{"gene":"PDCD7","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1999,"finding":"Mouse ES18 (PDCD7 ortholog) transient overexpression in mouse T-cell lymphoma increased apoptotic cell death, and its transcript was selectively regulated during T-cell apoptosis induced by dexamethasone, staurosporine, and C2-ceramide, suggesting ES18 is involved in specific apoptotic processes in T-cells.","method":"Transient overexpression in mouse T-cell lymphoma with apoptosis readout; transcript regulation analysis under multiple apoptotic stimuli","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with defined phenotype (apoptosis) in single study, multiple stimuli tested but no pathway placement or binding partner identified","pmids":["10037816"],"is_preprint":false},{"year":2005,"finding":"The U11/U12-65K protein directly interacts with the U11-associated 59K protein (PDCD7) via its N-terminal half, contributing to U11/U12 di-snRNP formation and intron bridging in the minor prespliceosome.","method":"Protein-protein interaction assays (direct binding); in vitro splicing inhibition with oligonucleotides targeting the 65K binding site on U12 snRNA","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated, functional consequence confirmed by splicing inhibition assay, multiple orthogonal methods in one study","pmids":["16096647"],"is_preprint":false},{"year":2008,"finding":"The U11-48K protein directly interacts with the U11-59K protein (PDCD7), as shown by site-specific cross-linking and co-immunoprecipitation; this interaction places 59K at the interface of the U11/U12 di-snRNP. Knockdown of 48K reduced di-snRNP stability, implicating the 48K–59K interaction in di-snRNP assembly.","method":"Site-specific RNA-protein cross-linking; RNAi knockdown with splicing and complex stability readouts","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-linking and RNAi with functional readouts in single lab; 59K interaction inferred from 48K studies rather than direct 59K manipulation","pmids":["18347052"],"is_preprint":false},{"year":2018,"finding":"PDCD7 knockout (via gene editing) in oral squamous cell carcinoma cells increased in vitro oncogenicity and neck nodal metastasis in mice, and reduced E-cadherin (E-cad) expression. PDCD7 was shown to transactivate E-cad expression via a GC-box in the E-cad promoter. miR-134 targets PDCD7 (confirmed by reporter assays with wild-type and mutant constructs), and miR-134-associated E-cad downregulation was attenuated by PDCD7, placing PDCD7 in a miR-134–PDCD7–E-cadherin pathway.","method":"CRISPR/gene editing knockout; luciferase reporter assay (wild-type and mutant 3'UTR constructs); promoter transactivation assay; in vivo mouse metastasis model","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO phenotype, reporter assay with mutant controls, promoter assay, in vivo model) in single study establishing pathway position","pmids":["29971778"],"is_preprint":false}],"current_model":"PDCD7 (59K) is a component of the U11/U12 di-snRNP in the minor spliceosome, where it interacts with both the U11/U12-65K protein and the U11-48K protein to contribute to di-snRNP formation and U12-type intron recognition; in addition, PDCD7 promotes apoptosis in T-cells and suppresses oral cancer progression by transactivating E-cadherin expression, acting downstream of miR-134."},"narrative":{"mechanistic_narrative":"PDCD7 (the U11-associated 59K protein) is a component of the U11/U12 di-snRNP of the minor spliceosome, where it bridges core di-snRNP proteins to support complex assembly and U12-type intron recognition [PMID:16096647, PMID:18347052]. It is directly bound by the U11/U12-65K protein through the 65K N-terminal half, an interaction that contributes to di-snRNP formation and intron bridging in the minor prespliceosome [PMID:16096647], and it also contacts the U11-48K protein at the U11/U12 interface, with 48K depletion destabilizing the di-snRNP [PMID:18347052]. Beyond its spliceosomal role, PDCD7 has context-specific functions: its murine ortholog ES18 promotes apoptosis in T-cells and is transcriptionally regulated during T-cell death induced by several stimuli [PMID:10037816], and in oral squamous cell carcinoma PDCD7 acts as a tumor suppressor, transactivating E-cadherin through a GC-box in its promoter while being repressed by miR-134, placing it in a miR-134–PDCD7–E-cadherin axis whose loss increases oncogenicity and metastasis [PMID:29971778]. How the splicing, apoptotic, and tumor-suppressive activities of PDCD7 relate mechanistically has not been characterized in the available corpus.","teleology":[{"year":1999,"claim":"Established the first cellular function for the PDCD7 ortholog by linking it to programmed cell death, addressing whether the gene had any phenotypic role.","evidence":"Transient overexpression of mouse ES18 in T-cell lymphoma with apoptosis readout and transcript regulation under dexamethasone, staurosporine, and C2-ceramide","pmids":["10037816"],"confidence":"Medium","gaps":["No binding partner or molecular mechanism for the apoptotic effect identified","No placement in a defined apoptotic signaling pathway","Relationship to later-defined splicing function unaddressed"]},{"year":2005,"claim":"Reframed PDCD7/59K as a minor-spliceosome component by demonstrating a direct interaction with the U11/U12-65K protein, answering what molecular complex the protein belongs to.","evidence":"Direct protein-protein binding assays plus in vitro splicing inhibition targeting the 65K binding site on U12 snRNA","pmids":["16096647"],"confidence":"High","gaps":["Region of 59K mediating the interaction not mapped","Functional consequence of disrupting the 65K–59K contact specifically not isolated"]},{"year":2008,"claim":"Positioned 59K at the U11/U12 di-snRNP interface by mapping a second direct contact to the U11-48K protein, refining how the protein integrates into the complex.","evidence":"Site-specific RNA-protein cross-linking and RNAi knockdown of 48K with splicing and complex-stability readouts","pmids":["18347052"],"confidence":"Medium","gaps":["59K role inferred largely from 48K manipulation rather than direct 59K knockdown","Quantitative contribution of 59K to di-snRNP stability not isolated"]},{"year":2018,"claim":"Defined a tumor-suppressive role by placing PDCD7 in a miR-134–PDCD7–E-cadherin transcriptional axis, answering how PDCD7 loss drives cancer progression.","evidence":"CRISPR knockout in oral squamous cell carcinoma, luciferase reporters with wild-type and mutant 3'UTR, E-cadherin promoter transactivation assay, and in vivo mouse metastasis model","pmids":["29971778"],"confidence":"High","gaps":["Mechanism of promoter transactivation (direct DNA binding vs cofactor recruitment) at the GC-box not resolved","Connection between nuclear transactivation activity and spliceosomal role unexplained","Generality beyond oral squamous cell carcinoma untested"]},{"year":null,"claim":"How PDCD7's roles in minor-spliceosome assembly, apoptosis, and E-cadherin transactivation are mechanistically unified remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of 59K within the U11/U12 di-snRNP","No demonstration that splicing function underlies the apoptotic or tumor-suppressive phenotypes","Mode of action in promoter transactivation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2]}],"complexes":["U11/U12 di-snRNP (minor spliceosome)"],"partners":["RNPC3","ZRSR2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N8D1","full_name":"Programmed cell death protein 7","aliases":["ES18","hES18"],"length_aa":485,"mass_kda":54.7,"function":"Promotes apoptosis when overexpressed","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8N8D1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PDCD7","classification":"Common Essential","n_dependent_lines":1022,"n_total_lines":1208,"dependency_fraction":0.8460264900662252},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PDCD7","total_profiled":1310},"omim":[{"mim_id":"608138","title":"PROGRAMMED CELL DEATH 7; PDCD7","url":"https://www.omim.org/entry/608138"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PDCD7"},"hgnc":{"alias_symbol":["HES18","ES18","59K"],"prev_symbol":[]},"alphafold":{"accession":"Q8N8D1","domains":[{"cath_id":"-","chopping":"423-481","consensus_level":"medium","plddt":77.4549,"start":423,"end":481},{"cath_id":"1.10.287","chopping":"170-267","consensus_level":"medium","plddt":93.2843,"start":170,"end":267},{"cath_id":"1.10.287","chopping":"268-411","consensus_level":"medium","plddt":92.0772,"start":268,"end":411}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N8D1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N8D1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N8D1-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDCD7","jax_strain_url":"https://www.jax.org/strain/search?query=PDCD7"},"sequence":{"accession":"Q8N8D1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N8D1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N8D1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N8D1"}},"corpus_meta":[{"pmid":"15659686","id":"PMC_15659686","title":"The generalized transducing Salmonella bacteriophage ES18: complete genome sequence and DNA packaging strategy.","date":"2005","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/15659686","citation_count":170,"is_preprint":false},{"pmid":"29971778","id":"PMC_29971778","title":"miR-134 targets PDCD7 to reduce E-cadherin expression and enhance oral cancer progression.","date":"2018","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29971778","citation_count":54,"is_preprint":false},{"pmid":"16096647","id":"PMC_16096647","title":"The U11/U12 snRNP 65K protein acts as a molecular bridge, binding the U12 snRNA and U11-59K protein.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16096647","citation_count":52,"is_preprint":false},{"pmid":"16559160","id":"PMC_16559160","title":"Mapping of rfa Genes in Salmonella typhimurium by ES18 and P22 Transduction and by Conjugation.","date":"1972","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/16559160","citation_count":44,"is_preprint":false},{"pmid":"18347052","id":"PMC_18347052","title":"The U11-48K protein contacts the 5' splice site of U12-type introns and the U11-59K protein.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18347052","citation_count":41,"is_preprint":false},{"pmid":"324978","id":"PMC_324978","title":"Genetics of sensitivity of Salmonella species to colicin M and bacteriophages T5, T1, and ES18.","date":"1977","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/324978","citation_count":39,"is_preprint":false},{"pmid":"783114","id":"PMC_783114","title":"Iron transport in Salmonella typhimurium LT-2: prevention, by ferrichrome, of adsorption of bacteriophages ES18 and ES18.h1 to a common cell envelope receptor.","date":"1976","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/783114","citation_count":20,"is_preprint":false},{"pmid":"9300826","id":"PMC_9300826","title":"Sequence comparison of the genes for immunity, DNA replication, and cell lysis of the P22-related Salmonella phages ES18 and L.","date":"1997","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9300826","citation_count":19,"is_preprint":false},{"pmid":"10037816","id":"PMC_10037816","title":"Characterization of a novel mouse cDNA, ES18, involved in apoptotic cell death of T-cells.","date":"1999","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10037816","citation_count":16,"is_preprint":false},{"pmid":"3242498","id":"PMC_3242498","title":"Esterase-18 (ES-18) of the house mouse (Mus musculus): biochemical characterization and genetics of an allozyme system linked to chromosome 19.","date":"1988","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3242498","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6233,"output_tokens":1448,"usd":0.020209,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7701,"output_tokens":1838,"usd":0.042228,"stage2_stop_reason":"end_turn"},"total_usd":0.062437,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about PDCD7 (also known as HES18, ES18, 59K as a human/mammalian gene).\n\n- Papers 1, 4, 6, 7, 8: These are about Salmonella bacteriophage ES18 — a phage, not the mammalian PDCD7/ES18 gene. EXCLUDE.\n- Paper 2: About PDCD7 in oral cancer — canonical PDCD7 protein. INCLUDE.\n- Paper 3: About U11/U12 snRNP 65K protein and its interaction with \"U11-59K protein\" — the 59K is an alias for PDCD7. INCLUDE.\n- Paper 5: About U11-48K protein interacting with U11-59K protein — 59K is PDCD7. INCLUDE.\n- Paper 9: About mouse ES18 cDNA involved in apoptosis — this is the mammalian ES18/PDCD7 ortholog. INCLUDE.\n- Paper 10: About murine esterase ES-18 linked to chromosome 19 — this is a different gene (esterase), not PDCD7. EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Mouse ES18 (PDCD7 ortholog) transient overexpression in mouse T-cell lymphoma increased apoptotic cell death, and its transcript was selectively regulated during T-cell apoptosis induced by dexamethasone, staurosporine, and C2-ceramide, suggesting ES18 is involved in specific apoptotic processes in T-cells.\",\n      \"method\": \"Transient overexpression in mouse T-cell lymphoma with apoptosis readout; transcript regulation analysis under multiple apoptotic stimuli\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with defined phenotype (apoptosis) in single study, multiple stimuli tested but no pathway placement or binding partner identified\",\n      \"pmids\": [\"10037816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The U11/U12-65K protein directly interacts with the U11-associated 59K protein (PDCD7) via its N-terminal half, contributing to U11/U12 di-snRNP formation and intron bridging in the minor prespliceosome.\",\n      \"method\": \"Protein-protein interaction assays (direct binding); in vitro splicing inhibition with oligonucleotides targeting the 65K binding site on U12 snRNA\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated, functional consequence confirmed by splicing inhibition assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16096647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The U11-48K protein directly interacts with the U11-59K protein (PDCD7), as shown by site-specific cross-linking and co-immunoprecipitation; this interaction places 59K at the interface of the U11/U12 di-snRNP. Knockdown of 48K reduced di-snRNP stability, implicating the 48K–59K interaction in di-snRNP assembly.\",\n      \"method\": \"Site-specific RNA-protein cross-linking; RNAi knockdown with splicing and complex stability readouts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-linking and RNAi with functional readouts in single lab; 59K interaction inferred from 48K studies rather than direct 59K manipulation\",\n      \"pmids\": [\"18347052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PDCD7 knockout (via gene editing) in oral squamous cell carcinoma cells increased in vitro oncogenicity and neck nodal metastasis in mice, and reduced E-cadherin (E-cad) expression. PDCD7 was shown to transactivate E-cad expression via a GC-box in the E-cad promoter. miR-134 targets PDCD7 (confirmed by reporter assays with wild-type and mutant constructs), and miR-134-associated E-cad downregulation was attenuated by PDCD7, placing PDCD7 in a miR-134–PDCD7–E-cadherin pathway.\",\n      \"method\": \"CRISPR/gene editing knockout; luciferase reporter assay (wild-type and mutant 3'UTR constructs); promoter transactivation assay; in vivo mouse metastasis model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO phenotype, reporter assay with mutant controls, promoter assay, in vivo model) in single study establishing pathway position\",\n      \"pmids\": [\"29971778\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDCD7 (59K) is a component of the U11/U12 di-snRNP in the minor spliceosome, where it interacts with both the U11/U12-65K protein and the U11-48K protein to contribute to di-snRNP formation and U12-type intron recognition; in addition, PDCD7 promotes apoptosis in T-cells and suppresses oral cancer progression by transactivating E-cadherin expression, acting downstream of miR-134.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDCD7 (the U11-associated 59K protein) is a component of the U11/U12 di-snRNP of the minor spliceosome, where it bridges core di-snRNP proteins to support complex assembly and U12-type intron recognition [#1, #2]. It is directly bound by the U11/U12-65K protein through the 65K N-terminal half, an interaction that contributes to di-snRNP formation and intron bridging in the minor prespliceosome [#1], and it also contacts the U11-48K protein at the U11/U12 interface, with 48K depletion destabilizing the di-snRNP [#2]. Beyond its spliceosomal role, PDCD7 has context-specific functions: its murine ortholog ES18 promotes apoptosis in T-cells and is transcriptionally regulated during T-cell death induced by several stimuli [#0], and in oral squamous cell carcinoma PDCD7 acts as a tumor suppressor, transactivating E-cadherin through a GC-box in its promoter while being repressed by miR-134, placing it in a miR-134–PDCD7–E-cadherin axis whose loss increases oncogenicity and metastasis [#3]. How the splicing, apoptotic, and tumor-suppressive activities of PDCD7 relate mechanistically has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the first cellular function for the PDCD7 ortholog by linking it to programmed cell death, addressing whether the gene had any phenotypic role.\",\n      \"evidence\": \"Transient overexpression of mouse ES18 in T-cell lymphoma with apoptosis readout and transcript regulation under dexamethasone, staurosporine, and C2-ceramide\",\n      \"pmids\": [\"10037816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No binding partner or molecular mechanism for the apoptotic effect identified\", \"No placement in a defined apoptotic signaling pathway\", \"Relationship to later-defined splicing function unaddressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Reframed PDCD7/59K as a minor-spliceosome component by demonstrating a direct interaction with the U11/U12-65K protein, answering what molecular complex the protein belongs to.\",\n      \"evidence\": \"Direct protein-protein binding assays plus in vitro splicing inhibition targeting the 65K binding site on U12 snRNA\",\n      \"pmids\": [\"16096647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Region of 59K mediating the interaction not mapped\", \"Functional consequence of disrupting the 65K–59K contact specifically not isolated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Positioned 59K at the U11/U12 di-snRNP interface by mapping a second direct contact to the U11-48K protein, refining how the protein integrates into the complex.\",\n      \"evidence\": \"Site-specific RNA-protein cross-linking and RNAi knockdown of 48K with splicing and complex-stability readouts\",\n      \"pmids\": [\"18347052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"59K role inferred largely from 48K manipulation rather than direct 59K knockdown\", \"Quantitative contribution of 59K to di-snRNP stability not isolated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a tumor-suppressive role by placing PDCD7 in a miR-134–PDCD7–E-cadherin transcriptional axis, answering how PDCD7 loss drives cancer progression.\",\n      \"evidence\": \"CRISPR knockout in oral squamous cell carcinoma, luciferase reporters with wild-type and mutant 3'UTR, E-cadherin promoter transactivation assay, and in vivo mouse metastasis model\",\n      \"pmids\": [\"29971778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of promoter transactivation (direct DNA binding vs cofactor recruitment) at the GC-box not resolved\", \"Connection between nuclear transactivation activity and spliceosomal role unexplained\", \"Generality beyond oral squamous cell carcinoma untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PDCD7's roles in minor-spliceosome assembly, apoptosis, and E-cadherin transactivation are mechanistically unified remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of 59K within the U11/U12 di-snRNP\", \"No demonstration that splicing function underlies the apoptotic or tumor-suppressive phenotypes\", \"Mode of action in promoter transactivation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"U11/U12 di-snRNP (minor spliceosome)\"],\n    \"partners\": [\"RNPC3\", \"ZRSR2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}