL deficiency was open; a de novo Y79C variant was shown to recapitulate pVHL-deficient hypoxic signalling.","evidence":"Trio whole-exome sequencing, paired tumor/blood analysis, IHC for hypoxia-responsive proteins, RCC dataset bioinformatics","pmids":["35323939"],"confidence":"Medium","gaps":["Single proband study","Direct biochemical demonstration of disrupted VCB-CR assembly not performed"]},{"year":2023,"claim":"To distinguish ELOC-driven from VHL-driven RCC, mutual exclusivity and downstream HIF output were compared, showing convergent HIF pathway activation despite reduced ELOC expression.","evidence":"OncoScan copy number, WES, HADDOCK docking of an ELOC duplication, and hyper reaction monitoring mass spectrometry of CA9/VEGF-A","pmids":["37088333"],"confidence":"Medium","gaps":["Structural disruption modeled computationally, not by experimental structure","Single-lab proteomic cohort"]},{"year":2024,"claim":"It was unclear whether the ELOC-containing Vif-CUL5 complex acted only through degradation; functional assays revealed a direct, degradation-independent inhibition of APOBEC3G deamination.","evidence":"SELEX aptamer selection against the VβBCC complex and DNA deamination activity/inhibition assays","pmids":["38740386"],"confidence":"Medium","gaps":["Mechanism of direct A3G inhibition by the complex not structurally resolved here","Contribution of ELOC specifically versus other subunits not isolated"]},{"year":2025,"claim":"Two advances clarified ELOC druggability and disease genetics: a multigenerational E92G family established ELOC as a VHL-disease gene rescuable by HIF-2α inhibition, and fragment screening defined a ligandable ELOC pocket distinguishing CUL2 from CUL5 binding.","evidence":"Germline co-segregation, tumor LOH, belzutifan clinical response (family study); fragment screening with binding-site/interface mapping of the VBC complex","pmids":["41224595","39881207"],"confidence":"Medium","gaps":["Family study is a single pedigree","Fragment-binding structural method not explicitly defined and selective CRL2 modulation only inferred from interface overlap"]},{"year":null,"claim":"How ELOC's invasion-promoting transcriptional role mechanistically relates to its E3 adaptor function remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No molecular link between ELOC E3 adaptor activity and the pro-invasive transcriptional program","No experimental high-resolution structure of mutant ELOC interfaces in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,8]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3]}],"complexes":["VCB-CR (pVHL-elongin C-elongin B-CUL2-RBX1)","Vif-CBFβ-ELOB-ELOC-CUL5 (VβBCC)"],"partners":["VHL","ELOB","CUL2","CUL5","RBX1","VIF","CBFB","STAU1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15369","full_name":"Elongin-C","aliases":["Elongin 15 kDa subunit","RNA polymerase II transcription factor SIII subunit C","SIII p15","Transcription elongation factor B polypeptide 1"],"length_aa":112,"mass_kda":12.5,"function":"SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex) (PubMed:7821821). In embryonic stem cells, the elongin BC complex is recruited by EPOP to Polycomb group (PcG) target genes in order generate genomic region that display both active and repressive chromatin properties, an important feature of pluripotent stem cells (By similarity) Core component of multiple cullin-RING-based ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins (PubMed:10205047, PubMed:12004076, PubMed:12050673, PubMed:15590694, PubMed:21199876, PubMed:26138980, PubMed:29775578, PubMed:29779948, PubMed:30166453, PubMed:33268465, PubMed:38326650, PubMed:35512830, PubMed:37844242, PubMed:39039081, PubMed:40440427). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes (PubMed:10205047, PubMed:12004076, PubMed:12050673, PubMed:15590694). Component the von Hippel-Lindau ubiquitination complex CBC(VHL) (PubMed:10205047, PubMed:12004076, PubMed:12050673, PubMed:15590694). A number of ECS complexes (containing either KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:26138980, PubMed:29775578, PubMed:29779948, PubMed:36805027, PubMed:37844242, PubMed:38177675). The ECS(ASB9) complex mediates ubiquitination and degradation of CKB (PubMed:33268465). As part of a multisubunit ubiquitin ligase complex, polyubiquitinates monoubiquitinated POLR2A (PubMed:19920177). ECS(LRR1) ubiquitinates MCM7 and promotes CMG replisome disassembly by VCP and chromatin extraction during S-phase (By similarity). As part of the ECS(RAB40C) complex, mediates ANKRD28 ubiquitination and degradation, thereby inhibiting protein phosphatase 6 (PP6) complex activity and focal adhesion assembly during cell migration (PubMed:35512830). The ECS(ASB7) complex acts a negative regulator of H3K9me3 histone mark by mediating ubiquitination and degradation of SUV39H1 (PubMed:40440427) (Microbial infection) Following infection by HIV-1 virus, component of a cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex) hijacked by the HIV-1 Vif protein, which catalyzes ubiquitination and degradation of APOBEC3F and APOBEC3G (PubMed:18562529, PubMed:20532212, PubMed:22190037, PubMed:24225024, PubMed:24402281, PubMed:36754086). The complex can also ubiquitinate APOBEC3H to some extent (PubMed:37640699)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15369/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ELOC","classification":"Common Essential","n_dependent_lines":1202,"n_total_lines":1208,"dependency_fraction":0.9950331125827815},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDB1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"NRBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ELOC","total_profiled":1310},"omim":[{"mim_id":"620091","title":"PROTEIN-L-ISOASPARTATE (D-ASPARTATE) O-METHYLTRANSFERASE DOMAIN-CONTAINING PROTEIN 1; PCMTD1","url":"https://www.omim.org/entry/620091"},{"mim_id":"620077","title":"PROTEIN-L-ISOASPARTATE (D-ASPARTATE) O-METHYLTRANSFERASE DOMAIN-CONTAINING PROTEIN 2; PCMTD2","url":"https://www.omim.org/entry/620077"},{"mim_id":"618753","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 41; LRRC41","url":"https://www.omim.org/entry/618753"},{"mim_id":"617795","title":"ELONGIN BC- AND POLYCOMB REPRESSIVE COMPLEX 2-ASSOCIATED PROTEIN; EPOP","url":"https://www.omim.org/entry/617795"},{"mim_id":"617764","title":"ZYG11-RELATED CELL CYCLE REGULATOR; ZER1","url":"https://www.omim.org/entry/617764"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ELOC"},"hgnc":{"alias_symbol":["SIII"],"prev_symbol":["TCEB1"]},"alphafold":{"accession":"Q15369","domains":[{"cath_id":"3.30.710.10","chopping":"17-109","consensus_level":"high","plddt":92.0508,"start":17,"end":109}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15369","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15369-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15369-F1-predicted_aligned_error_v6.png","plddt_mean":89.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELOC","jax_strain_url":"https://www.jax.org/strain/search?query=ELOC"},"sequence":{"accession":"Q15369","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15369.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15369/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15369"}},"corpus_meta":[{"pmid":"25676555","id":"PMC_25676555","title":"TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype.","date":"2015","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/25676555","citation_count":131,"is_preprint":false},{"pmid":"31850909","id":"PMC_31850909","title":"\"Renal Cell Carcinoma With Leiomyomatous Stroma\" Harbor Somatic Mutations of TSC1, TSC2, MTOR, and/or ELOC (TCEB1): Clinicopathologic and Molecular Characterization of 18 Sporadic Tumors Supports a Distinct Entity.","date":"2020","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31850909","citation_count":95,"is_preprint":false},{"pmid":"31813809","id":"PMC_31813809","title":"Putative Drivers of Aggressiveness in TCEB1-mutant Renal Cell Carcinoma: An Emerging Entity with Variable Clinical Course.","date":"2019","source":"European urology focus","url":"https://pubmed.ncbi.nlm.nih.gov/31813809","citation_count":41,"is_preprint":false},{"pmid":"35323939","id":"PMC_35323939","title":"Elongin C (ELOC/TCEB1)-associated von Hippel-Lindau disease.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35323939","citation_count":31,"is_preprint":false},{"pmid":"34163032","id":"PMC_34163032","title":"NF-κB-activated SPRY4-IT1 promotes cancer cell metastasis by downregulating TCEB1 mRNA via Staufen1-mediated mRNA decay.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34163032","citation_count":28,"is_preprint":false},{"pmid":"18844214","id":"PMC_18844214","title":"TCEB1 promotes invasion of prostate cancer cells.","date":"2009","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18844214","citation_count":28,"is_preprint":false},{"pmid":"37088333","id":"PMC_37088333","title":"Biallelic ELOC-Inactivated Renal Cell Carcinoma: Molecular Features Supporting Classification as a Distinct Entity.","date":"2023","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/37088333","citation_count":20,"is_preprint":false},{"pmid":"35653922","id":"PMC_35653922","title":"Analysis of clinicopathological and molecular features of ELOC(TCEB1)-mutant renal cell carcinoma.","date":"2022","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/35653922","citation_count":16,"is_preprint":false},{"pmid":"24586532","id":"PMC_24586532","title":"Structural analysis of viral infectivity factor of HIV type 1 and its interaction with A3G, EloC and EloB.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24586532","citation_count":16,"is_preprint":false},{"pmid":"40246078","id":"PMC_40246078","title":"ELOC-Mutated Renal Cell Carcinoma is a Rare Indolent Tumor With Distinctive Genomic Characteristics.","date":"2025","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/40246078","citation_count":11,"is_preprint":false},{"pmid":"40557827","id":"PMC_40557827","title":"Comprehensive Analysis of 15 Cases of ELOC -RCC and Identification of Novel Mutation Site.","date":"2025","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40557827","citation_count":5,"is_preprint":false},{"pmid":"41224595","id":"PMC_41224595","title":"Multigenerational VHL family characterized by pathogenic germline ELOC variant: Response to belzutifan.","date":"2025","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41224595","citation_count":2,"is_preprint":false},{"pmid":"39881207","id":"PMC_39881207","title":"Identification of novel 7-hydroxycoumarin derivatives as ELOC binders with potential to modulate CRL2 complex 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proceedings","url":"https://pubmed.ncbi.nlm.nih.gov/41686095","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15241,"output_tokens":2735,"usd":0.043374,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10098,"output_tokens":2779,"usd":0.059983,"stage2_stop_reason":"end_turn"},"total_usd":0.103357,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"ELOC (elongin C) encodes a key component of the VCB-CR E3 ubiquitin ligase complex (comprising pVHL, elongin C, elongin B, cullin 2, and ring box 1), which mediates oxygen sensing and degradation of hypoxia-inducible factors. A germline de novo pathogenic variant ELOC p.Tyr79Cys was shown to mimic the effects of pVHL deficiency on hypoxic signalling, and tumor analysis demonstrated chromosome 8 loss and expression of hypoxia-responsive proteins consistent with loss of VCB-CR complex activity.\",\n      \"method\": \"Whole-exome sequencing of proband trio, paired tumor/blood DNA analysis, bioinformatics analysis of RCC dataset, immunohistochemistry for hypoxia-responsive proteins\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal molecular and tumor analysis in a single study with orthogonal methods (WES, IHC, LOH analysis), single lab\",\n      \"pmids\": [\"35323939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A germline ELOC p.E92G variant in a multigenerational family causes VHL disease manifestations (hemangioblastomas, ccRCC, pancreatic neuroendocrine tumors, pheochromocytomas). Tumor analysis demonstrated loss of heterozygosity at chromosome 8 (encoding ELOC), consistent with biallelic ELOC inactivation and loss of VCB-Cul2 E3-ubiquitin ligase complex activity. Treatment with belzutifan (a HIF-2α inhibitor) caused tumor regression, confirming that these tumors are driven by HIF pathway activation downstream of ELOC loss.\",\n      \"method\": \"Germline sequencing, tumor LOH analysis, chromosomal copy number analysis, clinical response to belzutifan (HIF-2α inhibitor)\",\n      \"journal\": \"Urologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — germline variant co-segregation, tumor LOH, pharmacological rescue with HIF-2α inhibitor, single family study\",\n      \"pmids\": [\"41224595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ELOC mutations (especially Y79C) result in biallelic ELOC inactivation in RCC and are mutually exclusive with biallelic VHL aberrations. A novel ELOC duplication variant was modeled by High Ambiguity Driven biomolecular DOCKing to disrupt the ELOC-VHL interaction interface. Mass spectrometry (hyper reaction monitoring) showed that RCCs with biallelic ELOC alterations have significantly reduced ELOC expression but similar carbonic anhydrase 9 and VEGF-A expression compared with VHL-null ccRCC, indicating convergent HIF pathway activation.\",\n      \"method\": \"OncoScan copy number analysis, whole-exome sequencing, computational docking (HADDOCK), hyper reaction monitoring mass spectrometry\",\n      \"journal\": \"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — molecular docking for structural claim (computational, not experimental structure), MS proteomics for expression; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37088333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TCEB1 (ELOC) hotspot mutations in RCC (Y79C/S/F/N) were experimentally shown to always affect residues involved in hydrophobic interactions with VHL, and all tumors showed biallelic inactivation of the TCEB1 gene by combined somatic mutation and copy number alteration analysis, consistent with a tumor suppressor mechanism disrupting the VHL-elongin C interaction.\",\n      \"method\": \"Somatic mutation analysis, copy number alteration analysis, cancer cell fraction estimation (clonal analysis)\",\n      \"journal\": \"European urology focus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biallelic inactivation confirmed across multiple tumors by orthogonal methods (sequencing + CNA), but mechanistic detail (hydrophobic interactions with VHL) is computationally inferred from mutation position, not directly assayed\",\n      \"pmids\": [\"31813809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"shRNA-mediated silencing of TCEB1 (ELOC) significantly decreased cellular invasion of prostate cancer cells (PC-3 and DU145) through Matrigel and reduced anchorage-independent growth of PC-3 cells. Transcriptional profiling of TCEB1-silenced cells revealed decreased expression of genes involved in invasion and metastasis. Overexpression of TCEB1 in NIH 3T3 cells increased growth rate.\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, Matrigel invasion assay, anchorage-independent growth assay, transcriptional profiling, lentiviral overexpression\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function experiments in multiple cell lines with defined cellular phenotypic readouts, single lab\",\n      \"pmids\": [\"18844214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fragment screening of the VHL-ELOB-ELOC (VBC) complex identified 7-hydroxycoumarin (7HC) derivatives that bind specifically to the ELOC component rather than VHL. The 7HC binding site on ELOC overlaps with the CUL2 binding interface but not the CUL5 binding interface, indicating that these compounds may selectively modulate CRL2 (but not CRL5) complex formation by competing with CUL2 for ELOC binding.\",\n      \"method\": \"Fragment screening, X-ray crystallography or binding assays (implied by binding site characterization), interface mapping\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — binding site characterization described but structural method not explicitly named in abstract; single lab, mechanistic inference from binding site overlap\",\n      \"pmids\": [\"39881207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Computational modeling of HIV Vif showed that residues L146 and L149 of the BC-box motif bind to ELOC (EloC) by hydrophobic interactions, and residue P162 of the PPLP motif is important for EloB binding. Molecular dynamics simulation evaluated stability of the Vif-EloBC complex.\",\n      \"method\": \"Ab initio protein modeling (Rosetta), molecular docking, molecular dynamics simulation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — purely computational (ab initio modeling, docking, MD simulation), no experimental validation of the binding interface in this study\",\n      \"pmids\": [\"24586532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STAU1 (Staufen1) was shown to bind SPRY4-IT1 lncRNA, which promotes STAU1 recruitment to the 3'-UTR of TCEB1 mRNA (via Alu element base-pairing between SPRY4-IT1 and TCEB1 3'-UTR), leading to STAU1-mediated mRNA decay (SMD) of TCEB1, reduced TCEB1 protein, and consequent upregulation of HIF-1α. STAU1 depletion abrogated TCEB1 SMD. NF-κB/p65 transactivates SPRY4-IT1 to initiate this cascade.\",\n      \"method\": \"RNA overexpression/knockdown, microarray, RNA pulldown/binding assays (STAU1-SPRY4-IT1 interaction), STAU1 depletion rescue, NF-κB reporter/ChIP (implied)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA binding, mRNA decay assay, rescue by STAU1 depletion), single lab; this concerns regulation of ELOC/TCEB1 mRNA stability, not direct protein mechanism\",\n      \"pmids\": [\"34163032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The Vif-CBFβ-ELOB-ELOC-CUL5 (VβBCC) complex was shown by cryo-EM and SELEX to directly impede A3G-mediated DNA deamination independently of proteasomal degradation. RNA aptamers selected against the VβBCC complex restored A3G DNA deamination activity by inhibiting the complex, demonstrating that ELOC-containing VβBCC complex has a direct inhibitory function on A3G beyond promoting its ubiquitination.\",\n      \"method\": \"SELEX (aptamer selection), DNA deamination activity assay, cryo-EM (referenced from prior studies), functional inhibition assay\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional biochemical assays (DNA deamination activity) plus aptamer selection demonstrating direct complex inhibition of A3G, single lab\",\n      \"pmids\": [\"38740386\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELOC (elongin C, TCEB1) is an adaptor subunit of the VCB-CR (VHL-elongin C-elongin B-cullin 2-RBX1) E3 ubiquitin ligase complex, where it bridges VHL to the cullin scaffold via hydrophobic interactions at residues including Y79 and A100; hotspot mutations at these residues disrupt VHL binding, phenocopying VHL loss to cause HIF pathway activation and drive renal cell carcinoma through biallelic ELOC inactivation, while ELOC also participates in CRL5-containing complexes (e.g., Vif-CBFβ-ELOB-ELOC-CUL5) that ubiquitinate antiviral proteins, and ELOC expression promotes cancer cell invasion through transcriptional regulation of pro-invasive genes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ELOC (elongin C, TCEB1) is an adaptor subunit of cullin-RING E3 ubiquitin ligase complexes, most prominently the VCB-CR/VBC complex (pVHL–elongin C–elongin B–cullin 2–RBX1) that mediates oxygen sensing and degradation of hypoxia-inducible factors [#0]. Within this complex ELOC bridges VHL to the cullin scaffold through hydrophobic contacts, and germline and somatic hotspot mutations at residues such as Y79 and E92 disrupt the ELOC–VHL interface; combined with chromosome 8 loss of heterozygosity, biallelic ELOC inactivation phenocopies VHL loss, drives convergent HIF pathway activation, and causes renal cell carcinoma and a VHL-disease-like syndrome that regresses under HIF-2α inhibition [#0, #1, #2, #3]. ELOC additionally serves as an adaptor in CUL5-based complexes: as part of the HIV Vif–CBFβ–ELOB–ELOC–CUL5 assembly it directly impedes APOBEC3G DNA deamination independently of proteasomal degradation [#8]. The ELOC binding surfaces for CUL2 and CUL5 are spatially distinct, allowing selective small-molecule modulation of CRL2 versus CRL5 assembly [#5]. Beyond its E3 adaptor role, ELOC expression promotes cancer cell invasion and anchorage-independent growth through transcriptional regulation of pro-invasive genes [#4], and its protein level is controlled post-transcriptionally by Staufen1-mediated decay of TCEB1 mRNA, which derepresses HIF-1α [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Before its tumor-suppressor role was defined, ELOC was tested directly for a pro-tumorigenic cellular function, establishing that ELOC expression supports invasion and growth.\",\n      \"evidence\": \"shRNA knockdown and overexpression with Matrigel invasion, anchorage-independent growth, and transcriptional profiling in prostate cancer and NIH 3T3 cells\",\n      \"pmids\": [\"18844214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the molecular activity of ELOC mediating the invasive transcriptional program\", \"No link to E3 ligase function established here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"To explain how viral hijacking of ELOC occurs, the Vif binding mode was modeled, indicating that BC-box leucines engage ELOC by hydrophobic interactions.\",\n      \"evidence\": \"Ab initio modeling (Rosetta), docking, and molecular dynamics of the Vif-EloBC complex\",\n      \"pmids\": [\"24586532\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational with no experimental validation of the interface\", \"Does not assay complex function or ubiquitination activity\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"It was unknown whether ELOC mutations in RCC act as drivers; clonal and copy-number analysis established biallelic ELOC inactivation at the VHL-binding hotspot as a tumor-suppressor mechanism.\",\n      \"evidence\": \"Somatic mutation, copy number, and cancer cell fraction analysis of RCC tumors\",\n      \"pmids\": [\"31813809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hydrophobic interaction disruption inferred from mutation position, not directly assayed\", \"No functional rescue or HIF readout in this study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether a germline ELOC variant could cause disease by mimicking VHL deficiency was open; a de novo Y79C variant was shown to recapitulate pVHL-deficient hypoxic signalling.\",\n      \"evidence\": \"Trio whole-exome sequencing, paired tumor/blood analysis, IHC for hypoxia-responsive proteins, RCC dataset bioinformatics\",\n      \"pmids\": [\"35323939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single proband study\", \"Direct biochemical demonstration of disrupted VCB-CR assembly not performed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To distinguish ELOC-driven from VHL-driven RCC, mutual exclusivity and downstream HIF output were compared, showing convergent HIF pathway activation despite reduced ELOC expression.\",\n      \"evidence\": \"OncoScan copy number, WES, HADDOCK docking of an ELOC duplication, and hyper reaction monitoring mass spectrometry of CA9/VEGF-A\",\n      \"pmids\": [\"37088333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural disruption modeled computationally, not by experimental structure\", \"Single-lab proteomic cohort\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"It was unclear whether the ELOC-containing Vif-CUL5 complex acted only through degradation; functional assays revealed a direct, degradation-independent inhibition of APOBEC3G deamination.\",\n      \"evidence\": \"SELEX aptamer selection against the VβBCC complex and DNA deamination activity/inhibition assays\",\n      \"pmids\": [\"38740386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of direct A3G inhibition by the complex not structurally resolved here\", \"Contribution of ELOC specifically versus other subunits not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two advances clarified ELOC druggability and disease genetics: a multigenerational E92G family established ELOC as a VHL-disease gene rescuable by HIF-2α inhibition, and fragment screening defined a ligandable ELOC pocket distinguishing CUL2 from CUL5 binding.\",\n      \"evidence\": \"Germline co-segregation, tumor LOH, belzutifan clinical response (family study); fragment screening with binding-site/interface mapping of the VBC complex\",\n      \"pmids\": [\"41224595\", \"39881207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Family study is a single pedigree\", \"Fragment-binding structural method not explicitly defined and selective CRL2 modulation only inferred from interface overlap\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ELOC's invasion-promoting transcriptional role mechanistically relates to its E3 adaptor function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular link between ELOC E3 adaptor activity and the pro-invasive transcriptional program\", \"No experimental high-resolution structure of mutant ELOC interfaces in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [\"VCB-CR (pVHL-elongin C-elongin B-CUL2-RBX1)\", \"Vif-CBFβ-ELOB-ELOC-CUL5 (VβBCC)\"],\n    \"partners\": [\"VHL\", \"ELOB\", \"CUL2\", \"CUL5\", \"RBX1\", \"Vif\", \"CBFB\", \"STAU1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}