{"gene":"RPS14","run_date":"2026-04-28T20:42:06","timeline":{"discoveries":[{"year":2008,"finding":"RPS14 was identified as the causal gene for the 5q- syndrome myelodysplastic syndrome subtype. Partial loss-of-function of RPS14 via RNAi in normal haematopoietic progenitor cells phenocopied the erythroid differentiation defect, and forced RPS14 expression rescued the phenotype in patient-derived bone marrow cells. A block in pre-ribosomal RNA processing was identified in RPS14-deficient cells, functionally linking 5q- syndrome to Diamond-Blackfan anaemia through defective ribosomal protein function.","method":"RNAi screen in haematopoietic progenitor cells, rescue experiments with forced expression in patient bone marrow cells, pre-rRNA processing assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — bidirectional genetic rescue (loss-of-function phenocopies disease, gain-of-function rescues patient cells), replicated across multiple experimental systems","pmids":["18202658"],"is_preprint":false},{"year":2016,"finding":"Conditional inactivation of Rps14 in mice causes a p53-dependent erythroid differentiation block at the transition from polychromatic to orthochromatic erythroblasts, resulting in progressive anemia, megakaryocyte dysplasia, and loss of HSC quiescence. Mechanistically, Rps14 haploinsufficiency upregulates S100A8 and S100A9 (innate immune signaling proteins) in erythroblasts, monocytes, and macrophages; addition of recombinant S100A8 was sufficient to induce erythroid differentiation defects in wild-type cells, and genetic inactivation of S100a8 rescued the erythroid defect of Rps14-haploinsufficient HSCs.","method":"Conditional knockout mouse model, quantitative proteomics, recombinant protein treatment, genetic rescue (S100a8 knockout cross)","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including conditional KO, proteomics, recombinant protein sufficiency, and genetic epistasis in one study","pmids":["26878232"],"is_preprint":false},{"year":2012,"finding":"RPS14 binds the central acidic domain of MDM2 and inhibits its E3 ubiquitin ligase activity toward p53, thereby stabilizing and activating p53. This RPS14-MDM2 interaction is induced upon ribosomal stress (actinomycin D or mycophenolic acid treatment). Overexpression of RPS14 elevated p53 level and activity leading to G1 or G2 arrest; knockdown of RPS14 alleviated p53 induction. Knockdown of RPS14 also itself caused ribosomal stress-induced p53 activation that was dependent on RPL11 and RPL5.","method":"Co-immunoprecipitation, overexpression and knockdown in cells, MDM2 E3 ligase activity assays, cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple functional assays in one lab; Co-IP binding, enzymatic inhibition assay, and cellular phenotyping","pmids":["22391559"],"is_preprint":false},{"year":2013,"finding":"RPS14 interacts with the Myc homology box II (MBII) and the C-terminal bHLH-LZ domains of c-Myc, inhibits c-Myc transcriptional activity by preventing recruitment of c-Myc and its cofactor TRRAP to target gene promoters. RPS14 also promotes c-Myc mRNA degradation through an Argonaute 2 (Ago2)- and microRNA-mediated pathway, independently of p53.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, reporter assays, mRNA stability assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple orthogonal methods (Co-IP for interaction, ChIP for functional consequence, mRNA stability assays) in single lab","pmids":["23775087"],"is_preprint":false},{"year":2004,"finding":"The carboxy-terminal extension of yeast ribosomal protein rpS14 is required for maturation of 43S preribosomes. Specific rps14 mutations cause extraordinary accumulation of 43S preribosomes containing 20S pre-rRNA in the cytoplasm, demonstrating that rpS14's C-terminal extension—located near the 3' end of 18S rRNA—is required for 3' end processing of 20S pre-rRNA and late steps of 40S ribosomal subunit biogenesis.","method":"Yeast rpS14 mutant analysis, northern blotting for pre-rRNA intermediates, electron microscopy, ribosome fractionation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — genetic structure-function analysis with multiple rpS14 mutations, biochemical pre-rRNA processing readout, structural localization context; single rigorous study with multiple orthogonal methods","pmids":["15125836"],"is_preprint":false},{"year":2010,"finding":"Haploinsufficiency of RPS14 (or RPS19) selectively activates p53 in erythroid progenitor cells but not in other lineages. This lineage-specific p53 accumulation leads to p21 induction and cell cycle arrest specifically in erythroid cells. Pharmacological inhibition of p53 rescued the erythroid defect, whereas nutlin-3-mediated p53 activation selectively impaired erythropoiesis, establishing a mechanistic basis for erythroid failure in 5q- syndrome.","method":"shRNA knockdown in human hematopoietic progenitors, p53/p21 western blotting, pharmacological rescue (pifithrin-α, nutlin-3), immunohistochemistry in patient bone marrow biopsies","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — bidirectional pharmacological manipulation of p53 with specific erythroid phenotype, validated in patient samples; replicated across RPS14 and RPS19","pmids":["21068437"],"is_preprint":false},{"year":2016,"finding":"In a zebrafish CRISPR/Cas9 RPS14 knockout model, erythropoietic failure occurs by a late-stage defect that is initially p53-independent and then becomes p53-dependent, revealing a two-phase mechanism. Pharmacological agents including L-leucine and dexamethasone could partially reverse the anemic phenotype.","method":"CRISPR/Cas9 knockout in zebrafish, morpholino knockdown, pharmacological testing, blood cell counts and erythroid staging","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic model with temporal dissection of p53-dependent vs. p53-independent phases; single study","pmids":["27216296"],"is_preprint":false},{"year":2019,"finding":"Combined haploinsufficiency of Rps14, Csnk1a1, and miR-145/miR-146a in mice recapitulates the cardinal features of the 5q- syndrome including severe anemia and megakaryocyte dysplasia. Rps14/Csnk1a1/miR-145/146a-deficient macrophages activate the innate immune response (increased S100A8) and alter the mesenchymal stem cell niche microenvironment, demonstrating that hematopoietic cell-intrinsic defects extrinsically impair erythropoiesis through niche signaling.","method":"Conditional compound mouse knockouts, bone marrow transplantation, flow cytometry, S100A8 immunostaining in patient samples","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis through compound knockouts, mechanistic link to microenvironment via S100A8 niche signaling","pmids":["30651631"],"is_preprint":false},{"year":1982,"finding":"The human RPS14 gene (emtB locus) was mapped to chromosome 5 by studying human-Chinese hamster hybrid cells. The human RPS14 protein is incorporated into functional ribosomes in place of the Chinese hamster protein, demonstrating functional conservation of the ribosomal subunit protein across species.","method":"Somatic cell hybrid analysis, selective pressure experiments, biochemical incorporation assay","journal":"Somatic cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical demonstration of functional incorporation plus genetic mapping","pmids":["9732752"],"is_preprint":false},{"year":1985,"finding":"The CHO cell emetine-resistance mutations (emtB) in ribosomal protein S14 map to two adjacent arginine codons in the basic C-terminal region of the protein, established by cDNA cloning and sequencing of wild-type and mutant transcripts. This identified the C-terminal basic region as critical for S14 function in the 40S ribosomal subunit.","method":"cDNA cloning and sequencing of wild-type and emetine-resistant mutant S14 mRNAs, polypeptide sequence analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct sequencing of genetic variants with known functional consequence (emetine resistance/ribosome structure)","pmids":["3839563"],"is_preprint":false},{"year":1983,"finding":"Two-step emetine resistance mutations in Chinese hamster cells cause additional alterations in ribosomal protein S14 and destabilize the 40S ribosomal subunit. 40S subunits from two-step emtB mutants dissociated into core particles at lower ionic strength than wild-type, directly linking S14 mutations to 40S subunit structural integrity.","method":"Two-dimensional PAGE of ribosomal proteins, salt stability assays of ribosomal subunits, complementation testing","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical measurement of ribosome stability plus genetic complementation","pmids":["6835209"],"is_preprint":false},{"year":2013,"finding":"Cryo-EM structures of Drosophila melanogaster and Homo sapiens 80S ribosomes reveal the position and interactions of RPS14 within the 40S small subunit, including metazoan-specific features such as additional structural layers formed by ribosomal RNA co-evolving with ribosomal proteins.","method":"High-resolution cryo-electron microscopy and atomic model building","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure at near-atomic resolution defining RPS14 position in ribosome","pmids":["23636399"],"is_preprint":false},{"year":2015,"finding":"The near-atomic resolution (3.6 Å, reaching 2.9 Å) cryo-EM structure of the human 80S ribosome provides detailed information on RPS14's position and interactions within the 40S subunit, including contacts at the subunit interface that remodel during rotational movements of ribosomal subunits during translation.","method":"Single-particle cryo-electron microscopy and atomic model building","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — near-atomic resolution structure of human ribosome","pmids":["25901680"],"is_preprint":false},{"year":2017,"finding":"Hyperactivation of the thrombopoietin/MPL axis in myelofibrosis induces RPS14 deficiency in megakaryocytes, which impairs GATA1 mRNA translation, contributing to megakaryocyte dysplasia and myelofibrosis pathophysiology.","method":"Mouse model analysis (Gata1low), western blotting, polysome profiling, electron microscopy","journal":"Blood cancer journal","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic link between TPO signaling and RPS14 deficiency affecting GATA1 translation; single study with multiple methods","pmids":["28622305"],"is_preprint":false}],"current_model":"RPS14 is a component of the 40S ribosomal subunit whose C-terminal extension is required for pre-rRNA processing and late steps of 40S biogenesis; haploinsufficiency causes a p53-dependent erythroid differentiation block (via MDM2 inhibition and S100A8/S100A9 innate immune activation) that underlies the 5q- myelodysplastic syndrome, while excess free RPS14 also suppresses c-Myc transcriptional activity through direct binding and promotes c-Myc mRNA degradation via Ago2/miRNA pathways."},"narrative":{"teleology":[{"year":1982,"claim":"Mapping the human RPS14 gene to chromosome 5 and demonstrating that human RPS14 functionally replaces its hamster ortholog in ribosomes established S14 as a conserved core 40S subunit protein.","evidence":"Somatic cell hybrid panels with selective pressure and biochemical ribosome incorporation assays","pmids":["9732752"],"confidence":"Medium","gaps":["No structural detail on S14's position within the subunit","Functional conservation shown only between mammalian species"]},{"year":1985,"claim":"Identification of emetine-resistance mutations at two adjacent arginine codons in the C-terminal basic region of S14 revealed this domain as functionally critical for 40S subunit activity and structural stability.","evidence":"cDNA sequencing of wild-type and emetine-resistant CHO mutants; salt-dissociation assays of 40S subunits from two-step emtB mutants","pmids":["3839563","6835209"],"confidence":"Medium","gaps":["Precise molecular contacts of the C-terminal extension with rRNA were unknown","Mechanism of emetine binding to the ribosome not resolved"]},{"year":2004,"claim":"Structure–function analysis in yeast showed that the C-terminal extension of rpS14 is required for cytoplasmic processing of 20S pre-rRNA to mature 18S rRNA, establishing a specific role in late 40S biogenesis beyond structural integrity.","evidence":"Yeast rpS14 C-terminal mutants analyzed by northern blotting and ribosome fractionation","pmids":["15125836"],"confidence":"High","gaps":["Whether the same pre-rRNA processing requirement holds in mammalian cells","Identity of the endonuclease(s) gated by rpS14 C-terminal contacts"]},{"year":2008,"claim":"An RNAi screen identified RPS14 haploinsufficiency as the causative event in 5q− myelodysplastic syndrome, linking a ribosomal protein deficiency to a specific human hematologic disease and connecting it mechanistically to Diamond-Blackfan anemia via shared pre-rRNA processing defects.","evidence":"RNAi knockdown in human CD34+ progenitors phenocopying erythroid failure; forced RPS14 expression rescuing 5q− patient bone marrow","pmids":["18202658"],"confidence":"High","gaps":["Whether co-deleted genes on 5q contribute to the full disease spectrum","Mechanism of erythroid selectivity not resolved"]},{"year":2010,"claim":"Demonstration that RPS14 haploinsufficiency activates p53 selectively in erythroid progenitors, with pharmacological p53 inhibition rescuing the defect, explained the lineage-specific vulnerability underlying the 5q− erythroid failure.","evidence":"shRNA knockdown in human hematopoietic progenitors; pifithrin-α rescue and nutlin-3 phenocopy; immunohistochemistry in patient biopsies","pmids":["21068437"],"confidence":"High","gaps":["Why p53 is activated selectively in erythroid cells rather than other lineages","Contribution of p53-independent pathways"]},{"year":2012,"claim":"Discovery that RPS14 directly binds the central acidic domain of MDM2 and inhibits its E3 ligase activity toward p53 provided a molecular mechanism for ribosomal-stress-induced p53 stabilization, complementing the RPL5/RPL11 pathway.","evidence":"Co-immunoprecipitation, in vitro MDM2 ubiquitin ligase assays, overexpression/knockdown in cell lines","pmids":["22391559"],"confidence":"Medium","gaps":["Relative quantitative contribution of RPS14 versus RPL5/RPL11 to MDM2 inhibition in vivo","No structural model of the RPS14–MDM2 complex","Single-laboratory study"]},{"year":2013,"claim":"RPS14 was shown to act as an extra-ribosomal inhibitor of c-Myc by binding its MBII and bHLH-LZ domains, blocking TRRAP recruitment to promoters, and promoting c-Myc mRNA degradation through Ago2/miRNA—establishing a ribosomal-protein–oncogene regulatory axis independent of p53.","evidence":"Co-IP, chromatin IP, reporter assays, mRNA stability assays with siRNA knockdown","pmids":["23775087"],"confidence":"Medium","gaps":["Physiological conditions that generate sufficient free RPS14 to repress c-Myc in vivo","Identity of the specific miRNAs involved","Single-laboratory study"]},{"year":2013,"claim":"High-resolution cryo-EM structures of metazoan 80S ribosomes defined the precise position and contacts of RPS14 within the 40S subunit, including metazoan-specific structural elaborations.","evidence":"Cryo-EM at near-atomic resolution of Drosophila and human 80S ribosomes","pmids":["23636399","25901680"],"confidence":"High","gaps":["Dynamics of RPS14 contacts during active translation elongation cycles","No structure of a ribosome assembly intermediate containing RPS14"]},{"year":2016,"claim":"A conditional Rps14 knockout mouse recapitulated 5q− syndrome features (anemia, megakaryocyte dysplasia, HSC defects) and revealed that upregulation of S100A8/S100A9 in the innate immune compartment is both necessary and sufficient for the erythroid differentiation block, as demonstrated by genetic rescue with S100a8 knockout.","evidence":"Conditional KO mice, quantitative proteomics, recombinant S100A8 sufficiency tests, S100a8 genetic rescue","pmids":["26878232"],"confidence":"High","gaps":["Receptor and signaling pathway through which S100A8 impairs erythropoiesis","Whether S100A8 contributes to clonal advantage in MDS"]},{"year":2019,"claim":"Compound haploinsufficiency of Rps14 with Csnk1a1 and miR-145/146a in mice demonstrated that hematopoietic cell-intrinsic innate immune activation (S100A8) extrinsically impairs erythropoiesis by remodeling the mesenchymal niche, explaining how multiple 5q deletions cooperate.","evidence":"Compound conditional mouse knockouts, bone marrow transplantation, flow cytometry, S100A8 immunostaining in patient samples","pmids":["30651631"],"confidence":"Medium","gaps":["Precise niche signals downstream of S100A8 that suppress erythropoiesis","Whether therapeutic targeting of S100A8 is feasible in patients"]},{"year":null,"claim":"Key unresolved questions include the structural basis of the RPS14–MDM2 interaction, the identity of the miRNAs mediating RPS14-dependent c-Myc mRNA degradation, and the molecular mechanism by which S100A8/S100A9 selectively impairs erythroid differentiation downstream of RPS14 haploinsufficiency.","evidence":"","pmids":[],"confidence":"High","gaps":["No co-crystal or cryo-EM structure of RPS14–MDM2","miRNA identities in c-Myc degradation pathway uncharacterized","S100A8 receptor/signaling in erythroid progenitors not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,8,9,10,11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[8,10,11,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,11,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,5,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,5]}],"complexes":["40S ribosomal subunit","80S ribosome"],"partners":["MDM2","C-MYC","TRRAP","AGO2","S100A8","S100A9","RPL11","RPL5"],"other_free_text":[]},"mechanistic_narrative":"RPS14 (uS11) is a structural component of the 40S ribosomal subunit that is essential for ribosome biogenesis, translational fidelity, and erythropoiesis. Its C-terminal basic extension is required for 3′-end processing of 20S pre-rRNA during late 40S subunit maturation, and mutations in this region destabilize the small subunit [PMID:15125836, PMID:6835209]. Haploinsufficiency of RPS14 is the causative lesion in 5q− myelodysplastic syndrome: it triggers a lineage-selective, p53-dependent erythroid differentiation block mediated by MDM2 inhibition and S100A8/S100A9 innate immune activation, which also remodels the bone-marrow niche [PMID:18202658, PMID:26878232, PMID:21068437]. Beyond its ribosomal role, free RPS14 directly binds c-Myc to inhibit its transcriptional activity and promotes c-Myc mRNA degradation through an Ago2/miRNA-dependent pathway [PMID:23775087]."},"prefetch_data":{"uniprot":{"accession":"P62263","full_name":"Small ribosomal subunit protein uS11","aliases":["40S ribosomal protein S14"],"length_aa":151,"mass_kda":16.3,"function":"Component of the small ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797)","subcellular_location":"Cytoplasm; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P62263/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPS14","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000164587","cell_line_id":"CID000866","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleolus_gc","grade":1}],"interactors":[{"gene":"CAPRIN1","stoichiometry":10.0},{"gene":"EIF2S3","stoichiometry":10.0},{"gene":"EIF3B","stoichiometry":10.0},{"gene":"RACK1","stoichiometry":10.0},{"gene":"RBM8A","stoichiometry":10.0},{"gene":"RPL4","stoichiometry":10.0},{"gene":"RPL5","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"SRP72","stoichiometry":10.0},{"gene":"DRG1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000866","total_profiled":1310},"omim":[{"mim_id":"619357","title":"ADENYLATE KINASE 6; AK6","url":"https://www.omim.org/entry/619357"},{"mim_id":"618100","title":"MPV17 MITOCHONDRIAL INNER MEMBRANE PROTEIN-LIKE; MPV17L","url":"https://www.omim.org/entry/618100"},{"mim_id":"606847","title":"TREACLE RIBOSOME BIOGENESIS FACTOR 1; TCOF1","url":"https://www.omim.org/entry/606847"},{"mim_id":"180466","title":"RIBOSOMAL PROTEIN L19; RPL19","url":"https://www.omim.org/entry/180466"},{"mim_id":"153550","title":"CHROMOSOME 5q DELETION SYNDROME","url":"https://www.omim.org/entry/153550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPS14"},"hgnc":{"alias_symbol":["EMTB","S14","uS11"],"prev_symbol":[]},"alphafold":{"accession":"P62263","domains":[{"cath_id":"3.30.420.80","chopping":"27-130","consensus_level":"high","plddt":95.2074,"start":27,"end":130}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62263","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62263-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62263-F1-predicted_aligned_error_v6.png","plddt_mean":90.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPS14","jax_strain_url":"https://www.jax.org/strain/search?query=RPS14"},"sequence":{"accession":"P62263","fasta_url":"https://rest.uniprot.org/uniprotkb/P62263.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62263/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62263"}},"corpus_meta":[{"pmid":"8625414","id":"PMC_8625414","title":"The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol.","date":"1996","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8625414","citation_count":895,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18202658","id":"PMC_18202658","title":"Identification of RPS14 as a 5q- syndrome gene by RNA interference screen.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18202658","citation_count":714,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16988111","id":"PMC_16988111","title":"SREBP1 and thyroid hormone responsive spot 14 (S14) are involved in the regulation of bovine mammary lipid synthesis during diet-induced milk fat depression and treatment with CLA.","date":"2006","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/16988111","citation_count":201,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26878232","id":"PMC_26878232","title":"Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9.","date":"2016","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26878232","citation_count":198,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11070019","id":"PMC_11070019","title":"Inhibition of PKR activation by the proline-rich RNA binding domain of the herpes simplex virus type 1 Us11 protein.","date":"2000","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/11070019","citation_count":177,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2313387","id":"PMC_2313387","title":"Dietary polyunsaturated fats uniquely suppress rat liver fatty acid synthase and S14 mRNA content.","date":"1990","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/2313387","citation_count":153,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10551830","id":"PMC_10551830","title":"Sterol response element-binding protein 1c (SREBP1c) is involved in the polyunsaturated fatty acid suppression of hepatic S14 gene transcription.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10551830","citation_count":147,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1618827","id":"PMC_1618827","title":"Definition of the carbohydrate response element of the rat S14 gene. 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cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/8722009","citation_count":265,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47122,"output_tokens":2819,"usd":0.091826},"stage2":{"model":"claude-opus-4-6","input_tokens":6166,"output_tokens":2797,"usd":0.151133},"total_usd":0.535813,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58041,"output_tokens":6158,"usd":0.133246},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7261,"output_tokens":2804,"usd":0.159608}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Partial loss of function of RPS14 (ribosomal protein small subunit 14) phenocopies 5q- syndrome in normal haematopoietic progenitor cells via RNAi knockdown, and forced expression of RPS14 rescues the disease phenotype in patient-derived bone marrow cells; RPS14 deficiency causes a block in pre-ribosomal RNA processing equivalent to that seen in Diamond-Blackfan anaemia, linking 5q- syndrome to a ribosomal protein function defect.\",\n      \"method\": \"RNAi screen in haematopoietic progenitor cells; rescue by forced RPS14 expression in patient bone marrow; pre-rRNA processing assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function phenotype with defined cellular readout plus rescue experiment, replicated across patient and normal cells\",\n      \"pmids\": [\"18202658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RPS14 binds to the central acidic domain of MDM2 (similar to RPL5 and RPL23) and inhibits MDM2's E3 ubiquitin ligase activity toward p53, thereby stabilising p53 and inducing G1/G2 cell-cycle arrest upon ribosomal stress; this binding is induced by actinomycin D or mycophenolic acid treatment.\",\n      \"method\": \"Co-immunoprecipitation; in vitro ubiquitin ligase assay; overexpression and siRNA knockdown with p53 level/activity and cell-cycle readouts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus functional in vitro ubiquitination assay plus genetic manipulation with defined molecular readouts\",\n      \"pmids\": [\"22391559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RPS14 interacts with the Myc homology box II (MBII) and bHLH-LZ domains of c-Myc, inhibits c-Myc transcriptional activity by preventing recruitment of c-Myc and TRRAP to target gene promoters, and promotes c-Myc mRNA degradation via an Ago2- and microRNA-mediated pathway.\",\n      \"method\": \"Co-immunoprecipitation; chromatin immunoprecipitation; siRNA knockdown with target gene expression readouts; mRNA stability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — co-IP plus ChIP plus KD phenotype, single lab study\",\n      \"pmids\": [\"23775087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Conditional inactivation of Rps14 in mice causes a p53-dependent erythroid differentiation block at the polychromatic-to-orthochromatic erythroblast transition; Rps14 haploinsufficiency upregulates S100A8/S100A9 in erythroblasts and macrophages, and genetic inactivation of S100a8 rescues the erythroid defect, placing S100A8-mediated innate immune signalling downstream of Rps14 loss.\",\n      \"method\": \"Conditional knockout mouse; quantitative proteomics; recombinant S100A8 addition to wild-type erythroid cells; genetic epistasis (Rps14 KO × S100a8 KO double mutant)\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vivo conditional KO plus proteomics plus double-mutant epistasis plus reconstitution with recombinant protein, independently validated with patient cells\",\n      \"pmids\": [\"26878232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The carboxy-terminal extension of yeast ribosomal protein rpS14 is required for maturation of 43S preribosomes: rps14 carboxy-terminal mutations cause accumulation of 43S particles containing 20S pre-rRNA in the cytoplasm, and the extension is located near the 3' end of 18S rRNA in the 40S subunit, consistent with a role in 3' end processing of 20S pre-rRNA.\",\n      \"method\": \"Yeast mutant analysis; sucrose gradient sedimentation; pre-rRNA processing assay; structural localisation within 40S subunit\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — structure-function mutagenesis combined with biochemical pre-rRNA processing assay and structural context\",\n      \"pmids\": [\"15125836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1983,\n      \"finding\": \"Ribosomal protein S14 is the component of the 40S ribosomal subunit altered by emetine-resistance mutations in Chinese hamster cells; two-step emtB mutations in S14 directly affect S14 protein structure and indirectly destabilise the 40S ribosomal subunit (loss of salt stability).\",\n      \"method\": \"2D polyacrylamide gel electrophoresis; complementation testing; ribosomal subunit stability assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic complementation plus direct biochemical characterisation of mutant ribosomal subunits\",\n      \"pmids\": [\"6835209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Two-step emtB mutations in S14 map to two adjacent arginine codons within the basic carboxy-terminal region, indicating a significant role for this region in mammalian 40S ribosomal subunit function and architecture.\",\n      \"method\": \"cDNA cloning and sequencing of wild-type and mutant S14; amino acid sequence determination\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct sequencing of causative mutations with biochemical validation of protein polymorphisms\",\n      \"pmids\": [\"3839563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1982,\n      \"finding\": \"RPS14 (emtB gene product) is encoded on human chromosome 5; the human S14 ribosomal protein is incorporated into functional ribosomes in interspecific human-Chinese hamster hybrids, replacing the hamster counterpart.\",\n      \"method\": \"Interspecific somatic cell hybrid selection; cytogenetic and biochemical analysis; functional complementation\",\n      \"journal\": \"Somatic cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional complementation in hybrid cells with chromosomal mapping\",\n      \"pmids\": [\"9732752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Puromycin photoaffinity labelling of E. coli ribosomal protein S14 identifies its tryptophan-containing peptide as the modification site; reconstituted 30S subunits with stoichiometrically puromycin-modified S14 lack Phe-tRNA binding activity, demonstrating that S14 is essential for tRNA binding at both A and P sites.\",\n      \"method\": \"Puromycin photoaffinity labelling; tryptic fingerprinting; ribosome reconstitution; tRNA binding assay; tetracycline site differentiation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution experiment with site-specific chemical modification and functional readout\",\n      \"pmids\": [\"3542041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Haploinsufficiency of RPS14 in 5q- syndrome is associated with coordinated downregulation of multiple ribosomal- and translation-related genes in CD34+ cells, consistent with a defect in ribosome biogenesis analogous to Diamond-Blackfan anaemia.\",\n      \"method\": \"Microarray gene expression profiling of patient CD34+ cells; hierarchical clustering\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — transcriptomic association without direct mechanistic experiment\",\n      \"pmids\": [\"18477045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In zebrafish, CRISPR/Cas9-mediated disruption of RPS14 causes anemia due to a late-stage erythropoietic defect that is initially p53-independent and subsequently becomes p53-dependent.\",\n      \"method\": \"CRISPR/Cas9 zebrafish knockout; haematopoiesis and apoptosis phenotyping; p53 pathway analysis\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype and pathway placement (p53-dependent vs independent stages)\",\n      \"pmids\": [\"27216296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Combined haploinsufficiency of Rps14, Csnk1a1, and miR-145/146a in mice causes macrophages to activate innate immune signalling (elevated S100A8) and induce S100A8 expression in the mesenchymal stem cell niche, demonstrating that Rps14-deficient haematopoietic stem cells alter the bone marrow microenvironment as an extrinsic mechanism of erythroid failure.\",\n      \"method\": \"Conditional heterozygous mouse knockouts; stable miRNA knockdown; quantitative S100A8 expression analysis; macrophage functional assays; patient bone marrow validation\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — combinatorial genetic mouse model with patient validation, single lab\",\n      \"pmids\": [\"30651631\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPS14 is a structural component of the 40S ribosomal subunit whose carboxy-terminal basic region is critical for tRNA binding and 20S pre-rRNA processing; haploinsufficiency causes a p53-dependent erythroid differentiation block mediated through S100A8/S100A9 innate immune signalling, and free extra-ribosomal RPS14 also directly inhibits MDM2 E3 ligase activity to stabilise p53 and suppresses c-Myc transcriptional activity, together restraining cell proliferation during ribosomal stress.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nPapers about canonical RPS14 (ribosomal protein S14, 40S subunit, human/mammalian/ortholog in model organisms):\n- PMID:18202658 - KEEP (RPS14 in 5q- syndrome)\n- PMID:26878232 - KEEP (Rps14 haploinsufficiency mouse model)\n- PMID:22391559 - KEEP (RPS14-MDM2-p53)\n- PMID:23775087 - KEEP (RPS14-c-Myc)\n- PMID:15125836 - KEEP (yeast rpS14, ribosome biogenesis - ortholog)\n- PMID:18477045 - KEEP (RPS14 haploinsufficiency, ribosome biogenesis)\n- PMID:27216296 - KEEP (zebrafish RPS14, p53)\n- PMID:21068437 - KEEP (RPS14 haploinsufficiency, p53 in erythroid)\n- PMID:30651631 - KEEP (Rps14 mouse model)\n- PMID:9732752 - KEEP (human RPS14/emtB on chromosome 5)\n- PMID:7177110 - KEEP (emtB/RPS14 mapping chromosome 5)\n- PMID:3839563 - KEEP (CHO cell S14 mRNA structure, emetine resistance)\n- PMID:6835209 - KEEP (ribosomal protein S14, emetine resistance)\n- PMID:8065299 - KEEP (RPS14 replication origin)\n- PMID:3141788 - KEEP (Drosophila RPS14 ortholog)\n- PMID:925037 - KEEP (isolation of rat 40S ribosomal proteins including S14)\n- PMID:8722009 - KEEP (structure/evolution of mammalian ribosomal proteins)\n- PMID:23636399 - KEEP (human 80S ribosome structure - includes RPS14)\n- PMID:25901680 - KEEP (human 80S ribosome structure)\n- PMID:3542041 - KEEP (E. coli S14 puromycin reconstitution - but E. coli S14 is not ortholog of human RPS14; E. coli S14 = uS11 in universal nomenclature, different from eukaryotic RPS14. EXCLUDE - symbol collision)\n- PMID:1100389 - EXCLUDE (E. coli 16S RNA with S14 - prokaryotic, not ortholog)\n- PMID:2459390 - EXCLUDE (E. coli 30S assembly with S14 - prokaryotic)\n- PMID:3405753 - EXCLUDE (broad bean mitochondrial rps14 - plant mitochondria)\n- PMID:10430921 - EXCLUDE (rice nuclear rps14 - plant)\n- PMID:2326162 - EXCLUDE (Oenothera mitochondrial rps14 - plant)\n- PMID:21708151 - EXCLUDE (moss mitochondrial rps14 editing - plant)\n- PMID:15144376 - EXCLUDE (Arabidopsis chloroplast rps14 - plant)\n- PMID:16842621 - EXCLUDE (grass mitochondrial rps14 - plant)\n- PMID:14693379 - EXCLUDE (grass mitochondrial rps14 transfer - plant)\n- PMID:29648606 - EXCLUDE (Arabidopsis chloroplast rps14 editing - plant)\n- PMID:7916674 - EXCLUDE (Arabidopsis mitochondrial rps14 pseudogene - plant)\n- PMID:1463850 - EXCLUDE (Arabidopsis mitochondrial rps14 - plant)\n- PMID:10503545 - EXCLUDE (Arabidopsis nuclear rps14 - plant)\n- PMID:8806426 - EXCLUDE (potato mitochondrial rps14 - plant)\n- PMID:8252643 - EXCLUDE (Brassica mitochondrial rps14 - plant)\n- PMID:3305503 - EXCLUDE (Halobacterium S14 - archaebacterium, symbol collision)\n- PMID:16988111 - EXCLUDE (bovine S14 = Thrsp/Spot 14, alias collision - different gene)\n- PMID:2313387 - EXCLUDE (rat S14 = Thrsp/Spot 14, alias collision)\n- PMID:10551830 - EXCLUDE (S14 = Thrsp, alias collision)\n- PMID:1618827 - EXCLUDE (S14 = Thrsp, alias collision)\n- PMID:2308335 - EXCLUDE (S14 = Thrsp)\n- PMID:4065033 - EXCLUDE (S14 = Thrsp/Spot 14, alias collision)\n- PMID:8378318 - EXCLUDE (S14 = Thrsp, alias collision)\n- PMID:2175783 - EXCLUDE (S14 = Thrsp)\n- PMID:2159469 - EXCLUDE (S14 = Thrsp)\n- PMID:8132677 - EXCLUDE (S14 = Thrsp)\n- PMID:7997231 - EXCLUDE (S14 = Thrsp)\n- PMID:2808335 - EXCLUDE (S14 = Thrsp)\n- PMID:8194479 - EXCLUDE (S14 = Thrsp)\n- PMID:3760185 - EXCLUDE (S14 = Thrsp)\n- PMID:3830060 - EXCLUDE (S14 = Thrsp)\n- PMID:3688223 - EXCLUDE (S14 = Thrsp)\n- PMID:2925662 - EXCLUDE (S14 = Thrsp)\n- PMID:8346938 (Jump 1994 NF-Y) - checking: PMID:9346922 - EXCLUDE (S14 = Thrsp)\n- PMID:16809440 - EXCLUDE (S14 = Thrsp knockout)\n- PMID:20233797 - EXCLUDE (S14/S14R = Thrsp)\n- PMID:1744084 - EXCLUDE (S14 = Thrsp)\n- PMID:3366778 - EXCLUDE (S14 = Thrsp)\n- PMID:2177838 - EXCLUDE (S14 = Thrsp)\n- All US11 HCMV/HSV papers - EXCLUDE (US11 = viral gene, alias collision)\n- PMID:8625414, 10508854, 11514634, 10411907, 11717308, etc. - EXCLUDE (HCMV US11)\n- PMID:11070019, 12368348, 17229694, 12915535, 11884553, 12023332 (US11 HSV/HCMV) - EXCLUDE\n- PMID:15640244 - EXCLUDE (Bacillus S14, symbol collision)\n- PMID:12527810 - EXCLUDE (S14-95 compound, not gene)\n- PMID:36276641 - EXCLUDE (PA-S14 compound)\n- PMID:7928955 - EXCLUDE (Vibrio S14)\n- PMID:9440506 - EXCLUDE (Vibrio S14)\n- PMID:17218035 - EXCLUDE (duck reovirus S14)\n- PMID:28622305 - KEEP (RPS14 deficiency in myelofibrosis)\n- PMID:15489334 - not mechanistic for RPS14 specifically - EXCLUDE\n- PMID:12477932 - EXCLUDE (cDNA project, not mechanistic)\n\nAdditional curated papers:\n- PMID:16189514 - large-scale interactome, RPS14 mentioned but not mechanistic - EXCLUDE for discovery\n- PMID:28514442 - BioPlex, not mechanistic - EXCLUDE\n- PMID:26496610 - interactome, not mechanistic - EXCLUDE\n- PMID:25416956 - interactome - EXCLUDE\n- PMID:22681889 - mRNA-bound proteome, RPS14 as RNA-binding - potentially KEEP but no mechanism\n- PMID:32296183 - interactome - EXCLUDE\n- PMID:29507755 - m6A, not about RPS14 - EXCLUDE\n- PMID:17353931 - MS interactome - EXCLUDE\n- PMID:33961781 - BioPlex - EXCLUDE\n- PMID:22939629 - protein complexes census - EXCLUDE\n- PMID:21873635 - GO annotations - EXCLUDE\n- PMID:16713569 - ataxia network - EXCLUDE\n- PMID:28302793 - RBM39/splicing - EXCLUDE\n- PMID:21423176 - focal adhesion - EXCLUDE\n- PMID:23636399 - KEEP (human 80S ribosome structure including RPS14)\n- PMID:25901680 - KEEP (human 80S ribosome structure)\n- PMID:15189156 - eukaryotic translation review - EXCLUDE (no specific RPS14 mechanism)\n- PMID:21170055 - postsynaptic density - EXCLUDE\n- PMID:17643375 - transcription machinery - EXCLUDE\n- PMID:34079125 - BioID map - EXCLUDE\n- PMID:20020773 - TDP-43 - EXCLUDE\n- PMID:23463506 - tetraspanin - EXCLUDE\n- PMID:26344197 - metazoan complexes - EXCLUDE\n- PMID:21145461 - CRL network - EXCLUDE\n- PMID:22863883 - interactome - EXCLUDE\n- PMID:8722009 - KEEP (mammalian ribosomal protein structure/evolution)\n\nNow extracting discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"RPS14 was identified as the causal gene for the 5q- syndrome myelodysplastic syndrome subtype. Partial loss-of-function of RPS14 via RNAi in normal haematopoietic progenitor cells phenocopied the erythroid differentiation defect, and forced RPS14 expression rescued the phenotype in patient-derived bone marrow cells. A block in pre-ribosomal RNA processing was identified in RPS14-deficient cells, functionally linking 5q- syndrome to Diamond-Blackfan anaemia through defective ribosomal protein function.\",\n      \"method\": \"RNAi screen in haematopoietic progenitor cells, rescue experiments with forced expression in patient bone marrow cells, pre-rRNA processing assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic rescue (loss-of-function phenocopies disease, gain-of-function rescues patient cells), replicated across multiple experimental systems\",\n      \"pmids\": [\"18202658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Conditional inactivation of Rps14 in mice causes a p53-dependent erythroid differentiation block at the transition from polychromatic to orthochromatic erythroblasts, resulting in progressive anemia, megakaryocyte dysplasia, and loss of HSC quiescence. Mechanistically, Rps14 haploinsufficiency upregulates S100A8 and S100A9 (innate immune signaling proteins) in erythroblasts, monocytes, and macrophages; addition of recombinant S100A8 was sufficient to induce erythroid differentiation defects in wild-type cells, and genetic inactivation of S100a8 rescued the erythroid defect of Rps14-haploinsufficient HSCs.\",\n      \"method\": \"Conditional knockout mouse model, quantitative proteomics, recombinant protein treatment, genetic rescue (S100a8 knockout cross)\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including conditional KO, proteomics, recombinant protein sufficiency, and genetic epistasis in one study\",\n      \"pmids\": [\"26878232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RPS14 binds the central acidic domain of MDM2 and inhibits its E3 ubiquitin ligase activity toward p53, thereby stabilizing and activating p53. This RPS14-MDM2 interaction is induced upon ribosomal stress (actinomycin D or mycophenolic acid treatment). Overexpression of RPS14 elevated p53 level and activity leading to G1 or G2 arrest; knockdown of RPS14 alleviated p53 induction. Knockdown of RPS14 also itself caused ribosomal stress-induced p53 activation that was dependent on RPL11 and RPL5.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown in cells, MDM2 E3 ligase activity assays, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple functional assays in one lab; Co-IP binding, enzymatic inhibition assay, and cellular phenotyping\",\n      \"pmids\": [\"22391559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RPS14 interacts with the Myc homology box II (MBII) and the C-terminal bHLH-LZ domains of c-Myc, inhibits c-Myc transcriptional activity by preventing recruitment of c-Myc and its cofactor TRRAP to target gene promoters. RPS14 also promotes c-Myc mRNA degradation through an Argonaute 2 (Ago2)- and microRNA-mediated pathway, independently of p53.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, reporter assays, mRNA stability assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple orthogonal methods (Co-IP for interaction, ChIP for functional consequence, mRNA stability assays) in single lab\",\n      \"pmids\": [\"23775087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The carboxy-terminal extension of yeast ribosomal protein rpS14 is required for maturation of 43S preribosomes. Specific rps14 mutations cause extraordinary accumulation of 43S preribosomes containing 20S pre-rRNA in the cytoplasm, demonstrating that rpS14's C-terminal extension—located near the 3' end of 18S rRNA—is required for 3' end processing of 20S pre-rRNA and late steps of 40S ribosomal subunit biogenesis.\",\n      \"method\": \"Yeast rpS14 mutant analysis, northern blotting for pre-rRNA intermediates, electron microscopy, ribosome fractionation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic structure-function analysis with multiple rpS14 mutations, biochemical pre-rRNA processing readout, structural localization context; single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"15125836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Haploinsufficiency of RPS14 (or RPS19) selectively activates p53 in erythroid progenitor cells but not in other lineages. This lineage-specific p53 accumulation leads to p21 induction and cell cycle arrest specifically in erythroid cells. Pharmacological inhibition of p53 rescued the erythroid defect, whereas nutlin-3-mediated p53 activation selectively impaired erythropoiesis, establishing a mechanistic basis for erythroid failure in 5q- syndrome.\",\n      \"method\": \"shRNA knockdown in human hematopoietic progenitors, p53/p21 western blotting, pharmacological rescue (pifithrin-α, nutlin-3), immunohistochemistry in patient bone marrow biopsies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional pharmacological manipulation of p53 with specific erythroid phenotype, validated in patient samples; replicated across RPS14 and RPS19\",\n      \"pmids\": [\"21068437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In a zebrafish CRISPR/Cas9 RPS14 knockout model, erythropoietic failure occurs by a late-stage defect that is initially p53-independent and then becomes p53-dependent, revealing a two-phase mechanism. Pharmacological agents including L-leucine and dexamethasone could partially reverse the anemic phenotype.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish, morpholino knockdown, pharmacological testing, blood cell counts and erythroid staging\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic model with temporal dissection of p53-dependent vs. p53-independent phases; single study\",\n      \"pmids\": [\"27216296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Combined haploinsufficiency of Rps14, Csnk1a1, and miR-145/miR-146a in mice recapitulates the cardinal features of the 5q- syndrome including severe anemia and megakaryocyte dysplasia. Rps14/Csnk1a1/miR-145/146a-deficient macrophages activate the innate immune response (increased S100A8) and alter the mesenchymal stem cell niche microenvironment, demonstrating that hematopoietic cell-intrinsic defects extrinsically impair erythropoiesis through niche signaling.\",\n      \"method\": \"Conditional compound mouse knockouts, bone marrow transplantation, flow cytometry, S100A8 immunostaining in patient samples\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis through compound knockouts, mechanistic link to microenvironment via S100A8 niche signaling\",\n      \"pmids\": [\"30651631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1982,\n      \"finding\": \"The human RPS14 gene (emtB locus) was mapped to chromosome 5 by studying human-Chinese hamster hybrid cells. The human RPS14 protein is incorporated into functional ribosomes in place of the Chinese hamster protein, demonstrating functional conservation of the ribosomal subunit protein across species.\",\n      \"method\": \"Somatic cell hybrid analysis, selective pressure experiments, biochemical incorporation assay\",\n      \"journal\": \"Somatic cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical demonstration of functional incorporation plus genetic mapping\",\n      \"pmids\": [\"9732752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"The CHO cell emetine-resistance mutations (emtB) in ribosomal protein S14 map to two adjacent arginine codons in the basic C-terminal region of the protein, established by cDNA cloning and sequencing of wild-type and mutant transcripts. This identified the C-terminal basic region as critical for S14 function in the 40S ribosomal subunit.\",\n      \"method\": \"cDNA cloning and sequencing of wild-type and emetine-resistant mutant S14 mRNAs, polypeptide sequence analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct sequencing of genetic variants with known functional consequence (emetine resistance/ribosome structure)\",\n      \"pmids\": [\"3839563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1983,\n      \"finding\": \"Two-step emetine resistance mutations in Chinese hamster cells cause additional alterations in ribosomal protein S14 and destabilize the 40S ribosomal subunit. 40S subunits from two-step emtB mutants dissociated into core particles at lower ionic strength than wild-type, directly linking S14 mutations to 40S subunit structural integrity.\",\n      \"method\": \"Two-dimensional PAGE of ribosomal proteins, salt stability assays of ribosomal subunits, complementation testing\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical measurement of ribosome stability plus genetic complementation\",\n      \"pmids\": [\"6835209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cryo-EM structures of Drosophila melanogaster and Homo sapiens 80S ribosomes reveal the position and interactions of RPS14 within the 40S small subunit, including metazoan-specific features such as additional structural layers formed by ribosomal RNA co-evolving with ribosomal proteins.\",\n      \"method\": \"High-resolution cryo-electron microscopy and atomic model building\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure at near-atomic resolution defining RPS14 position in ribosome\",\n      \"pmids\": [\"23636399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The near-atomic resolution (3.6 Å, reaching 2.9 Å) cryo-EM structure of the human 80S ribosome provides detailed information on RPS14's position and interactions within the 40S subunit, including contacts at the subunit interface that remodel during rotational movements of ribosomal subunits during translation.\",\n      \"method\": \"Single-particle cryo-electron microscopy and atomic model building\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic resolution structure of human ribosome\",\n      \"pmids\": [\"25901680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hyperactivation of the thrombopoietin/MPL axis in myelofibrosis induces RPS14 deficiency in megakaryocytes, which impairs GATA1 mRNA translation, contributing to megakaryocyte dysplasia and myelofibrosis pathophysiology.\",\n      \"method\": \"Mouse model analysis (Gata1low), western blotting, polysome profiling, electron microscopy\",\n      \"journal\": \"Blood cancer journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic link between TPO signaling and RPS14 deficiency affecting GATA1 translation; single study with multiple methods\",\n      \"pmids\": [\"28622305\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPS14 is a component of the 40S ribosomal subunit whose C-terminal extension is required for pre-rRNA processing and late steps of 40S biogenesis; haploinsufficiency causes a p53-dependent erythroid differentiation block (via MDM2 inhibition and S100A8/S100A9 innate immune activation) that underlies the 5q- myelodysplastic syndrome, while excess free RPS14 also suppresses c-Myc transcriptional activity through direct binding and promotes c-Myc mRNA degradation via Ago2/miRNA pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RPS14 is a core structural component of the 40S ribosomal subunit that is essential for ribosome biogenesis, tRNA binding, and erythropoiesis. Its carboxy-terminal basic region is required for 20S pre-rRNA processing during 40S subunit maturation and for tRNA binding at both the A and P sites [PMID:15125836, PMID:3542041], while emetine-resistance mutations in this region destabilize the 40S subunit [PMID:6835209, PMID:3839563]. Haploinsufficiency of RPS14 causes the erythroid differentiation block characteristic of 5q- myelodysplastic syndrome: this block is p53-dependent and is mediated by upregulation of S100A8/S100A9 innate immune signaling in erythroblasts and bone marrow macrophages, as demonstrated by genetic rescue with forced RPS14 expression and S100a8 knockout epistasis [PMID:18202658, PMID:26878232]. In an extra-ribosomal capacity, free RPS14 directly binds and inhibits MDM2 E3 ligase activity to stabilize p53 and interacts with c-Myc to suppress its transcriptional activity, linking ribosomal stress to cell-cycle arrest and proliferation control [PMID:22391559, PMID:23775087].\",\n  \"teleology\": [\n    {\n      \"year\": 1982,\n      \"claim\": \"Establishing that RPS14 is the product of a human chromosome 5 gene resolved its genomic origin and showed that human S14 can functionally replace its hamster ortholog in interspecific hybrids.\",\n      \"evidence\": \"Somatic cell hybrid selection with cytogenetic mapping and functional complementation\",\n      \"pmids\": [\"9732752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise chromosomal band not yet defined\", \"No structural or biochemical characterization of the protein\"]\n    },\n    {\n      \"year\": 1983,\n      \"claim\": \"Identifying RPS14 as the protein altered by emetine-resistance mutations established it as a functionally important 40S subunit component whose structural integrity governs subunit stability.\",\n      \"evidence\": \"2D gel electrophoresis, complementation testing, and ribosomal salt-stability assays in Chinese hamster cells\",\n      \"pmids\": [\"6835209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact residues responsible for the phenotype not yet identified\", \"No direct structural data on RPS14's position within the 40S subunit\"]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"Mapping emetine-resistance mutations to adjacent arginine codons in the carboxy-terminal basic region pinpointed this domain as critical for 40S subunit architecture and function.\",\n      \"evidence\": \"cDNA cloning and sequencing of wild-type versus mutant S14\",\n      \"pmids\": [\"3839563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which arginine substitutions affect ribosome function unknown\", \"No reconstitution with purified mutant protein\"]\n    },\n    {\n      \"year\": 1986,\n      \"claim\": \"Demonstrating that puromycin-modified S14 abolishes tRNA binding at both the A and P sites established a direct role for RPS14 in the functional core of the decoding center.\",\n      \"evidence\": \"Puromycin photoaffinity labeling of E. coli S14 followed by 30S reconstitution and tRNA binding assay\",\n      \"pmids\": [\"3542041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bacterial system; conservation of the exact tRNA-contact surface in eukaryotic RPS14 not confirmed\", \"No high-resolution structural view of the S14-tRNA interface\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that the yeast RPS14 carboxy-terminal extension is required for 20S pre-rRNA processing connected its structural role to a specific step in 40S subunit maturation.\",\n      \"evidence\": \"Yeast C-terminal truncation mutants analyzed by sucrose gradient sedimentation and pre-rRNA northern blots\",\n      \"pmids\": [\"15125836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endonuclease responsible for 20S cleavage not identified as an RPS14 partner\", \"Whether this role is conserved in mammalian ribosome biogenesis was untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying RPS14 haploinsufficiency as the causative defect in 5q- myelodysplastic syndrome linked a ribosomal protein to a specific human blood disease and connected it to pre-rRNA processing defects analogous to Diamond-Blackfan anaemia.\",\n      \"evidence\": \"RNAi screen in human haematopoietic progenitors; rescue by forced RPS14 expression in patient bone marrow; pre-rRNA processing assays\",\n      \"pmids\": [\"18202658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector pathways (p53, innate immunity) not yet delineated\", \"Whether the erythroid specificity of the phenotype reflects lineage-specific ribosome requirements was unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that free RPS14 binds MDM2 and inhibits its E3 ligase activity toward p53 established an extra-ribosomal mechanism through which ribosomal stress activates the p53 checkpoint.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation; in vitro ubiquitination assay; actinomycin D/mycophenolic acid-induced ribosomal stress with p53 stabilization and cell-cycle arrest readouts\",\n      \"pmids\": [\"22391559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of RPS14-MDM2 versus other RP-MDM2 interactions during ribosomal stress unclear\", \"In vivo validation in haematopoietic cells not performed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealing that RPS14 directly binds c-Myc and suppresses its transcriptional activity — partly via Ago2/miRNA-mediated mRNA degradation — expanded RPS14's extra-ribosomal roles to oncogene control.\",\n      \"evidence\": \"Co-immunoprecipitation; ChIP for c-Myc/TRRAP on target promoters; siRNA knockdown; mRNA stability assays\",\n      \"pmids\": [\"23775087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific miRNAs mediating c-Myc mRNA degradation downstream of RPS14 not identified\", \"Physiological context (stress condition, cell type) for this activity not defined\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Conditional Rps14 knockout in mice and CRISPR disruption in zebrafish converged on a p53-dependent erythroid differentiation block, and mouse genetic epistasis placed S100A8/S100A9 innate immune signaling as the critical mediator downstream of Rps14 loss.\",\n      \"evidence\": \"Mouse conditional KO with S100a8 double-KO epistasis and quantitative proteomics; zebrafish CRISPR/Cas9 KO with p53 pathway analysis\",\n      \"pmids\": [\"26878232\", \"27216296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and signaling cascade through which S100A8 blocks erythroid differentiation not fully resolved\", \"Whether p53-independent early effects (zebrafish) operate via the same S100A8 axis is unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Combinatorial mouse models showed that Rps14-haploinsufficient haematopoietic cells instruct S100A8 expression in the mesenchymal niche via macrophage-mediated innate immune activation, establishing an extrinsic (microenvironment) component of erythroid failure.\",\n      \"evidence\": \"Conditional heterozygous knockout of Rps14, Csnk1a1, and miR-145/146a in mice; macrophage and niche cell functional assays; patient bone marrow validation\",\n      \"pmids\": [\"30651631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of cell-intrinsic vs niche-mediated erythroid failure not quantified\", \"Whether therapeutic targeting of S100A8 signaling can rescue human 5q- disease untested\", \"Single-lab combinatorial model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of RPS14's extra-ribosomal interactions with MDM2 and c-Myc, the receptor and downstream cascade by which S100A8 blocks terminal erythroid differentiation, and whether the erythroid lineage specificity of RPS14 haploinsufficiency reflects specialized ribosome composition or differential p53/innate immune sensitivity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of RPS14-MDM2 or RPS14-c-Myc complexes\", \"S100A8 receptor on erythroblasts not identified\", \"Lineage-specific ribosome composition hypothesis untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 6, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [5, 6, 4, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"40S ribosomal subunit\"\n    ],\n    \"partners\": [\n      \"MDM2\",\n      \"MYC\",\n      \"S100A8\",\n      \"S100A9\",\n      \"TRRAP\",\n      \"AGO2\",\n      \"TP53\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"RPS14 (uS11) is a structural component of the 40S ribosomal subunit that is essential for ribosome biogenesis, translational fidelity, and erythropoiesis. Its C-terminal basic extension is required for 3′-end processing of 20S pre-rRNA during late 40S subunit maturation, and mutations in this region destabilize the small subunit [PMID:15125836, PMID:6835209]. Haploinsufficiency of RPS14 is the causative lesion in 5q− myelodysplastic syndrome: it triggers a lineage-selective, p53-dependent erythroid differentiation block mediated by MDM2 inhibition and S100A8/S100A9 innate immune activation, which also remodels the bone-marrow niche [PMID:18202658, PMID:26878232, PMID:21068437]. Beyond its ribosomal role, free RPS14 directly binds c-Myc to inhibit its transcriptional activity and promotes c-Myc mRNA degradation through an Ago2/miRNA-dependent pathway [PMID:23775087].\",\n  \"teleology\": [\n    {\n      \"year\": 1982,\n      \"claim\": \"Mapping the human RPS14 gene to chromosome 5 and demonstrating that human RPS14 functionally replaces its hamster ortholog in ribosomes established S14 as a conserved core 40S subunit protein.\",\n      \"evidence\": \"Somatic cell hybrid panels with selective pressure and biochemical ribosome incorporation assays\",\n      \"pmids\": [\"9732752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural detail on S14's position within the subunit\", \"Functional conservation shown only between mammalian species\"]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"Identification of emetine-resistance mutations at two adjacent arginine codons in the C-terminal basic region of S14 revealed this domain as functionally critical for 40S subunit activity and structural stability.\",\n      \"evidence\": \"cDNA sequencing of wild-type and emetine-resistant CHO mutants; salt-dissociation assays of 40S subunits from two-step emtB mutants\",\n      \"pmids\": [\"3839563\", \"6835209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise molecular contacts of the C-terminal extension with rRNA were unknown\", \"Mechanism of emetine binding to the ribosome not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Structure–function analysis in yeast showed that the C-terminal extension of rpS14 is required for cytoplasmic processing of 20S pre-rRNA to mature 18S rRNA, establishing a specific role in late 40S biogenesis beyond structural integrity.\",\n      \"evidence\": \"Yeast rpS14 C-terminal mutants analyzed by northern blotting and ribosome fractionation\",\n      \"pmids\": [\"15125836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same pre-rRNA processing requirement holds in mammalian cells\", \"Identity of the endonuclease(s) gated by rpS14 C-terminal contacts\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"An RNAi screen identified RPS14 haploinsufficiency as the causative event in 5q− myelodysplastic syndrome, linking a ribosomal protein deficiency to a specific human hematologic disease and connecting it mechanistically to Diamond-Blackfan anemia via shared pre-rRNA processing defects.\",\n      \"evidence\": \"RNAi knockdown in human CD34+ progenitors phenocopying erythroid failure; forced RPS14 expression rescuing 5q− patient bone marrow\",\n      \"pmids\": [\"18202658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether co-deleted genes on 5q contribute to the full disease spectrum\", \"Mechanism of erythroid selectivity not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that RPS14 haploinsufficiency activates p53 selectively in erythroid progenitors, with pharmacological p53 inhibition rescuing the defect, explained the lineage-specific vulnerability underlying the 5q− erythroid failure.\",\n      \"evidence\": \"shRNA knockdown in human hematopoietic progenitors; pifithrin-α rescue and nutlin-3 phenocopy; immunohistochemistry in patient biopsies\",\n      \"pmids\": [\"21068437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why p53 is activated selectively in erythroid cells rather than other lineages\", \"Contribution of p53-independent pathways\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that RPS14 directly binds the central acidic domain of MDM2 and inhibits its E3 ligase activity toward p53 provided a molecular mechanism for ribosomal-stress-induced p53 stabilization, complementing the RPL5/RPL11 pathway.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro MDM2 ubiquitin ligase assays, overexpression/knockdown in cell lines\",\n      \"pmids\": [\"22391559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative quantitative contribution of RPS14 versus RPL5/RPL11 to MDM2 inhibition in vivo\", \"No structural model of the RPS14–MDM2 complex\", \"Single-laboratory study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"RPS14 was shown to act as an extra-ribosomal inhibitor of c-Myc by binding its MBII and bHLH-LZ domains, blocking TRRAP recruitment to promoters, and promoting c-Myc mRNA degradation through Ago2/miRNA—establishing a ribosomal-protein–oncogene regulatory axis independent of p53.\",\n      \"evidence\": \"Co-IP, chromatin IP, reporter assays, mRNA stability assays with siRNA knockdown\",\n      \"pmids\": [\"23775087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological conditions that generate sufficient free RPS14 to repress c-Myc in vivo\", \"Identity of the specific miRNAs involved\", \"Single-laboratory study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"High-resolution cryo-EM structures of metazoan 80S ribosomes defined the precise position and contacts of RPS14 within the 40S subunit, including metazoan-specific structural elaborations.\",\n      \"evidence\": \"Cryo-EM at near-atomic resolution of Drosophila and human 80S ribosomes\",\n      \"pmids\": [\"23636399\", \"25901680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of RPS14 contacts during active translation elongation cycles\", \"No structure of a ribosome assembly intermediate containing RPS14\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A conditional Rps14 knockout mouse recapitulated 5q− syndrome features (anemia, megakaryocyte dysplasia, HSC defects) and revealed that upregulation of S100A8/S100A9 in the innate immune compartment is both necessary and sufficient for the erythroid differentiation block, as demonstrated by genetic rescue with S100a8 knockout.\",\n      \"evidence\": \"Conditional KO mice, quantitative proteomics, recombinant S100A8 sufficiency tests, S100a8 genetic rescue\",\n      \"pmids\": [\"26878232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and signaling pathway through which S100A8 impairs erythropoiesis\", \"Whether S100A8 contributes to clonal advantage in MDS\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Compound haploinsufficiency of Rps14 with Csnk1a1 and miR-145/146a in mice demonstrated that hematopoietic cell-intrinsic innate immune activation (S100A8) extrinsically impairs erythropoiesis by remodeling the mesenchymal niche, explaining how multiple 5q deletions cooperate.\",\n      \"evidence\": \"Compound conditional mouse knockouts, bone marrow transplantation, flow cytometry, S100A8 immunostaining in patient samples\",\n      \"pmids\": [\"30651631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise niche signals downstream of S100A8 that suppress erythropoiesis\", \"Whether therapeutic targeting of S100A8 is feasible in patients\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the RPS14–MDM2 interaction, the identity of the miRNAs mediating RPS14-dependent c-Myc mRNA degradation, and the molecular mechanism by which S100A8/S100A9 selectively impairs erythroid differentiation downstream of RPS14 haploinsufficiency.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal or cryo-EM structure of RPS14–MDM2\", \"miRNA identities in c-Myc degradation pathway uncharacterized\", \"S100A8 receptor/signaling in erythroid progenitors not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 8, 9, 10, 11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [8, 10, 11, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0392499\", \"supporting_discovery_ids\": [4, 11, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 11, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 5, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"complexes\": [\"40S ribosomal subunit\", \"80S ribosome\"],\n    \"partners\": [\"MDM2\", \"c-Myc\", \"TRRAP\", \"AGO2\", \"S100A8\", \"S100A9\", \"RPL11\", \"RPL5\"],\n    \"other_free_text\": []\n  }\n}\n```"}