{"gene":"ANAPC4","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2024,"finding":"TRMT13 (a tRNA methyltransferase) regulates ANAPC4 expression as a downstream target: TRMT13 overexpression increases ANAPC4 levels, silencing of TRMT13 reduces ANAPC4 levels, and rescue experiments with ANAPC4 overexpression restore the anti-tumorigenic phenotype, placing ANAPC4 downstream of TRMT13 in papillary thyroid cancer cells.","method":"siRNA knockdown, overexpression, rescue experiments, nude mouse xenograft tumor model","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD, OE, rescue, in vivo xenograft) in a single lab establishing pathway position, but no biochemical reconstitution or structural data","pmids":["38425244"],"is_preprint":false},{"year":2024,"finding":"ANAPC4 functions as a tumor suppressor in papillary thyroid cancer: loss-of-function (siRNA) promotes proliferation, migration and invasion, while overexpression inhibits tumor growth in a nude mouse xenograft model.","method":"siRNA knockdown, overexpression, cell proliferation/migration/invasion assays, nude mouse xenograft","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/OE with defined cellular phenotypes across multiple assays plus in vivo model, single lab","pmids":["38425244"],"is_preprint":false},{"year":2021,"finding":"An ANAPC4 E16K concurrent mutation (together with MFSD11 L242I) was associated with decreased trastuzumab sensitivity in BT-474 HER2-positive breast cancer cells, implicating ANAPC4 in drug resistance.","method":"Exome sequencing, single-cell targeted sequencing, validation of concurrent mutations by functional sensitivity assay","journal":"Breast cancer research and treatment","confidence":"Low","confidence_rationale":"Tier 3 / Weak — concurrent mutation validation is indirect; ANAPC4 E16K effect is not separated from MFSD11 co-mutation, single lab, single method","pmids":["33905021"],"is_preprint":false}],"current_model":"ANAPC4 is a component of the APC/C (Anaphase-Promoting Complex/Cyclosome) involved in cell cycle regulation; experimentally, it has been shown to function downstream of the tRNA methyltransferase TRMT13 as a tumor suppressor in papillary thyroid cancer (restraining proliferation, migration, and invasion), and an ANAPC4 E16K mutation has been linked to reduced trastuzumab sensitivity in breast cancer cells, but detailed biochemical or structural characterization of ANAPC4's catalytic or scaffolding mechanism within the APC/C is not represented in this corpus."},"narrative":{"mechanistic_narrative":"ANAPC4 acts as a tumor suppressor in papillary thyroid cancer, where its expression restrains cell proliferation, migration, and invasion, and its overexpression inhibits tumor growth in vivo [PMID:38425244]. It functions downstream of the tRNA methyltransferase TRMT13, whose levels positively control ANAPC4 abundance and whose anti-tumorigenic effect is mediated through ANAPC4 [PMID:38425244]. Beyond this regulatory placement and its tumor-suppressive cellular phenotype, the biochemical and structural basis of ANAPC4's activity has not been characterized in the available corpus.","teleology":[{"year":2021,"claim":"An exome-sequencing screen of HER2-positive breast cancer cells asked which mutations track with therapy resistance, implicating an ANAPC4 variant in trastuzumab sensitivity.","evidence":"Exome and single-cell targeted sequencing with functional sensitivity assays in BT-474 cells","pmids":["33905021"],"confidence":"Low","gaps":["ANAPC4 E16K effect is not separated from the concurrent MFSD11 L242I mutation","no mechanism linking the variant to resistance established","single lab, single method without isogenic validation"]},{"year":2024,"claim":"Loss- and gain-of-function experiments established ANAPC4 as a tumor suppressor in papillary thyroid cancer, defining a concrete cellular role.","evidence":"siRNA knockdown, overexpression, proliferation/migration/invasion assays, and nude mouse xenograft","pmids":["38425244"],"confidence":"Medium","gaps":["no biochemical or structural mechanism for the tumor-suppressive activity","relationship to APC/C catalytic function not addressed","single lab, single cancer type"]},{"year":2024,"claim":"Epistasis experiments placed ANAPC4 downstream of TRMT13, showing TRMT13 controls ANAPC4 levels and signals through it.","evidence":"TRMT13 knockdown/overexpression with ANAPC4 rescue in papillary thyroid cancer cells and xenografts","pmids":["38425244"],"confidence":"Medium","gaps":["molecular mechanism by which TRMT13 regulates ANAPC4 expression unknown","no direct biochemical interaction demonstrated","whether regulation is via tRNA methylation-dependent translation not resolved"]},{"year":null,"claim":"The catalytic or scaffolding role of ANAPC4 within the APC/C and how it executes tumor suppression remain undefined.","evidence":"No reconstitution, structural, or substrate-level evidence in the corpus","pmids":[],"confidence":"Low","gaps":["no structural model of ANAPC4 within APC/C","no substrates or direct partners identified","mechanism connecting TRMT13 regulation to cell-cycle control unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UJX5","full_name":"Anaphase-promoting complex subunit 4","aliases":["Cyclosome subunit 4"],"length_aa":808,"mass_kda":92.1,"function":"Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle (PubMed:18485873). The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:18485873). The APC/C complex catalyzes assembly of branched 'Lys-11'-/'Lys-48'-linked branched ubiquitin chains on target proteins (PubMed:29033132)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UJX5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ANAPC4","classification":"Common 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SENP1","url":"https://www.omim.org/entry/612157"},{"mim_id":"606947","title":"ANAPHASE-PROMOTING COMPLEX, SUBUNIT 4; ANAPC4","url":"https://www.omim.org/entry/606947"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANAPC4"},"hgnc":{"alias_symbol":["APC4"],"prev_symbol":[]},"alphafold":{"accession":"Q9UJX5","domains":[{"cath_id":"-","chopping":"571-717","consensus_level":"medium","plddt":83.4144,"start":571,"end":717},{"cath_id":"1.20.1270","chopping":"249-541","consensus_level":"medium","plddt":83.3189,"start":249,"end":541}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJX5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJX5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJX5-F1-predicted_aligned_error_v6.png","plddt_mean":80.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANAPC4","jax_strain_url":"https://www.jax.org/strain/search?query=ANAPC4"},"sequence":{"accession":"Q9UJX5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UJX5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UJX5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJX5"}},"corpus_meta":[{"pmid":"20596676","id":"PMC_20596676","title":"Y-box 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aflatoxin M1 could cause cell cycle arrest in differentiated Caco-2 cells.","date":"2019","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/30928695","citation_count":13,"is_preprint":false},{"pmid":"32899298","id":"PMC_32899298","title":"Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer.","date":"2020","source":"Methods and protocols","url":"https://pubmed.ncbi.nlm.nih.gov/32899298","citation_count":8,"is_preprint":false},{"pmid":"36653591","id":"PMC_36653591","title":"Transcriptome Analysis of Reciprocal Hybrids Between Crassostrea gigas and C. angulata Reveals the Potential Mechanisms Underlying Thermo-Resistant Heterosis.","date":"2023","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/36653591","citation_count":5,"is_preprint":false},{"pmid":"38425244","id":"PMC_38425244","title":"TRMT13 inhibits the growth of 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cells.\",\n      \"method\": \"siRNA knockdown, overexpression, rescue experiments, nude mouse xenograft tumor model\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD, OE, rescue, in vivo xenograft) in a single lab establishing pathway position, but no biochemical reconstitution or structural data\",\n      \"pmids\": [\"38425244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANAPC4 functions as a tumor suppressor in papillary thyroid cancer: loss-of-function (siRNA) promotes proliferation, migration and invasion, while overexpression inhibits tumor growth in a nude mouse xenograft model.\",\n      \"method\": \"siRNA knockdown, overexpression, cell proliferation/migration/invasion assays, nude mouse xenograft\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/OE with defined cellular phenotypes across multiple assays plus in vivo model, single lab\",\n      \"pmids\": [\"38425244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"An ANAPC4 E16K concurrent mutation (together with MFSD11 L242I) was associated with decreased trastuzumab sensitivity in BT-474 HER2-positive breast cancer cells, implicating ANAPC4 in drug resistance.\",\n      \"method\": \"Exome sequencing, single-cell targeted sequencing, validation of concurrent mutations by functional sensitivity assay\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — concurrent mutation validation is indirect; ANAPC4 E16K effect is not separated from MFSD11 co-mutation, single lab, single method\",\n      \"pmids\": [\"33905021\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANAPC4 is a component of the APC/C (Anaphase-Promoting Complex/Cyclosome) involved in cell cycle regulation; experimentally, it has been shown to function downstream of the tRNA methyltransferase TRMT13 as a tumor suppressor in papillary thyroid cancer (restraining proliferation, migration, and invasion), and an ANAPC4 E16K mutation has been linked to reduced trastuzumab sensitivity in breast cancer cells, but detailed biochemical or structural characterization of ANAPC4's catalytic or scaffolding mechanism within the APC/C is not represented in this corpus.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANAPC4 acts as a tumor suppressor in papillary thyroid cancer, where its expression restrains cell proliferation, migration, and invasion, and its overexpression inhibits tumor growth in vivo [#1]. It functions downstream of the tRNA methyltransferase TRMT13, whose levels positively control ANAPC4 abundance and whose anti-tumorigenic effect is mediated through ANAPC4 [#0]. Beyond this regulatory placement and its tumor-suppressive cellular phenotype, the biochemical and structural basis of ANAPC4's activity has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"An exome-sequencing screen of HER2-positive breast cancer cells asked which mutations track with therapy resistance, implicating an ANAPC4 variant in trastuzumab sensitivity.\",\n      \"evidence\": \"Exome and single-cell targeted sequencing with functional sensitivity assays in BT-474 cells\",\n      \"pmids\": [\"33905021\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"ANAPC4 E16K effect is not separated from the concurrent MFSD11 L242I mutation\",\n        \"no mechanism linking the variant to resistance established\",\n        \"single lab, single method without isogenic validation\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Loss- and gain-of-function experiments established ANAPC4 as a tumor suppressor in papillary thyroid cancer, defining a concrete cellular role.\",\n      \"evidence\": \"siRNA knockdown, overexpression, proliferation/migration/invasion assays, and nude mouse xenograft\",\n      \"pmids\": [\"38425244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"no biochemical or structural mechanism for the tumor-suppressive activity\",\n        \"relationship to APC/C catalytic function not addressed\",\n        \"single lab, single cancer type\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Epistasis experiments placed ANAPC4 downstream of TRMT13, showing TRMT13 controls ANAPC4 levels and signals through it.\",\n      \"evidence\": \"TRMT13 knockdown/overexpression with ANAPC4 rescue in papillary thyroid cancer cells and xenografts\",\n      \"pmids\": [\"38425244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"molecular mechanism by which TRMT13 regulates ANAPC4 expression unknown\",\n        \"no direct biochemical interaction demonstrated\",\n        \"whether regulation is via tRNA methylation-dependent translation not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The catalytic or scaffolding role of ANAPC4 within the APC/C and how it executes tumor suppression remain undefined.\",\n      \"evidence\": \"No reconstitution, structural, or substrate-level evidence in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"no structural model of ANAPC4 within APC/C\",\n        \"no substrates or direct partners identified\",\n        \"mechanism connecting TRMT13 regulation to cell-cycle control unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":2,"faith_total":2,"faith_pct":100.0}}