{"gene":"PIR","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2014,"finding":"Basal transcription of the human PIR gene in HeLa cells is driven by NRF2 binding to an evolutionary conserved antioxidant response element (ARE) located 281 bp downstream of the transcription start site, as demonstrated by luciferase reporter assays with deletional constructs and chromatin immunoprecipitation showing NRF2 occupancy at this element in vivo.","method":"Luciferase reporter assay (deletion constructs), chromatin immunoprecipitation (ChIP), promoter analysis","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay in single lab with two orthogonal methods, but single study","pmids":["24390086"],"is_preprint":false},{"year":2019,"finding":"PIR (Pirin) promotes breast cancer cell proliferation and tumor growth by activating transcription of the cell cycle activator E2F1; PIR binds to the E2F1 promoter region (shown by ChIP and luciferase reporter assay), leading to upregulation of E2F1 target genes (cdk4, cdk6, cyclin D, cyclin E, DDR1) and G1/S progression. PIR knockdown also decreases cell migration/invasion and metastasis, partly attributed to DDR1 downregulation.","method":"shRNA knockdown, luciferase reporter assay, chromatin immunoprecipitation (ChIP), xenograft mouse model, in vitro invasion/migration assays","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO phenotype with ChIP and reporter assay validation of E2F1 promoter binding, single lab with multiple orthogonal methods","pmids":["31500513"],"is_preprint":false},{"year":2020,"finding":"HPV16 E7 oncoprotein promotes PIR (Pirin) upregulation in oral cancer cells via the EGFR/PI3K/AKT1/NRF2 signaling axis, and elevated PIR in turn activates NF-κB; pharmacological inhibition of EGFR, PI3K, or AKT1 reduced NRF2 and PIR levels, linking E7-driven oxidative signaling to PIR/NF-κB activation.","method":"Pharmacological inhibition (EGFR, PI3K, AKT1 inhibitors), Western blot, gene knockdown/overexpression, reporter assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement via pharmacological epistasis and knockdown in single lab with multiple inhibitors and orthogonal readouts","pmids":["32679705"],"is_preprint":false},{"year":2019,"finding":"In human pulmonary fibroblasts exposed to particulate matter (PM), SIRT1 inhibits SREBP1 which in turn downregulates PIR (Pirin) and NLRP3 inflammasome; inhibitors of SIRT1, SREBP1, and PIR each reversed PM-induced inflammatory signaling, placing PIR downstream of the SIRT1-SREBP1 axis in PM-induced pulmonary inflammation.","method":"Gene expression microarray, Ingenuity Pathway Analysis, qPCR, Western blot, pharmacological inhibitors, PM-treated cell model","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement inferred primarily from inhibitor experiments and expression data without direct biochemical reconstitution of PIR's molecular mechanism","pmids":["31299012"],"is_preprint":false}],"current_model":"Pirin (PIR) is a nuclear iron-binding cupin-superfamily protein whose basal expression is driven by NRF2 via an antioxidant response element in its promoter; it functions as a transcriptional coregulator that activates NF-κB signaling and promotes cell cycle progression by binding the E2F1 promoter and upregulating E2F1 target genes, and its expression is regulated upstream by the SIRT1-SREBP1 axis and by HPV16 E7-driven EGFR/PI3K/AKT1/NRF2 signaling."},"narrative":{"mechanistic_narrative":"Pirin (PIR) is a transcriptional coregulator that links oxidative and oncogenic signaling to cell-cycle progression and inflammatory gene expression [PMID:31500513, PMID:32679705]. Its basal transcription is driven by NRF2, which binds an evolutionarily conserved antioxidant response element located downstream of the PIR transcription start site, establishing PIR as a direct NRF2 target gene [PMID:24390086]. PIR in turn acts on the cell cycle by binding the E2F1 promoter and activating E2F1 transcription, raising the levels of E2F1 target genes (cdk4, cdk6, cyclin D, cyclin E, and DDR1) to drive G1/S progression and promote breast cancer proliferation, migration, invasion, and metastasis [PMID:31500513]. PIR is positioned downstream of upstream oncogenic and metabolic inputs: HPV16 E7 elevates PIR through an EGFR/PI3K/AKT1/NRF2 axis, and elevated PIR then activates NF-κB [PMID:32679705]. Beyond these transcriptional and signaling roles, the molecular-biochemical basis of PIR's coregulatory activity has not been reconstituted in the available corpus.","teleology":[{"year":2014,"claim":"Established how PIR expression is controlled, identifying it as a direct NRF2 target rather than a constitutively expressed gene, thereby placing PIR within the antioxidant/redox response.","evidence":"Luciferase reporter assays with deletion constructs and ChIP for NRF2 occupancy at a conserved ARE in HeLa cells","pmids":["24390086"],"confidence":"Medium","gaps":["Single study from one lab","Does not address what PIR does downstream once expressed","ARE function in non-HeLa, physiological contexts not tested"]},{"year":2019,"claim":"Defined a downstream effector function for PIR by showing it directly activates E2F1 transcription to drive cell-cycle progression and tumor growth, moving PIR from a redox-regulated gene to a pro-proliferative transcriptional coregulator.","evidence":"shRNA knockdown, E2F1 promoter ChIP and luciferase reporter, xenograft model, and invasion/migration assays in breast cancer cells","pmids":["31500513"],"confidence":"Medium","gaps":["Mechanism of PIR recruitment to the E2F1 promoter not resolved","Whether PIR binds DNA directly or via partners unknown","Single lab; no structural basis for transcriptional activation"]},{"year":2019,"claim":"Placed PIR within an inflammatory signaling cascade, showing it acts downstream of the SIRT1-SREBP1 axis to control NLRP3 inflammasome and inflammatory signaling in particulate-matter-exposed pulmonary fibroblasts.","evidence":"Microarray, pathway analysis, qPCR, Western blot, and SIRT1/SREBP1/PIR inhibitors in a PM-treated fibroblast model","pmids":["31299012"],"confidence":"Low","gaps":["Pathway placement inferred from inhibitor and expression data without biochemical reconstitution of PIR's molecular mechanism","Direct molecular target of PIR in inflammation not identified","Causality between PIR and NLRP3 not established at protein-interaction level"]},{"year":2020,"claim":"Connected upstream oncogenic signaling to PIR, demonstrating that HPV16 E7 elevates PIR via EGFR/PI3K/AKT1/NRF2 and that PIR then activates NF-κB, integrating viral oncoprotein signaling with PIR-driven transcriptional output.","evidence":"Pharmacological inhibition of EGFR/PI3K/AKT1, knockdown/overexpression, Western blot, and reporter assays in oral cancer cells","pmids":["32679705"],"confidence":"Medium","gaps":["Direct biochemical link between PIR and NF-κB activation not reconstituted","Whether NF-κB activation is transcriptional coregulation or indirect unclear","Single lab; epistasis inferred from inhibitors"]},{"year":null,"claim":"The molecular-biochemical mechanism by which PIR exerts transcriptional coregulation — its direct binding partners, whether it engages DNA directly, and the role of any cofactor in this activity — remains unresolved.","evidence":"No reconstitution or structural study in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model of PIR bound to promoter or partner","No reciprocally validated direct protein partner identified","Catalytic or cofactor-dependent activity, if any, uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00625","full_name":"Pirin","aliases":["Probable quercetin 2,3-dioxygenase PIR","Probable quercetinase"],"length_aa":290,"mass_kda":32.1,"function":"Transcriptional coregulator of NF-kappa-B which facilitates binding of NF-kappa-B proteins to target kappa-B genes in a redox-state-dependent manner. May be required for efficient terminal myeloid maturation of hematopoietic cells. Has quercetin 2,3-dioxygenase activity (in vitro)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O00625/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PIR","total_profiled":1310},"omim":[{"mim_id":"621221","title":"STX18 ANTISENSE RNA 1, NONCODING; STX18AS1","url":"https://www.omim.org/entry/621221"},{"mim_id":"620951","title":"WD REPEAT-CONTAINING PROTEIN 31; WDR31","url":"https://www.omim.org/entry/620951"},{"mim_id":"615427","title":"ELMO/CED12 DOMAIN-CONTAINING PROTEIN 3; ELMOD3","url":"https://www.omim.org/entry/615427"},{"mim_id":"606862","title":"OSTEOCLAST-ASSOCIATED RECEPTOR; OSCAR","url":"https://www.omim.org/entry/606862"},{"mim_id":"604821","title":"LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR, SUBFAMILY B, MEMBER 4; LILRB4","url":"https://www.omim.org/entry/604821"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PIR"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O00625","domains":[{"cath_id":"2.60.120.10","chopping":"120-172","consensus_level":"medium","plddt":97.7336,"start":120,"end":172},{"cath_id":"-","chopping":"249-290","consensus_level":"medium","plddt":95.9764,"start":249,"end":290}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00625","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00625-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00625-F1-predicted_aligned_error_v6.png","plddt_mean":96.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIR","jax_strain_url":"https://www.jax.org/strain/search?query=PIR"},"sequence":{"accession":"O00625","fasta_url":"https://rest.uniprot.org/uniprotkb/O00625.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00625/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00625"}},"corpus_meta":[{"pmid":"3945547","id":"PMC_3945547","title":"The protein identification resource (PIR).","date":"1986","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/3945547","citation_count":286,"is_preprint":false},{"pmid":"22047710","id":"PMC_22047710","title":"piR-823, a novel non-coding small RNA, demonstrates in vitro and in vivo tumor suppressive activity in human gastric cancer cells.","date":"2011","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/22047710","citation_count":235,"is_preprint":false},{"pmid":"25667334","id":"PMC_25667334","title":"Photorhabdus insect-related (Pir) toxin-like genes in a plasmid of Vibrio parahaemolyticus, the causative agent of acute hepatopancreatic necrosis disease (AHPND) of shrimp.","date":"2015","source":"Diseases of aquatic organisms","url":"https://pubmed.ncbi.nlm.nih.gov/25667334","citation_count":172,"is_preprint":false},{"pmid":"9547347","id":"PMC_9547347","title":"Requirement of SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 for paired immunoglobulin-like receptor B (PIR-B)-mediated inhibitory signal.","date":"1998","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9547347","citation_count":158,"is_preprint":false},{"pmid":"9482905","id":"PMC_9482905","title":"The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9482905","citation_count":157,"is_preprint":false},{"pmid":"16495216","id":"PMC_16495216","title":"Pir proteins of Saccharomyces cerevisiae are attached to beta-1,3-glucan by a new protein-carbohydrate linkage.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16495216","citation_count":127,"is_preprint":false},{"pmid":"12021780","id":"PMC_12021780","title":"Impaired dendritic cell maturation and increased T(H)2 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(members of the Pir protein family) in stability of the Saccharomyces cerevisiae cell wall.","date":"1999","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10407261","citation_count":89,"is_preprint":false},{"pmid":"15723811","id":"PMC_15723811","title":"The Src family kinases Hck and Fgr negatively regulate neutrophil and dendritic cell chemokine signaling via PIR-B.","date":"2005","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15723811","citation_count":85,"is_preprint":false},{"pmid":"3353227","id":"PMC_3353227","title":"The protein identification resource (PIR).","date":"1988","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/3353227","citation_count":85,"is_preprint":false},{"pmid":"29976566","id":"PMC_29976566","title":"Circulating PIWI-Interacting RNAs piR-5937 and piR-28876 Are Promising Diagnostic Biomarkers of Colon Cancer.","date":"2018","source":"Cancer epidemiology, biomarkers & prevention : a publication of 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suppression of cell stemness and angiogenesis in breast cancer.","date":"2023","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/37153732","citation_count":35,"is_preprint":false},{"pmid":"34799689","id":"PMC_34799689","title":"piR-39980 mediates doxorubicin resistance in fibrosarcoma by regulating drug accumulation and DNA repair.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/34799689","citation_count":35,"is_preprint":false},{"pmid":"31879982","id":"PMC_31879982","title":"piR-39980 promotes cell proliferation, migration and invasion, and inhibits apoptosis via repression of SERPINB1 in human osteosarcoma.","date":"2020","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/31879982","citation_count":35,"is_preprint":false},{"pmid":"33376191","id":"PMC_33376191","title":"Circulating SNORD57 rather than piR-54265 is a promising biomarker for colorectal cancer: common pitfalls in the study of somatic piRNAs in cancer.","date":"2020","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/33376191","citation_count":34,"is_preprint":false},{"pmid":"26996203","id":"PMC_26996203","title":"Characterization of the Plasmodium Interspersed Repeats (PIR) proteins of Plasmodium chabaudi indicates functional diversity.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26996203","citation_count":33,"is_preprint":false},{"pmid":"32679705","id":"PMC_32679705","title":"Human Papillomavirus 16 E7 Promotes EGFR/PI3K/AKT1/NRF2 Signaling Pathway Contributing to PIR/NF-κB Activation in Oral Cancer Cells.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32679705","citation_count":33,"is_preprint":false},{"pmid":"21911569","id":"PMC_21911569","title":"Complete sequence of pJIE143, a pir-type plasmid carrying ISEcp1-blaCTX-M-15 from an Escherichia coli ST131 isolate.","date":"2011","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/21911569","citation_count":33,"is_preprint":false},{"pmid":"39106633","id":"PMC_39106633","title":"piR-27222 mediates PM2.5-induced lung cancer by resisting cell PANoptosis through the WTAP/m6A axis.","date":"2024","source":"Environment international","url":"https://pubmed.ncbi.nlm.nih.gov/39106633","citation_count":32,"is_preprint":false},{"pmid":"21636572","id":"PMC_21636572","title":"Differential but competitive binding of Nogo protein and class i major histocompatibility complex (MHCI) to the PIR-B ectodomain provides an inhibition of cells.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21636572","citation_count":32,"is_preprint":false},{"pmid":"16278454","id":"PMC_16278454","title":"Comparison of cell wall localization among Pir family proteins and functional dissection of the region required for cell wall binding and bud scar recruitment of Pir1p.","date":"2005","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/16278454","citation_count":32,"is_preprint":false},{"pmid":"7937060","id":"PMC_7937060","title":"The PIR-International Protein Sequence Database.","date":"1994","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/7937060","citation_count":32,"is_preprint":false},{"pmid":"33389678","id":"PMC_33389678","title":"PIWIL1 interacting RNA piR-017061 inhibits pancreatic cancer growth via regulating EFNA5.","date":"2021","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/33389678","citation_count":31,"is_preprint":false},{"pmid":"36482201","id":"PMC_36482201","title":"Tumour-derived exosomal piR-25783 promotes omental metastasis of ovarian carcinoma by inducing the fibroblast to myofibroblast transition.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36482201","citation_count":31,"is_preprint":false},{"pmid":"10802178","id":"PMC_10802178","title":"Evidence for the presence of pir-like proteins in Candida albicans.","date":"2000","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/10802178","citation_count":31,"is_preprint":false},{"pmid":"35581181","id":"PMC_35581181","title":"piR-823 inhibits cell apoptosis via modulating mitophagy by binding to PINK1 in colorectal cancer.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35581181","citation_count":30,"is_preprint":false},{"pmid":"20976309","id":"PMC_20976309","title":"Role of PIR-B in autoimmune glomerulonephritis.","date":"2010","source":"Journal of biomedicine & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/20976309","citation_count":30,"is_preprint":false},{"pmid":"28826361","id":"PMC_28826361","title":"Spermatozoa Expression of piR-31704, piR-39888, and piR-40349 and Their Correlation to Sperm Concentration and Fertilization Rate After ICSI.","date":"2017","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/28826361","citation_count":29,"is_preprint":false},{"pmid":"31299012","id":"PMC_31299012","title":"Ambient particulate matter attenuates Sirtuin1 and augments SREBP1-PIR axis to induce human pulmonary fibroblast inflammation: molecular mechanism of microenvironment associated with COPD.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31299012","citation_count":29,"is_preprint":false},{"pmid":"31940941","id":"PMC_31940941","title":"Small RNA Profiling of piRNAs in Colorectal Cancer Identifies Consistent Overexpression of piR-24000 That Correlates Clinically with an Aggressive Disease Phenotype.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31940941","citation_count":29,"is_preprint":false},{"pmid":"2259697","id":"PMC_2259697","title":"NRL-3D: a sequence-structure database derived from the protein data bank (PDB) and searchable within the PIR environment.","date":"1990","source":"Protein sequences & data analysis","url":"https://pubmed.ncbi.nlm.nih.gov/2259697","citation_count":29,"is_preprint":false},{"pmid":"24390086","id":"PMC_24390086","title":"Basal PIR expression in HeLa cells is driven by NRF2 via evolutionary conserved antioxidant response element.","date":"2014","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24390086","citation_count":28,"is_preprint":false},{"pmid":"38625937","id":"PMC_38625937","title":"The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38625937","citation_count":27,"is_preprint":false},{"pmid":"9550322","id":"PMC_9550322","title":"Genomic structure of PIR-B, the inhibitory member of the paired immunoglobulin-like receptor genes in mice.","date":"1998","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9550322","citation_count":27,"is_preprint":false},{"pmid":"10477705","id":"PMC_10477705","title":"Functional association of FcepsilonRIgamma with arginine(632) of paired immunoglobulin-like receptor (PIR)-A3 in murine macrophages.","date":"1999","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10477705","citation_count":27,"is_preprint":false},{"pmid":"10869023","id":"PMC_10869023","title":"PIR: a new resource for bioinformatics.","date":"2000","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10869023","citation_count":26,"is_preprint":false},{"pmid":"21360733","id":"PMC_21360733","title":"Isolation of Pichia pastoris PIR genes and their utilization for cell surface display and recombinant protein secretion.","date":"2010","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21360733","citation_count":24,"is_preprint":false},{"pmid":"36249068","id":"PMC_36249068","title":"Serum-derived piR-hsa-164586 of extracellular vesicles as a novel biomarker for early diagnosis of non-small cell lung cancer.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36249068","citation_count":23,"is_preprint":false},{"pmid":"12673625","id":"PMC_12673625","title":"Characterization of a disulphide-bound Pir-cell wall protein (Pir-CWP) of Yarrowia lipolytica.","date":"2003","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12673625","citation_count":22,"is_preprint":false},{"pmid":"14623073","id":"PMC_14623073","title":"The PIR domain of Grb14 is an intrinsically unstructured protein: implication in insulin signaling.","date":"2003","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/14623073","citation_count":22,"is_preprint":false},{"pmid":"22433797","id":"PMC_22433797","title":"A simple method for construction of pir+ Enterobacterial hosts for maintenance of R6K replicon plasmids.","date":"2012","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/22433797","citation_count":22,"is_preprint":false},{"pmid":"39102033","id":"PMC_39102033","title":"piR-823 tale as emerging cancer-hallmark molecular marker in different cancer types: a step-toward ncRNA-precision.","date":"2024","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39102033","citation_count":21,"is_preprint":false},{"pmid":"31500513","id":"PMC_31500513","title":"PIR promotes tumorigenesis of breast cancer by upregulating cell cycle activator E2F1.","date":"2019","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/31500513","citation_count":20,"is_preprint":false},{"pmid":"24493571","id":"PMC_24493571","title":"The contribution of Pir protein family to yeast cell surface display.","date":"2014","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/24493571","citation_count":19,"is_preprint":false},{"pmid":"37503320","id":"PMC_37503320","title":"PIWIL1 interacting RNA piR-017724 inhibits proliferation, invasion, and migration, and inhibits the development of HCC by silencing PLIN3.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37503320","citation_count":19,"is_preprint":false},{"pmid":"37473805","id":"PMC_37473805","title":"FDFT1 repression by piR-39980 prevents oncogenesis by regulating proliferation and apoptosis through hypoxia in tongue squamous cell carcinoma.","date":"2023","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37473805","citation_count":19,"is_preprint":false},{"pmid":"34249688","id":"PMC_34249688","title":"piR-hsa-211106 Inhibits the Progression of Lung Adenocarcinoma Through Pyruvate Carboxylase and Enhances Chemotherapy Sensitivity.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34249688","citation_count":19,"is_preprint":false},{"pmid":"38572963","id":"PMC_38572963","title":"Small Extracellular Vesicle piR-hsa-30937 Derived from Pancreatic Neuroendocrine Neoplasms Upregulates CD276 in Macrophages to Promote Immune Evasion.","date":"2024","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/38572963","citation_count":19,"is_preprint":false},{"pmid":"30576786","id":"PMC_30576786","title":"Multiplex SYBR Green and duplex TaqMan real-time PCR assays for the detection of Photorhabdus Insect-Related (Pir) toxin genes pirA and pirB.","date":"2018","source":"Molecular and cellular probes","url":"https://pubmed.ncbi.nlm.nih.gov/30576786","citation_count":19,"is_preprint":false},{"pmid":"33378643","id":"PMC_33378643","title":"The RNA phosphatase PIR-1 regulates endogenous small RNA pathways in C. elegans.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33378643","citation_count":18,"is_preprint":false},{"pmid":"32881713","id":"PMC_32881713","title":"piR-19166 inhibits migration and metastasis through CTTN/MMPs pathway in prostate carcinoma.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32881713","citation_count":18,"is_preprint":false},{"pmid":"31286407","id":"PMC_31286407","title":"Nogo-A/Pir-B/TrkB Signaling Pathway Activation Inhibits Neuronal Survival and Axonal Regeneration After Experimental Intracerebral Hemorrhage in Rats.","date":"2019","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/31286407","citation_count":18,"is_preprint":false},{"pmid":"29040791","id":"PMC_29040791","title":"From the Cover: Roles of mmu_piR_003399 in Microcystin-Leucine Arginine-Induced Reproductive Toxicity in the Spermatogonial Cells and Testis.","date":"2018","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/29040791","citation_count":18,"is_preprint":false},{"pmid":"24145365","id":"PMC_24145365","title":"Nevirapine-raltegravir combination, an NRTI and PI/r sparing regimen, as maintenance antiretroviral therapy in virologically suppressed HIV-1-infected patients.","date":"2013","source":"Antiviral therapy","url":"https://pubmed.ncbi.nlm.nih.gov/24145365","citation_count":18,"is_preprint":false},{"pmid":"32428871","id":"PMC_32428871","title":"PIWI-interacting RNAs piR-13643 and piR-21238 are promising diagnostic biomarkers of papillary thyroid carcinoma.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32428871","citation_count":17,"is_preprint":false},{"pmid":"14734022","id":"PMC_14734022","title":"Yeast cells harboring human alpha-1,3-fucosyltransferase at the cell surface engineered using Pir, a cell wall-anchored protein.","date":"2004","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/14734022","citation_count":17,"is_preprint":false},{"pmid":"10366659","id":"PMC_10366659","title":"PIR-ALN: a database of protein sequence alignments.","date":"1999","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10366659","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46979,"output_tokens":1603,"usd":0.082491,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7793,"output_tokens":1980,"usd":0.044233,"stage2_stop_reason":"end_turn"},"total_usd":0.126724,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about the human/mammalian canonical protein PIR (Pirin, the iron-binding nuclear protein / NF-κB coregulator). I also see papers about:\n- PIR-A/PIR-B (paired immunoglobulin-like receptors) - these are PIRB/PIRA genes, not PIR/Pirin\n- piRNAs (PIWI-interacting RNAs) - non-coding RNA products, not the PIR protein\n- PIR database (Protein Information Resource) - bioinformatics tool\n- Pir proteins of yeast (cell wall proteins) - different organism/function\n- Plasmodium pir genes - parasite genes\n- Bacterial pir genes (R6K plasmid, Erwinia, Vibrio) - bacterial genes\n- PIR domain in Grb7/14 family - this is a domain name, not the PIR gene\n- PIR-1 in C. elegans (RNA phosphatase) - could be ortholog but different function\n- IRS-1 PIR domain - domain name, not the PIR gene\n\nThe human PIR gene encodes Pirin, a cupin superfamily iron-binding protein that acts as a transcriptional coregulator. Relevant papers: PMID:32679705 (HPV16 E7/EGFR/PI3K/AKT1/NRF2/PIR/NF-κB), PMID:24390086 (NRF2 drives PIR transcription via ARE), PMID:31500513 (PIR activates E2F1), PMID:31299012 (SIRT1-SREBP1-PIR axis in COPD).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Basal transcription of the human PIR gene in HeLa cells is driven by NRF2 binding to an evolutionary conserved antioxidant response element (ARE) located 281 bp downstream of the transcription start site, as demonstrated by luciferase reporter assays with deletional constructs and chromatin immunoprecipitation showing NRF2 occupancy at this element in vivo.\",\n      \"method\": \"Luciferase reporter assay (deletion constructs), chromatin immunoprecipitation (ChIP), promoter analysis\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay in single lab with two orthogonal methods, but single study\",\n      \"pmids\": [\"24390086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PIR (Pirin) promotes breast cancer cell proliferation and tumor growth by activating transcription of the cell cycle activator E2F1; PIR binds to the E2F1 promoter region (shown by ChIP and luciferase reporter assay), leading to upregulation of E2F1 target genes (cdk4, cdk6, cyclin D, cyclin E, DDR1) and G1/S progression. PIR knockdown also decreases cell migration/invasion and metastasis, partly attributed to DDR1 downregulation.\",\n      \"method\": \"shRNA knockdown, luciferase reporter assay, chromatin immunoprecipitation (ChIP), xenograft mouse model, in vitro invasion/migration assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype with ChIP and reporter assay validation of E2F1 promoter binding, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31500513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HPV16 E7 oncoprotein promotes PIR (Pirin) upregulation in oral cancer cells via the EGFR/PI3K/AKT1/NRF2 signaling axis, and elevated PIR in turn activates NF-κB; pharmacological inhibition of EGFR, PI3K, or AKT1 reduced NRF2 and PIR levels, linking E7-driven oxidative signaling to PIR/NF-κB activation.\",\n      \"method\": \"Pharmacological inhibition (EGFR, PI3K, AKT1 inhibitors), Western blot, gene knockdown/overexpression, reporter assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement via pharmacological epistasis and knockdown in single lab with multiple inhibitors and orthogonal readouts\",\n      \"pmids\": [\"32679705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In human pulmonary fibroblasts exposed to particulate matter (PM), SIRT1 inhibits SREBP1 which in turn downregulates PIR (Pirin) and NLRP3 inflammasome; inhibitors of SIRT1, SREBP1, and PIR each reversed PM-induced inflammatory signaling, placing PIR downstream of the SIRT1-SREBP1 axis in PM-induced pulmonary inflammation.\",\n      \"method\": \"Gene expression microarray, Ingenuity Pathway Analysis, qPCR, Western blot, pharmacological inhibitors, PM-treated cell model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement inferred primarily from inhibitor experiments and expression data without direct biochemical reconstitution of PIR's molecular mechanism\",\n      \"pmids\": [\"31299012\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Pirin (PIR) is a nuclear iron-binding cupin-superfamily protein whose basal expression is driven by NRF2 via an antioxidant response element in its promoter; it functions as a transcriptional coregulator that activates NF-κB signaling and promotes cell cycle progression by binding the E2F1 promoter and upregulating E2F1 target genes, and its expression is regulated upstream by the SIRT1-SREBP1 axis and by HPV16 E7-driven EGFR/PI3K/AKT1/NRF2 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Pirin (PIR) is a transcriptional coregulator that links oxidative and oncogenic signaling to cell-cycle progression and inflammatory gene expression [#1, #2]. Its basal transcription is driven by NRF2, which binds an evolutionarily conserved antioxidant response element located downstream of the PIR transcription start site, establishing PIR as a direct NRF2 target gene [#0]. PIR in turn acts on the cell cycle by binding the E2F1 promoter and activating E2F1 transcription, raising the levels of E2F1 target genes (cdk4, cdk6, cyclin D, cyclin E, and DDR1) to drive G1/S progression and promote breast cancer proliferation, migration, invasion, and metastasis [#1]. PIR is positioned downstream of upstream oncogenic and metabolic inputs: HPV16 E7 elevates PIR through an EGFR/PI3K/AKT1/NRF2 axis, and elevated PIR then activates NF-\\u03baB [#2]. Beyond these transcriptional and signaling roles, the molecular-biochemical basis of PIR's coregulatory activity has not been reconstituted in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established how PIR expression is controlled, identifying it as a direct NRF2 target rather than a constitutively expressed gene, thereby placing PIR within the antioxidant/redox response.\",\n      \"evidence\": \"Luciferase reporter assays with deletion constructs and ChIP for NRF2 occupancy at a conserved ARE in HeLa cells\",\n      \"pmids\": [\"24390086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study from one lab\",\n        \"Does not address what PIR does downstream once expressed\",\n        \"ARE function in non-HeLa, physiological contexts not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a downstream effector function for PIR by showing it directly activates E2F1 transcription to drive cell-cycle progression and tumor growth, moving PIR from a redox-regulated gene to a pro-proliferative transcriptional coregulator.\",\n      \"evidence\": \"shRNA knockdown, E2F1 promoter ChIP and luciferase reporter, xenograft model, and invasion/migration assays in breast cancer cells\",\n      \"pmids\": [\"31500513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of PIR recruitment to the E2F1 promoter not resolved\",\n        \"Whether PIR binds DNA directly or via partners unknown\",\n        \"Single lab; no structural basis for transcriptional activation\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed PIR within an inflammatory signaling cascade, showing it acts downstream of the SIRT1-SREBP1 axis to control NLRP3 inflammasome and inflammatory signaling in particulate-matter-exposed pulmonary fibroblasts.\",\n      \"evidence\": \"Microarray, pathway analysis, qPCR, Western blot, and SIRT1/SREBP1/PIR inhibitors in a PM-treated fibroblast model\",\n      \"pmids\": [\"31299012\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Pathway placement inferred from inhibitor and expression data without biochemical reconstitution of PIR's molecular mechanism\",\n        \"Direct molecular target of PIR in inflammation not identified\",\n        \"Causality between PIR and NLRP3 not established at protein-interaction level\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected upstream oncogenic signaling to PIR, demonstrating that HPV16 E7 elevates PIR via EGFR/PI3K/AKT1/NRF2 and that PIR then activates NF-\\u03baB, integrating viral oncoprotein signaling with PIR-driven transcriptional output.\",\n      \"evidence\": \"Pharmacological inhibition of EGFR/PI3K/AKT1, knockdown/overexpression, Western blot, and reporter assays in oral cancer cells\",\n      \"pmids\": [\"32679705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical link between PIR and NF-\\u03baB activation not reconstituted\",\n        \"Whether NF-\\u03baB activation is transcriptional coregulation or indirect unclear\",\n        \"Single lab; epistasis inferred from inhibitors\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular-biochemical mechanism by which PIR exerts transcriptional coregulation — its direct binding partners, whether it engages DNA directly, and the role of any cofactor in this activity — remains unresolved.\",\n      \"evidence\": \"No reconstitution or structural study in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of PIR bound to promoter or partner\",\n        \"No reciprocally validated direct protein partner identified\",\n        \"Catalytic or cofactor-dependent activity, if any, uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}