{"gene":"CP","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":1984,"finding":"Human ceruloplasmin is a single polypeptide chain of 1,046 amino acid residues (Mr ~120 kDa) with four N-linked glucosamine oligosaccharide attachment sites; the apparent subunit-like fragments (67-, 50-, and 19-kDa) arise from proteolytic cleavage during purification rather than reflecting a multi-chain structure.","method":"Protein sequencing of proteolytic fragments with overlap determination; SDS-PAGE","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — complete primary structure determination with overlapping peptide sequencing; foundational structural study","pmids":["6582496"],"is_preprint":false},{"year":1995,"finding":"Loss-of-function mutations in the ceruloplasmin (CP) gene cause aceruloplasminemia, an autosomal recessive disorder characterized by iron accumulation in the brain (basal ganglia), liver, and retina, establishing ceruloplasmin as essential for normal iron efflux from cells with mobilizable iron stores. A 5-bp insertion in exon 7 causing a frameshift and truncated protein was identified as the causative mutation.","method":"PCR amplification and DNA sequence analysis of all 19 exons of the CP gene; Southern blotting; MRI and liver biopsy for iron deposition phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via human loss-of-function mutation with defined molecular lesion and multi-organ iron accumulation phenotype; replicated across multiple aceruloplasminemia patients","pmids":["7708681"],"is_preprint":false},{"year":1996,"finding":"Ceruloplasmin gene expression is localized specifically to glial cells (astrocytes) associated with the brain microvasculature, glial cells surrounding dopaminergic neurons in the substantia nigra, and cells in the inner nuclear layer of the retina — tissues that correspond to sites of neurodegeneration in aceruloplasminemia — indicating that glial ceruloplasmin is essential for iron homeostasis and neuronal survival in the CNS.","method":"RNA blot analysis; RNase protection; biosynthetic labeling; in situ hybridization with ceruloplasmin cRNA probes in human brain and retinal tissue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — direct localization by in situ hybridization and biosynthetic studies in human tissue with functional inference from aceruloplasminemia pathology","pmids":["8968753"],"is_preprint":false},{"year":1998,"finding":"Ceruloplasmin (Cp) facilitates cellular iron uptake by HepG2 hepatocytes, increasing the apparent affinity for iron substrate approximately 3-fold; Cp synthesis is transcriptionally upregulated 4–5-fold by iron depletion, establishing a transcriptional feedback loop for intracellular iron homeostasis distinct from the post-transcriptional regulation of other iron-handling proteins.","method":"Iron uptake assays with radiolabeled iron in HepG2 cells ± Cp; iron depletion/repletion experiments; transcriptional regulation assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — direct functional assay in cells with quantified iron uptake; multiple conditions tested; unexpected result (uptake rather than efflux) with mechanistic follow-up","pmids":["9445478"],"is_preprint":false},{"year":2000,"finding":"A GPI-anchored isoform of ceruloplasmin is expressed on the surface of brain astrocytes, generated by alternative RNA splicing downstream of exon 18, which replaces the C-terminal 5 amino acids of the secreted hepatocyte form with 30 amino acids that signal GPI anchor addition. The GPI-anchored form is the predominant ceruloplasmin isoform in brain, whereas the secreted form predominates in liver.","method":"cDNA cloning; RNase protection analysis comparing brain and liver; sequence analysis of alternatively spliced exon","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — cDNA cloning with RNase protection quantification; definitive identification of novel splice isoform with distinct localization","pmids":["10660599"],"is_preprint":false},{"year":2002,"finding":"Ceruloplasmin functions as a serum ferroxidase that contains >95% of plasma copper and couples substrate (Fe2+) oxidation to the four-electron reduction of O2 to water, acting as a member of the multicopper oxidase family; its primary physiological role is determining the rate of iron efflux from cells with mobilizable iron stores (not copper transport).","method":"Review integrating biochemical assays of ferroxidase activity, aceruloplasminemia genetic studies, and multicopper oxidase family comparisons","journal":"Annual review of nutrition","confidence":"High","confidence_rationale":"Tier 1 — enzymatic characterization (ferroxidase) supported by multiple labs and genetic loss-of-function evidence; well-replicated","pmids":["12055353"],"is_preprint":false},{"year":2004,"finding":"Interferon-gamma (IFN-γ) triggers phosphorylation of glutamyl-prolyl-tRNA synthetase (GluProRS), releasing it from the multisynthetase complex; phosphorylated GluProRS then assembles with three additional proteins into the GAIT (IFN-γ-activated inhibitor of translation) complex, which binds the ceruloplasmin (Cp) 3'-UTR GAIT element and silences Cp mRNA translation. GluProRS was identified as a GAIT complex component by RNA affinity chromatography using the Cp GAIT element as ligand.","method":"RNA affinity chromatography with Cp GAIT element; mass spectrometry identification; co-immunoprecipitation; in vitro translation assays; mutagenesis of GluProRS and GAIT element","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — RNA affinity purification, MS identification, reconstitution, and mutagenesis in a single study; highly cited foundational mechanism paper","pmids":["15479637"],"is_preprint":false},{"year":2005,"finding":"Copper stabilizes HIF-1α under normoxic conditions by inhibiting prolyl-4-hydroxylase (PHD) activity, leading to HIF-1-dependent transcriptional induction of the ceruloplasmin (CP) gene. Hypoxia also induces hepatic ceruloplasmin in vivo in mice. Both copper and hypoxia drive CP promoter activity via hypoxia-response elements (HREs) in hepatoma cells, revealing that CP is a direct HIF-1 target gene regulated by oxygen, iron, and copper status.","method":"In vitro PHD hydroxylation assays with CuCl2; HRE-dependent reporter gene assays; real-time RT-PCR of CP mRNA in hepatoma cells and hypoxic mouse liver; CuCl2 treatment experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro enzyme assay + cell-based reporter + in vivo mouse model; orthogonal methods establishing HIF-1/CP regulatory axis","pmids":["15741220"],"is_preprint":false},{"year":2006,"finding":"Ceruloplasmin functions as a NO oxidase and nitrite synthase in plasma: it oxidizes nitric oxide (NO) to NO+, which is hydrated to nitrite, thereby maintaining endocrine NO homeostasis. Plasma NO oxidase activity was decreased after ceruloplasmin immunodepletion, in ceruloplasmin knockout (Cp−/−) mice, and in people with congenital aceruloplasminemia. Cp−/− mice had substantially reduced plasma nitrite and were more susceptible to hepatic ischemia-reperfusion injury, which was rescued by nitrite repletion.","method":"Ceruloplasmin immunodepletion from plasma; Cp knockout mice; aceruloplasminemia patient plasma; NO oxidase activity assays; plasma nitrite measurement; liver ischemia-reperfusion model with nitrite rescue","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal approaches (immunodepletion, KO mice, human genetic deficiency, in vivo rescue); identifies novel enzymatic function","pmids":["16906150"],"is_preprint":false},{"year":2020,"finding":"Ceruloplasmin (CP) suppresses ferroptosis in hepatocellular carcinoma (HCC) cells by regulating iron homeostasis: CP depletion promotes erastin- and RSL3-induced ferroptotic cell death with accumulation of intracellular Fe2+ and lipid ROS, while CP overexpression suppresses ferroptosis. A novel frameshift mutation in CP (c.1192-1196del) found in patients with iron accumulation and neurodegeneration abolishes CP's ability to regulate iron homeostasis and ferroptosis protection.","method":"siRNA knockdown and overexpression of CP in HCC cells; ferroptosis inducers (erastin, RSL3); Fe2+ and lipid ROS measurement; patient-derived CP frameshift mutation functional characterization","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 — KD/OE with specific ferroptotic phenotype, Fe2+/lipid ROS readouts, and pathogenic mutation validation; multiple orthogonal approaches","pmids":["32283255"],"is_preprint":false},{"year":2022,"finding":"The m6A reader Igf2bp1 is upregulated in LPS-activated microglia and enhances m6A methylation and stability of Cp (ceruloplasmin) mRNA (and Gbp11 mRNA), thereby mediating LPS-induced microglial inflammatory activation. Perturbation of Igf2bp1 function reduces Cp mRNA stability and microglial activation.","method":"High-throughput m6A sequencing (MeRIP-seq); RNA-seq; Igf2bp1 knockdown/overexpression; qRT-PCR; mRNA stability assays in LPS-activated microglia","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function with m6A sequencing identifies Igf2bp1 as writer/reader stabilizing Cp mRNA; single lab, moderate mechanistic depth","pmids":["35572575"],"is_preprint":false},{"year":2022,"finding":"In hepatocellular carcinoma, ionizing radiation reduces COMMD10 expression, causing intracellular copper accumulation, which stabilizes HIF1α (by impairing its ubiquitin-mediated degradation) and promotes HIF1α nuclear translocation. HIF1α then transcriptionally upregulates ceruloplasmin (CP) and SLC7A11, which jointly suppress ferroptosis and confer radioresistance. Elevated CP in turn reduces intracellular Fe2+ levels and further stabilizes HIF1α, forming a positive HIF1α/CP feedback loop.","method":"COMMD10 knockdown/overexpression; HIF1α nuclear translocation assays; ubiquitination assays; CP and SLC7A11 transcription analysis; ferroptosis markers (GSH, lipid peroxidation, MDA, Fe2+); in vivo lentivirus-modified mouse radiotherapy models","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vitro and in vivo methods; identifies mechanistic HIF1α/CP positive feedback loop with functional radioresistance phenotype","pmids":["35101526"],"is_preprint":false},{"year":2024,"finding":"In cerebral ischemia/reperfusion injury (CIRI), HIF-1α nuclear translocation transcriptionally upregulates CP expression; elevated CP then reduces intracellular iron-dependent ferroptosis but also increases cytoplasmic HIF-1α expression while inhibiting its nuclear translocation, forming an HIF-1α/CP regulatory loop. Chrysin inhibits HIF-1α nuclear translocation, thereby suppressing CP transcription and downstream ferroptosis in CIRI. Overexpression of CP increased HIF-1α expression yet inhibited its nuclear translocation, while CP silencing promoted HIF-1α nuclear accumulation and worsened CIRI.","method":"tMCAO rat model; OGD/R in PC12 cells; transcriptomics; qRT-PCR; Western blot; HIF-1α nuclear/cytoplasmic fractionation; CP overexpression and siRNA silencing; ferroptosis marker assays","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vivo and in vitro models with genetic gain/loss of function; single lab; replicated mechanistic HIF1α/CP loop concept from PMID:35101526","pmids":["38555815"],"is_preprint":false},{"year":2024,"finding":"In endometrial cancer, lncRNA LINC02936 interacts with the transcription factor SIX1 and recruits it to the CP (ceruloplasmin) promoter, upregulating CP expression, which suppresses ferroptosis and promotes cancer progression. SIX1 directly modulates CP transcription, and a small peptide blocking the LINC02936–SIX1 interaction reduces CP expression, promotes ferroptosis, and inhibits tumor growth.","method":"ChIP assay; Co-IP; promoter-reporter assays; LINC02936 and SIX1 KD/OE; ferroptosis assays; small peptide intervention; in vivo xenograft models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, co-IP, and functional rescue in vitro and in vivo establish SIX1 as a transcriptional regulator of CP; single lab","pmids":["38385087"],"is_preprint":false},{"year":2003,"finding":"The ceruloplasmin 3'-UTR GAIT element mediates IFN-γ-induced translational silencing of Cp mRNA through a mechanism involving mRNA circularization: 3'-UTR-binding proteins (the GAIT complex) interact with translation initiation machinery, and mRNA loop formation is required for the repression. This represents a model for 3'-UTR-mediated translational control.","method":"In vitro translation assays; RNA-protein binding studies with Cp 3'-UTR; analysis of GAIT element structure","journal":"Trends in biochemical sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — review synthesizing experimental evidence from multiple studies; mechanistic model supported by in vitro translation data","pmids":["12575997"],"is_preprint":false}],"current_model":"Ceruloplasmin (CP) is a secreted/GPI-anchored multicopper ferroxidase that oxidizes Fe2+ to Fe3+ (and also oxidizes NO to nitrite) to regulate cellular and systemic iron efflux and homeostasis; its expression is transcriptionally induced by HIF-1α (activated by hypoxia, iron deficiency, or copper) and by SIX1 (recruited by lncRNA LINC02936), while its translation is post-transcriptionally silenced by the IFN-γ-activated GAIT complex (containing phosphorylated GluProRS) binding the Cp 3'-UTR, and its mRNA is stabilized by the m6A reader Igf2bp1; CP suppresses ferroptosis by maintaining iron homeostasis (loss of CP promotes Fe2+ accumulation and lipid ROS), and CP engages in a positive HIF-1α/CP feedback loop relevant to radioresistance and ischemia-reperfusion injury."},"narrative":{"teleology":[{"year":1984,"claim":"Establishing that ceruloplasmin is a single-chain glycoprotein resolved longstanding uncertainty about whether it comprised multiple subunits and provided the primary structure foundation for all subsequent functional studies.","evidence":"Complete protein sequencing of proteolytic fragments with overlap determination from purified human ceruloplasmin","pmids":["6582496"],"confidence":"High","gaps":["Three-dimensional crystal structure not yet determined at this time","Copper binding sites not mapped to the primary sequence"]},{"year":1995,"claim":"Identification of loss-of-function CP mutations as the cause of aceruloplasminemia established that CP is essential for iron efflux, not merely a copper transport protein, and linked its absence to tissue iron overload and neurodegeneration.","evidence":"PCR sequencing of all 19 CP exons in aceruloplasminemia patients; MRI and liver biopsy confirming iron deposition","pmids":["7708681"],"confidence":"High","gaps":["Mechanism by which CP mediates iron efflux at the molecular level remained unclear","Whether brain-specific isoforms existed was unknown"]},{"year":1996,"claim":"Localizing CP expression to perivascular astrocytes and retinal cells explained the specific neurodegeneration pattern in aceruloplasminemia and indicated a non-hepatic, CNS-autonomous role for CP in iron homeostasis.","evidence":"In situ hybridization with CP cRNA probes in human brain and retinal tissue; RNase protection assays","pmids":["8968753"],"confidence":"High","gaps":["Whether CNS CP was membrane-anchored or secreted was unknown","The mechanism of CP-dependent neuronal protection was not defined"]},{"year":2000,"claim":"Discovery of a GPI-anchored CP splice isoform predominant in brain astrocytes resolved how CP could function at the cell surface to mediate local iron efflux independently of secreted hepatic ceruloplasmin.","evidence":"cDNA cloning of alternatively spliced exon downstream of exon 18; RNase protection comparing brain and liver","pmids":["10660599"],"confidence":"High","gaps":["Whether GPI-CP and secreted CP have identical ferroxidase activity was not tested","Regulation of alternative splicing not addressed"]},{"year":2003,"claim":"Elucidation of the GAIT-element-mediated translational silencing mechanism showed that CP mRNA is post-transcriptionally regulated by IFN-γ through 3′-UTR-dependent mRNA circularization, establishing a paradigm for cytokine-regulated translational control.","evidence":"In vitro translation assays and RNA-protein binding studies with the CP 3′-UTR GAIT element","pmids":["12575997"],"confidence":"Medium","gaps":["Identity of all GAIT complex components not yet known","Physiological significance of CP translational silencing during inflammation not demonstrated in vivo"]},{"year":2004,"claim":"Identification of phosphorylated GluProRS as a core GAIT complex component defined the molecular machinery responsible for IFN-γ-induced CP translational silencing, linking aminoacyl-tRNA synthetase moonlighting to immune-regulated gene expression.","evidence":"RNA affinity chromatography with CP GAIT element; mass spectrometry; co-immunoprecipitation; reconstituted in vitro translation","pmids":["15479637"],"confidence":"High","gaps":["In vivo relevance of GAIT-mediated CP silencing in infection or inflammation not shown","Whether other mRNAs are coordinately regulated by GAIT was unknown"]},{"year":2005,"claim":"Demonstrating that copper stabilizes HIF-1α by inhibiting prolyl hydroxylases, leading to HIF-1-dependent CP transcription, unified copper, oxygen, and iron sensing into a single transcriptional regulatory pathway for CP.","evidence":"In vitro PHD hydroxylation assays with CuCl₂; HRE-reporter assays; RT-PCR in hepatoma cells and hypoxic mouse liver","pmids":["15741220"],"confidence":"High","gaps":["Whether HIF-1α directly binds CP promoter HREs via ChIP was not shown","Contribution of other HIF isoforms not assessed"]},{"year":2006,"claim":"Discovery of CP's NO oxidase activity expanded its enzymatic repertoire beyond ferroxidase function and demonstrated a physiological role in maintaining plasma nitrite and protecting against ischemia-reperfusion injury.","evidence":"CP immunodepletion; Cp⁻/⁻ knockout mice; aceruloplasminemia patient plasma; NO oxidase assays; hepatic ischemia-reperfusion with nitrite rescue","pmids":["16906150"],"confidence":"High","gaps":["Structural basis of NO oxidation versus ferroxidation not resolved","Relative contribution of CP versus other NO oxidases in vivo unclear"]},{"year":2020,"claim":"Connecting CP to ferroptosis suppression showed that CP's iron-regulatory function directly protects against a specific form of regulated cell death, explaining pathological consequences of CP loss beyond simple iron accumulation.","evidence":"CP knockdown/overexpression in HCC cells with erastin and RSL3; Fe²⁺ and lipid ROS quantification; pathogenic CP frameshift mutation characterization","pmids":["32283255"],"confidence":"High","gaps":["Whether CP suppresses ferroptosis in non-cancer cell types not tested","Direct interaction between CP and ferroptosis machinery not identified"]},{"year":2022,"claim":"Identification of a HIF-1α/CP positive feedback loop in radioresistant HCC, where radiation-induced copper accumulation stabilizes HIF-1α which upregulates CP to suppress ferroptosis, provided a mechanistic basis for CP's role in therapy resistance.","evidence":"COMMD10 KD/OE; HIF-1α ubiquitination and nuclear translocation assays; ferroptosis markers; in vivo mouse radiotherapy models","pmids":["35101526"],"confidence":"High","gaps":["Whether COMMD10-HIF-1α-CP axis operates in non-hepatic cancers not established","Direct physical interaction between CP and HIF-1α not demonstrated"]},{"year":2022,"claim":"Identification of Igf2bp1 as an m6A reader that stabilizes CP mRNA in activated microglia linked epitranscriptomic regulation to CP expression in neuroinflammation.","evidence":"MeRIP-seq; Igf2bp1 knockdown/overexpression with mRNA stability assays in LPS-activated microglia","pmids":["35572575"],"confidence":"Medium","gaps":["Whether m6A modification of CP mRNA occurs in non-microglial cells not tested","Specific m6A sites on CP mRNA not mapped","Single-lab finding awaiting independent replication"]},{"year":2024,"claim":"Demonstration that lncRNA LINC02936 recruits SIX1 to the CP promoter to upregulate CP transcription and suppress ferroptosis in endometrial cancer revealed a tissue-specific transcriptional regulatory axis distinct from the HIF-1α pathway.","evidence":"ChIP; co-IP; promoter-reporter assays; KD/OE of LINC02936 and SIX1; small peptide intervention; xenograft models","pmids":["38385087"],"confidence":"Medium","gaps":["Whether SIX1 regulates CP in non-cancer contexts is unknown","Single-lab study; independent validation needed"]},{"year":null,"claim":"How CP coordinates its ferroxidase and NO oxidase activities at the structural level, and whether the HIF-1α/CP feedback loop and ferroptosis suppression represent general mechanisms across tissues or are context-restricted to specific pathologies, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Structural basis distinguishing ferroxidase versus NO oxidase active sites not defined","In vivo genetic validation of CP-ferroptosis axis outside liver/brain is lacking","Relative contribution of GPI-anchored versus secreted CP isoforms to ferroptosis suppression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[5,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,9,11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,3,5,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,11,12,13]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,10]}],"complexes":["GAIT complex (mRNA target, not subunit)"],"partners":["HIF1A","EPRS1","SIX1","IGF2BP1","COMMD10","SLC7A11"],"other_free_text":[]},"mechanistic_narrative":"Ceruloplasmin (CP) is a multicopper ferroxidase that oxidizes Fe²⁺ to Fe³⁺ to regulate iron efflux from cells, and also functions as a plasma NO oxidase converting NO to nitrite, thereby maintaining both systemic iron and nitric oxide homeostasis [PMID:12055353, PMID:16906150]. Loss-of-function mutations cause aceruloplasminemia, an autosomal recessive disorder of iron accumulation in brain, liver, and retina, with CP expression in CNS localized to perivascular astrocytes via a GPI-anchored splice isoform [PMID:7708681, PMID:8968753, PMID:10660599]. CP transcription is induced by HIF-1α in response to hypoxia, iron depletion, and copper accumulation, and CP in turn modulates HIF-1α stability, forming a positive feedback loop that suppresses ferroptosis by limiting intracellular Fe²⁺ and lipid ROS accumulation [PMID:15741220, PMID:35101526, PMID:32283255]. CP mRNA translation is post-transcriptionally silenced by the IFN-γ-activated GAIT complex, in which phosphorylated GluProRS binds the CP 3′-UTR GAIT element to repress translation via mRNA circularization [PMID:15479637, PMID:12575997]."},"prefetch_data":{"uniprot":{"accession":"P00450","full_name":"Ceruloplasmin","aliases":["Cuproxidase ceruloplasmin","Ferroxidase ceruloplasmin","Glutathione peroxidase ceruloplasmin","Glutathione-dependent peroxiredoxin ceruloplasmin"],"length_aa":1065,"mass_kda":122.2,"function":"Multifunctional blue, copper-binding (6-7 atoms per molecule) glycoprotein. It has ferroxidase activity oxidizing Fe(2+) to Fe(3+) without releasing radical oxygen species. It is involved in iron transport across the cell membrane (PubMed:16150804). Copper ions provide a large number of enzymatic activites. Oxidizes highly toxic ferrous ions to the ferric state for further incorporation onto apo-transferrins, catalyzes Cu(+) oxidation and promotes the oxidation of biogenic amines such as norepinephrin and serotonin (PubMed:14623105, PubMed:4643313, PubMed:5912351). Provides Cu(2+) ions for the ascorbate-mediated deaminase degradation of the heparan sulfate chains of GPC1 (By similarity). Has glutathione peroxidase-like activity, can remove both hydrogen peroxide and lipid hydroperoxide in the presence of thiols (PubMed:10481051). Also shows NO-oxidase and NO2 synthase activities that determine endocrine NO homeostasis (PubMed:16906150)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P00450/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CP","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/CP","total_profiled":1310},"omim":[{"mim_id":"621314","title":"POMPE DISEASE, LATE-ONSET; LOPD","url":"https://www.omim.org/entry/621314"},{"mim_id":"621266","title":"FETOMATERNAL ALLOIMMUNE THROMBOCYTOPENIA 2; FMAIT2","url":"https://www.omim.org/entry/621266"},{"mim_id":"621209","title":"SPERMATOGENIC FAILURE 100; SPGF100","url":"https://www.omim.org/entry/621209"},{"mim_id":"621183","title":"G-PATCH DOMAIN-CONTAINING PROTEIN 11; GPATCH11","url":"https://www.omim.org/entry/621183"},{"mim_id":"621108","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 18; DNAJC2","url":"https://www.omim.org/entry/621108"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":1750.2}],"url":"https://www.proteinatlas.org/search/CP"},"hgnc":{"alias_symbol":["AB073614"],"prev_symbol":[]},"alphafold":{"accession":"P00450","domains":[{"cath_id":"2.60.40.420","chopping":"20-354","consensus_level":"high","plddt":96.0101,"start":20,"end":354},{"cath_id":"2.60.40.420","chopping":"369-715","consensus_level":"medium","plddt":95.6423,"start":369,"end":715},{"cath_id":"2.60.40.420","chopping":"729-1056","consensus_level":"medium","plddt":95.0568,"start":729,"end":1056}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P00450","model_url":"https://alphafold.ebi.ac.uk/files/AF-P00450-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P00450-F1-predicted_aligned_error_v6.png","plddt_mean":93.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CP","jax_strain_url":"https://www.jax.org/strain/search?query=CP"},"sequence":{"accession":"P00450","fasta_url":"https://rest.uniprot.org/uniprotkb/P00450.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P00450/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P00450"}},"corpus_meta":[{"pmid":"21383241","id":"PMC_21383241","title":"Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550).","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21383241","citation_count":498,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7562537","id":"PMC_7562537","title":"Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity.","date":"1995","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/7562537","citation_count":270,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35101526","id":"PMC_35101526","title":"COMMD10 inhibits HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma.","date":"2022","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/35101526","citation_count":206,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8384323","id":"PMC_8384323","title":"Amino-aromatic interaction between histidine 197 of the neurokinin-1 receptor and CP 96345.","date":"1993","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8384323","citation_count":192,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7544198","id":"PMC_7544198","title":"The anti-emetic effects of CP-99,994 in the ferret and the dog: role of the NK1 receptor.","date":"1995","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/7544198","citation_count":182,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12837854","id":"PMC_12837854","title":"CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans.","date":"2003","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/12837854","citation_count":157,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11948395","id":"PMC_11948395","title":"Characterization of the p53-rescue drug CP-31398 in vitro and in living cells.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11948395","citation_count":147,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14614447","id":"PMC_14614447","title":"CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/14614447","citation_count":138,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12612087","id":"PMC_12612087","title":"Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12612087","citation_count":130,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9384494","id":"PMC_9384494","title":"Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist.","date":"1997","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/9384494","citation_count":115,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7996450","id":"PMC_7996450","title":"Development of cross-tolerance between delta 9-tetrahydrocannabinol, CP 55,940 and WIN 55,212.","date":"1994","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/7996450","citation_count":107,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15705896","id":"PMC_15705896","title":"Antiangiogenic and antitumor activity of a selective PDGFR tyrosine kinase inhibitor, CP-673,451.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15705896","citation_count":100,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27456838","id":"PMC_27456838","title":"Exogenous application of double-stranded RNA molecules from TMV p126 and CP genes confers resistance against TMV in tobacco.","date":"2016","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/27456838","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8592003","id":"PMC_8592003","title":"S100 protein CP-10 stimulates myeloid cell chemotaxis without activation.","date":"1996","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8592003","citation_count":87,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12595912","id":"PMC_12595912","title":"The pharmacology of CP-154,526, a non-peptide antagonist of the CRH1 receptor: a review.","date":"2003","source":"CNS drug reviews","url":"https://pubmed.ncbi.nlm.nih.gov/12595912","citation_count":85,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9389698","id":"PMC_9389698","title":"Induction of the S100 chemotactic protein, CP-10, in murine microvascular endothelial cells by proinflammatory stimuli.","date":"1997","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9389698","citation_count":85,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12101025","id":"PMC_12101025","title":"Antinociceptive, behavioural and neuroendocrine effects of CP 55,940 in young rats.","date":"2002","source":"Brain research. Developmental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/12101025","citation_count":73,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8611721","id":"PMC_8611721","title":"Induction of the chemotactic S100 protein, CP-10, in monocyte/macrophages by lipopolysaccharide.","date":"1996","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/8611721","citation_count":72,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17942920","id":"PMC_17942920","title":"Discovery and pharmacologic characterization of CP-724,714, a selective ErbB2 tyrosine kinase inhibitor.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17942920","citation_count":68,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21144599","id":"PMC_21144599","title":"Treating inflammation with the Janus kinase inhibitor CP-690,550.","date":"2010","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21144599","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28738539","id":"PMC_28738539","title":"LncRNA AB073614 regulates proliferation and metastasis of colorectal cancer cells via the PI3K/AKT signaling pathway.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28738539","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16314797","id":"PMC_16314797","title":"Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts.","date":"2005","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/16314797","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12909630","id":"PMC_12909630","title":"CP-481,715, a potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12909630","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9823017","id":"PMC_9823017","title":"Cardiovascular disease in the JCR:LA-cp rat.","date":"1998","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9823017","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31473418","id":"PMC_31473418","title":"Formation of soy protein isolate (SPI)-citrus pectin (CP) electrostatic complexes under a high-intensity ultrasonic field: Linking the enhanced emulsifying properties to physicochemical and structural properties.","date":"2019","source":"Ultrasonics sonochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31473418","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8281439","id":"PMC_8281439","title":"Conformationally restricted sumatriptan analogues, CP-122,288 and CP-122,638 exhibit enhanced potency against neurogenic inflammation in dura mater.","date":"1993","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8281439","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14767489","id":"PMC_14767489","title":"Comparison of renal morphology in the Streptozotocin and the SHR/N-cp models of diabetes.","date":"2004","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/14767489","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26866791","id":"PMC_26866791","title":"Selective amplification and sequencing of cyclic phosphate-containing RNAs by the cP-RNA-seq method.","date":"2016","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/26866791","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26708672","id":"PMC_26708672","title":"Dose-dependent teratogenicity of the synthetic cannabinoid CP-55,940 in mice.","date":"2015","source":"Neurotoxicology and teratology","url":"https://pubmed.ncbi.nlm.nih.gov/26708672","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1719543","id":"PMC_1719543","title":"Effect of CP-96,345, a nonpeptide substance P receptor antagonist, on salivation in rats.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1719543","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11804610","id":"PMC_11804610","title":"Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist.","date":"2002","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/11804610","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32073260","id":"PMC_32073260","title":"Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl2 Complexes.","date":"2020","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32073260","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29256613","id":"PMC_29256613","title":"Weakly Coordinating, Ketone-Directed Cp*Co(III)-Catalyzed C-H Allylation on Arenes and Indoles.","date":"2017","source":"Organic letters","url":"https://pubmed.ncbi.nlm.nih.gov/29256613","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24686252","id":"PMC_24686252","title":"Investigation of the in vitro toxicological properties of the synthetic cannabimimetic drug CP-47,497-C8.","date":"2014","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24686252","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29439310","id":"PMC_29439310","title":"LncRNA AB073614 induces epithelial- mesenchymal transition of colorectal cancer cells via regulating the JAK/STAT3 pathway.","date":"2018","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/29439310","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22002019","id":"PMC_22002019","title":"Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126.","date":"2011","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/22002019","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6308899","id":"PMC_6308899","title":"Pneumococcal bacteriophage Cp-1 contains a protein bound to the 5' termini of its DNA.","date":"1983","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/6308899","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29930509","id":"PMC_29930509","title":"A Modified Compound From Paeoniflorin, CP-25, Suppressed Immune Responses and Synovium Inflammation in Collagen-Induced Arthritis Mice.","date":"2018","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29930509","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12907618","id":"PMC_12907618","title":"The biological and biochemical effects of CP-654577, a selective erbB2 kinase inhibitor, on human breast cancer cells.","date":"2003","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12907618","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12556474","id":"PMC_12556474","title":"The KH-domain protein alpha CP has a direct role in mRNA stabilization independent of its cognate binding site.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12556474","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8606099","id":"PMC_8606099","title":"Functional chemotactic factor CP-10 and MRP-14 are abundant in murine abscesses.","date":"1996","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/8606099","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18794156","id":"PMC_18794156","title":"Suppression of familial adenomatous polyposis by CP-31398, a TP53 modulator, in APCmin/+ mice.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18794156","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8985330","id":"PMC_8985330","title":"Regulation of EBNA gene transcription in lymphoblastoid cell lines: characterization of sequences downstream of BCR2 (Cp).","date":"1997","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8985330","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20175655","id":"PMC_20175655","title":"Figitumumab (CP-751,871) for cancer therapy.","date":"2010","source":"Expert opinion on biological therapy","url":"https://pubmed.ncbi.nlm.nih.gov/20175655","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26249572","id":"PMC_26249572","title":"The role of nicotine, cotinine and caffeine on the electrochemical behavior and bacterial colonization to cp-Ti.","date":"2015","source":"Materials science & engineering. C, Materials for biological applications","url":"https://pubmed.ncbi.nlm.nih.gov/26249572","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8648690","id":"PMC_8648690","title":"Transcription of the Epstein-Barr virus nuclear antigen 1 (EBNA1) gene occurs before induction of the BCR2 (Cp) EBNA gene promoter during the initial stages of infection in B cells.","date":"1996","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8648690","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17081232","id":"PMC_17081232","title":"Janus kinase 3 inhibition with CP-690,550 prevents allograft vasculopathy.","date":"2006","source":"Transplant international : official journal of the European Society for Organ Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/17081232","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16139885","id":"PMC_16139885","title":"Effects of CP 154,526, a CRF1 receptor antagonist, on behavioral responses to cocaine in rats.","date":"2005","source":"Neuropeptides","url":"https://pubmed.ncbi.nlm.nih.gov/16139885","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12112408","id":"PMC_12112408","title":"PET imaging of brain acetylcholinesterase using [11C]CP-126,998, a brain selective enzyme inhibitor.","date":"2002","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12112408","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8627690","id":"PMC_8627690","title":"Molecular genetic analysis of Epstein-Barr virus Cp promoter function.","date":"1996","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8627690","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6328035","id":"PMC_6328035","title":"Vibrio cholerae bacteriophage CP-T1: characterization of bacteriophage DNA and restriction analysis.","date":"1984","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/6328035","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35572575","id":"PMC_35572575","title":"m6A Reader Igf2bp1 Regulates the Inflammatory Responses of Microglia by Stabilizing Gbp11 and Cp mRNAs.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35572575","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10813939","id":"PMC_10813939","title":"Investigations into a biomimetic approach toward CP-225,917 and CP-263,114.","date":"2000","source":"The Journal of organic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10813939","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1280591","id":"PMC_1280591","title":"CP-96,345 antagonism of NK1 receptors and smoke-induced protein extravasation in relation to its cardiovascular effects.","date":"1992","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1280591","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17713973","id":"PMC_17713973","title":"Phase I evaluation of the safety, pharmacokinetics and pharmacodynamics of CP-481,715.","date":"2007","source":"Clinical pharmacokinetics","url":"https://pubmed.ncbi.nlm.nih.gov/17713973","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15205328","id":"PMC_15205328","title":"Alpha CP-4, encoded by a putative tumor suppressor gene at 3p21, but not its alternative splice variant alpha CP-4a, is underexpressed in lung cancer.","date":"2004","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15205328","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34625504","id":"PMC_34625504","title":"Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506.","date":"2021","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34625504","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17218475","id":"PMC_17218475","title":"Effect of CP-96,345 on the expression of adhesion molecules in acute pancreatitis in mice.","date":"2007","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17218475","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8788962","id":"PMC_8788962","title":"Effects of selective activation of the 5-HT1B receptor with CP-94,253 on sleep and wakefulness in the rat.","date":"1995","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/8788962","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26156808","id":"PMC_26156808","title":"Real-time imaging of anti-biofilm effects using CP-OCT.","date":"2015","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/26156808","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27775800","id":"PMC_27775800","title":"Knockdown of long noncoding RNA AB073614 inhibits glioma cell proliferation and migration via affecting epithelial-mesenchymal transition.","date":"2016","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27775800","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29473135","id":"PMC_29473135","title":"Immunomodulatory Effects of CP-25 on Splenic T Cells of Rats with Adjuvant Arthritis.","date":"2018","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/29473135","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34442867","id":"PMC_34442867","title":"Effects of Age, Diet CP, NDF, EE, and Starch on the Rumen Bacteria Community and Function in Dairy Cattle.","date":"2021","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/34442867","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36010417","id":"PMC_36010417","title":"In Vitro Digestion and Storage Stability of β-Carotene-Loaded Nanoemulsion Stabilized by Soy Protein Isolate (SPI)-Citrus Pectin (CP) Complex/Conjugate Prepared with Ultrasound.","date":"2022","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36010417","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21857382","id":"PMC_21857382","title":"Candidate genes and risk for CP: a population-based study.","date":"2011","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/21857382","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15548325","id":"PMC_15548325","title":"CP-31398, a putative p53-stabilizing molecule tested in mammalian cells and in yeast for its effects on p53 transcriptional activity.","date":"2004","source":"Journal of negative results in biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/15548325","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11249721","id":"PMC_11249721","title":"CP-101606 Pfizer Inc.","date":"2000","source":"Current opinion in investigational drugs (London, England : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/11249721","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"5000543","id":"PMC_5000543","title":"Comparison of Bacillus cereus bacteriophages CP-51 and CP-53.","date":"1971","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/5000543","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19155038","id":"PMC_19155038","title":"Characterization of the 5'- and 3'-terminal subgenomic RNAs produced by a capillovirus: Evidence for a CP subgenomic RNA.","date":"2009","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/19155038","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22837421","id":"PMC_22837421","title":"Molecular evolution and phylogeography of potato virus Y based on the CP gene.","date":"2012","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/22837421","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33858651","id":"PMC_33858651","title":"CP-25 ameliorates methotrexate induced nephrotoxicity via improving renal apoptosis and methotrexate excretion.","date":"2021","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33858651","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31521892","id":"PMC_31521892","title":"Regulation of CP-25 on P-glycoprotein in synoviocytes of rats with adjuvant arthritis.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31521892","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24408776","id":"PMC_24408776","title":"Species-related differences in the electrophoretic behavior of CP 29 and CP 26: An immunochemical analysis.","date":"1992","source":"Photosynthesis research","url":"https://pubmed.ncbi.nlm.nih.gov/24408776","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30781292","id":"PMC_30781292","title":"Field Trials of Plum Clones Transformed with the Plum pox virus Coat Protein (PPV-CP) Gene.","date":"2006","source":"Plant disease","url":"https://pubmed.ncbi.nlm.nih.gov/30781292","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14757157","id":"PMC_14757157","title":"Antitussive activity of the tachykinin NK1 receptor antagonist, CP-99994, in dogs.","date":"2004","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/14757157","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18930809","id":"PMC_18930809","title":"Previous maternal chemotherapy by cyclophosphamide (Cp) causes numerical chromosome abnormalities in preimplantation mouse embryos.","date":"2008","source":"Reproductive toxicology (Elmsford, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18930809","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1406299","id":"PMC_1406299","title":"Genetically obese rats with (SHR/N-cp) and without diabetes (LA/N-cp) share abnormal islet responses to glucose.","date":"1992","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/1406299","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16225598","id":"PMC_16225598","title":"Mutant p53 melanoma cell lines respond differently to CP-31398-induced apoptosis.","date":"2005","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/16225598","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"4065151","id":"PMC_4065151","title":"Bacteriophage CP-T1 of Vibrio cholerae. Identification of the cell surface receptor.","date":"1985","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/4065151","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38555815","id":"PMC_38555815","title":"Chrysin inhibits ferroptosis of cerebral ischemia/reperfusion injury via regulating HIF-1α/CP loop.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/38555815","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26209012","id":"PMC_26209012","title":"Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26209012","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29461336","id":"PMC_29461336","title":"Sex differences in antinociceptive response to Δ-9-tetrahydrocannabinol and CP 55,940 in the mouse formalin test.","date":"2018","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/29461336","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25505094","id":"PMC_25505094","title":"Detection of circular permutations within protein structures using CE-CP.","date":"2014","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25505094","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8162950","id":"PMC_8162950","title":"Cardiovascular effects of CP-96,345, a non-peptide blocker of tachykinin NK1 receptors.","date":"1994","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/8162950","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38385087","id":"PMC_38385087","title":"Novel LncRNA LINC02936 Suppresses Ferroptosis and Promotes Tumor Progression by Interacting with SIX1/CP Axis in Endometrial Cancer.","date":"2024","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38385087","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29029454","id":"PMC_29029454","title":"Long noncoding RNA AB073614 promotes the malignance of glioma by activating Wnt/β-catenin signaling through downregulating SOX7.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29029454","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36764296","id":"PMC_36764296","title":"Excitotoxic glutamate levels drive spinal cord ependymal stem cell proliferation and fate specification through CP-AMPAR signaling.","date":"2023","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36764296","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29796827","id":"PMC_29796827","title":"In vitro cell response on CP-Ti surfaces functionalized with TGF-β1 inhibitory peptides.","date":"2018","source":"Journal of materials science. Materials in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29796827","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29857117","id":"PMC_29857117","title":"Inhibition of PDGFR by CP-673451 induces apoptosis and increases cisplatin cytotoxicity in NSCLC cells via inhibiting the Nrf2-mediated defense mechanism.","date":"2018","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29857117","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32147495","id":"PMC_32147495","title":"SOX9 represses hepatitis B virus replication through binding to HBV EnhII/Cp and inhibiting the promoter activity.","date":"2020","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/32147495","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29025263","id":"PMC_29025263","title":"Synthesis of Organophosphorus Compounds through Copper-Catalyzed Annulation Involving C-O and C-P Bond Formations.","date":"2017","source":"The Journal of organic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29025263","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7720401","id":"PMC_7720401","title":"Chromosomal locations of the genes for the beaded filament proteins CP 115 and CP 47.","date":"1995","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/7720401","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20638296","id":"PMC_20638296","title":"Protective effects of kappa-ca3000+CP against ultraviolet-induced damage in HaCaT and MEF cells.","date":"2010","source":"Journal of photochemistry and photobiology. B, Biology","url":"https://pubmed.ncbi.nlm.nih.gov/20638296","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14974969","id":"PMC_14974969","title":"The JCR:LA-cp rat: a novel model for impaired wound healing.","date":"2004","source":"Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society","url":"https://pubmed.ncbi.nlm.nih.gov/14974969","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34094126","id":"PMC_34094126","title":"Transformations of the cyclo-P4 ligand in [Cp'''Co(η4-P4)].","date":"2020","source":"Chemical science","url":"https://pubmed.ncbi.nlm.nih.gov/34094126","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32819561","id":"PMC_32819561","title":"Neuropathophysiological significance of the c.1449T>C/p.(Tyr64Cys) mutation in the CDC42 gene responsible for Takenouchi-Kosaki syndrome.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32819561","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11975600","id":"PMC_11975600","title":"Studies on the biosynthesis of phomoidride B (CP-263,114): evidence for a decarboxylative homodimerization pathway.","date":"2002","source":"Organic letters","url":"https://pubmed.ncbi.nlm.nih.gov/11975600","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29731970","id":"PMC_29731970","title":"Elevated seminal plasma estradiol and epigenetic inactivation of ESR1 and ESR2 is associated with CP/CPPS.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29731970","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26758729","id":"PMC_26758729","title":"Genetic diversity and molecular evolution of arabis mosaic virus based on the CP gene sequence.","date":"2016","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26758729","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17988890","id":"PMC_17988890","title":"The molecular design of a recombinant antimicrobial peptide CP and its in vitro activity.","date":"2007","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/17988890","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12055353","id":"PMC_12055353","title":"Ceruloplasmin metabolism and function.","date":"2002","source":"Annual review of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/12055353","citation_count":674,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14718574","id":"PMC_14718574","title":"The human plasma proteome: a nonredundant list developed by combination of four separate sources.","date":"2004","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/14718574","citation_count":658,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19056867","id":"PMC_19056867","title":"Large-scale proteomics and phosphoproteomics of urinary exosomes.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19056867","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7708681","id":"PMC_7708681","title":"Aceruloplasminemia: molecular characterization of this disorder of iron metabolism.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7708681","citation_count":449,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8889548","id":"PMC_8889548","title":"Normalization and subtraction: two approaches to facilitate gene discovery.","date":"1996","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/8889548","citation_count":401,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12575997","id":"PMC_12575997","title":"Translational control by the 3'-UTR: the ends specify the means.","date":"2003","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12575997","citation_count":396,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16335952","id":"PMC_16335952","title":"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.","date":"2005","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/16335952","citation_count":350,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16906150","id":"PMC_16906150","title":"Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis.","date":"2006","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/16906150","citation_count":281,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15741220","id":"PMC_15741220","title":"Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15741220","citation_count":267,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15174051","id":"PMC_15174051","title":"An investigation into the human serum \"interactome\".","date":"2004","source":"Electrophoresis","url":"https://pubmed.ncbi.nlm.nih.gov/15174051","citation_count":247,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20551380","id":"PMC_20551380","title":"Proteomics characterization of extracellular space components in the human aorta.","date":"2010","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/20551380","citation_count":231,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22589738","id":"PMC_22589738","title":"Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22589738","citation_count":222,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15479637","id":"PMC_15479637","title":"Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation.","date":"2004","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15479637","citation_count":221,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25281560","id":"PMC_25281560","title":"Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes.","date":"2014","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25281560","citation_count":215,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"6582496","id":"PMC_6582496","title":"Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule.","date":"1984","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6582496","citation_count":195,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10660599","id":"PMC_10660599","title":"Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10660599","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17897319","id":"PMC_17897319","title":"Integral and associated lysosomal membrane proteins.","date":"2007","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/17897319","citation_count":163,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9445478","id":"PMC_9445478","title":"Role of ceruloplasmin in cellular iron uptake.","date":"1998","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9445478","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14760718","id":"PMC_14760718","title":"Screening for N-glycosylated proteins by liquid chromatography mass spectrometry.","date":"2004","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/14760718","citation_count":156,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32283255","id":"PMC_32283255","title":"Ceruloplasmin suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma cells.","date":"2020","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/32283255","citation_count":144,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8968753","id":"PMC_8968753","title":"Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia.","date":"1996","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8968753","citation_count":142,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23533145","id":"PMC_23533145","title":"In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.","date":"2013","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23533145","citation_count":138,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18307039","id":"PMC_18307039","title":"Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NO(x) content in the CSF. A different marker profile in four neurodegenerative diseases.","date":"2008","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/18307039","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49271,"output_tokens":1576,"usd":0.085726},"stage2":{"model":"claude-opus-4-6","input_tokens":4614,"output_tokens":1939,"usd":0.107317},"total_usd":0.497008,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62253,"output_tokens":5011,"usd":0.130962},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8132,"output_tokens":2987,"usd":0.173003}},"stage1_raw":"Looking at these abstracts, I need to identify which ones are about the human/mammalian gene **CP** (ceruloplasmin), the multicopper ferroxidase involved in iron metabolism. Let me distinguish these from the many \"CP\" symbol collisions (drug compound codes like CP-690,550, CP-96,345, viral coat proteins, etc.).\n\nRelevant papers about ceruloplasmin (CP) the gene/protein:\n- PMID 35101526: COMMD10/HIF1α/CP loop in ferroptosis\n- PMID 35572575: Igf2bp1 stabilizes CP mRNA in microglia\n- PMID 38555815: HIF-1α/CP loop in cerebral ischemia ferroptosis\n- PMID 38385087: LINC02936/SIX1/CP axis in endometrial cancer ferroptosis\n- PMID 26209012: APP and CP mRNA decrease in Alzheimer's disease iron export\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"HIF1α transcriptionally activates ceruloplasmin (CP) expression; elevated CP in turn promotes HIF1α expression by reducing intracellular iron (Fe), forming a positive feedback loop (HIF1α/CP loop) that inhibits ferroptosis in hepatocellular carcinoma. COMMD10 disrupts this loop by promoting ubiquitin-dependent degradation of HIF1α and impairing its nuclear translocation, thereby suppressing CP transcription and restoring ferroptosis.\",\n      \"method\": \"Western blot, qRT-PCR, ubiquitination assays, nuclear fractionation, lentiviral overexpression/knockdown, in vivo mouse xenograft models, ferroptosis markers (GSH, lipid peroxidation, MDA, Fe2+ levels)\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in vitro and in vivo, mechanistic pathway placement with defined upstream regulator and downstream consequence\",\n      \"pmids\": [\"35101526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In cerebral ischemia/reperfusion injury, HIF1α nuclear translocation promotes CP transcription and translation; elevated CP in turn sustains HIF1α expression but inhibits its nuclear translocation, forming a regulatory loop that controls ferroptosis. The flavonoid chrysin inhibits HIF1α nuclear translocation, thereby suppressing CP transcription and reducing downstream ferroptosis.\",\n      \"method\": \"tMCAO rat model, OGD/R cell model, transcriptomics, qRT-PCR, Western blot, nuclear/cytoplasmic fractionation, HIF1α inhibition and CP overexpression/silencing experiments\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, single lab, consistent with PMID 35101526 findings on HIF1α/CP axis\",\n      \"pmids\": [\"38555815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The m6A reader Igf2bp1 stabilizes CP mRNA in LPS-activated microglia by enhancing m6A methylation, thereby sustaining CP expression and promoting microglial inflammatory responses; Igf2bp1 perturbation reduces CP mRNA stability and attenuates microglial activation.\",\n      \"method\": \"m6A-seq, MeRIP, RNA immunoprecipitation, knockdown/overexpression, qRT-PCR, Western blot in primary microglia\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — high-throughput m6A profiling combined with functional perturbation, single lab\",\n      \"pmids\": [\"35572575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In endometrial cancer, lncRNA LINC02936 interacts with transcription factor SIX1 and recruits it to the CP promoter, upregulating CP expression; elevated CP suppresses ferroptosis and promotes tumor progression. Blocking the LINC02936-SIX1 interaction with a small peptide inhibits EC progression by restoring ferroptosis.\",\n      \"method\": \"ChIP assay, co-immunoprecipitation, reporter assays, small peptide interference, gain/loss-of-function experiments, ferroptosis markers\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and Co-IP with functional rescue, single lab\",\n      \"pmids\": [\"38385087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CP mRNA expression is significantly decreased in peripheral blood mononuclear cells from Alzheimer's disease patients alongside APP and ACO1 downregulation, suggesting impaired ferroportin-mediated cellular iron export contributes to iron retention and oxidative stress in AD.\",\n      \"method\": \"Quantitative PCR of CP, APP, and ACO1 in PBMCs from 73 AD patients vs. 74 controls\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression-level measurement without direct functional mechanistic experiment on CP protein activity\",\n      \"pmids\": [\"26209012\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Ceruloplasmin (CP), a multicopper ferroxidase, is transcriptionally activated by HIF1α under hypoxic or stress conditions and reciprocally sustains HIF1α expression by reducing intracellular iron, forming a HIF1α/CP positive feedback loop that suppresses ferroptosis; CP mRNA stability is further regulated post-transcriptionally by the m6A reader Igf2bp1 in microglia, and its promoter is controlled by the lncRNA LINC02936/SIX1 axis in cancer cells, collectively placing CP as a central node linking iron/copper homeostasis, hypoxia signaling, and ferroptosis regulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from papers about the canonical human CP gene (ceruloplasmin).\n\n**Classification:**\n\nFrom the retrieved papers corpus, papers about ceruloplasmin (CP) gene/protein:\n- PMID:35101526 — KEEP (COMMD10/HIF1α/CP loop, ceruloplasmin role in ferroptosis)\n- PMID:35572575 — KEEP (Igf2bp1 stabilizes Cp mRNA in microglia)\n- PMID:38555815 — KEEP (HIF-1α/CP loop in CIRI, chrysin)\n- PMID:38385087 — KEEP (LINC02936/SIX1/CP axis in endometrial cancer, ceruloplasmin)\n\nAll other retrieved papers are EXCLUDE (alias collisions with drug codes like CP-690550, CP-96345, etc., plant virus coat proteins, bacteriophages, cannabinoids, etc.)\n\nFrom the gene2pubmed papers, all CP (ceruloplasmin) papers:\n- PMID:12055353 — KEEP (ceruloplasmin review)\n- PMID:7708681 — KEEP (aceruloplasminemia, ceruloplasmin gene mutations)\n- PMID:15479637 — KEEP (GluProRS/GAIT complex silences Cp mRNA translation)\n- PMID:16906150 — KEEP (ceruloplasmin as NO oxidase/nitrite synthase)\n- PMID:15741220 — KEEP (HIF-1 copper-dependent activation, ceruloplasmin regulation)\n- PMID:10660599 — KEEP (GPI-anchored ceruloplasmin in brain)\n- PMID:9445478 — KEEP (ceruloplasmin role in cellular iron uptake)\n- PMID:8968753 — KEEP (ceruloplasmin expression in retina/brain, glial cells)\n- PMID:6582496 — KEEP (complete amino acid sequence of ceruloplasmin)\n- PMID:32283255 — KEEP (ceruloplasmin suppresses ferroptosis via iron homeostasis)\n- PMID:26209012 — KEEP (APP and CP mRNA decrease in Alzheimer's)\n- PMID:18307039 — KEEP (ferroxidase activity in CSF)\n- PMID:12575997 — KEEP (translational control by 3'-UTR, ceruloplasmin GAIT element)\n\nOthers in gene2pubmed are proteomics/database papers not providing mechanistic findings about CP specifically.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1984,\n      \"finding\": \"Human ceruloplasmin is a single polypeptide chain of 1,046 amino acid residues (Mr ~120 kDa) with four N-linked glucosamine oligosaccharide attachment sites; the apparent subunit-like fragments (67-, 50-, and 19-kDa) arise from proteolytic cleavage during purification rather than reflecting a multi-chain structure.\",\n      \"method\": \"Protein sequencing of proteolytic fragments with overlap determination; SDS-PAGE\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete primary structure determination with overlapping peptide sequencing; foundational structural study\",\n      \"pmids\": [\"6582496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Loss-of-function mutations in the ceruloplasmin (CP) gene cause aceruloplasminemia, an autosomal recessive disorder characterized by iron accumulation in the brain (basal ganglia), liver, and retina, establishing ceruloplasmin as essential for normal iron efflux from cells with mobilizable iron stores. A 5-bp insertion in exon 7 causing a frameshift and truncated protein was identified as the causative mutation.\",\n      \"method\": \"PCR amplification and DNA sequence analysis of all 19 exons of the CP gene; Southern blotting; MRI and liver biopsy for iron deposition phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via human loss-of-function mutation with defined molecular lesion and multi-organ iron accumulation phenotype; replicated across multiple aceruloplasminemia patients\",\n      \"pmids\": [\"7708681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Ceruloplasmin gene expression is localized specifically to glial cells (astrocytes) associated with the brain microvasculature, glial cells surrounding dopaminergic neurons in the substantia nigra, and cells in the inner nuclear layer of the retina — tissues that correspond to sites of neurodegeneration in aceruloplasminemia — indicating that glial ceruloplasmin is essential for iron homeostasis and neuronal survival in the CNS.\",\n      \"method\": \"RNA blot analysis; RNase protection; biosynthetic labeling; in situ hybridization with ceruloplasmin cRNA probes in human brain and retinal tissue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by in situ hybridization and biosynthetic studies in human tissue with functional inference from aceruloplasminemia pathology\",\n      \"pmids\": [\"8968753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Ceruloplasmin (Cp) facilitates cellular iron uptake by HepG2 hepatocytes, increasing the apparent affinity for iron substrate approximately 3-fold; Cp synthesis is transcriptionally upregulated 4–5-fold by iron depletion, establishing a transcriptional feedback loop for intracellular iron homeostasis distinct from the post-transcriptional regulation of other iron-handling proteins.\",\n      \"method\": \"Iron uptake assays with radiolabeled iron in HepG2 cells ± Cp; iron depletion/repletion experiments; transcriptional regulation assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay in cells with quantified iron uptake; multiple conditions tested; unexpected result (uptake rather than efflux) with mechanistic follow-up\",\n      \"pmids\": [\"9445478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A GPI-anchored isoform of ceruloplasmin is expressed on the surface of brain astrocytes, generated by alternative RNA splicing downstream of exon 18, which replaces the C-terminal 5 amino acids of the secreted hepatocyte form with 30 amino acids that signal GPI anchor addition. The GPI-anchored form is the predominant ceruloplasmin isoform in brain, whereas the secreted form predominates in liver.\",\n      \"method\": \"cDNA cloning; RNase protection analysis comparing brain and liver; sequence analysis of alternatively spliced exon\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cDNA cloning with RNase protection quantification; definitive identification of novel splice isoform with distinct localization\",\n      \"pmids\": [\"10660599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Ceruloplasmin functions as a serum ferroxidase that contains >95% of plasma copper and couples substrate (Fe2+) oxidation to the four-electron reduction of O2 to water, acting as a member of the multicopper oxidase family; its primary physiological role is determining the rate of iron efflux from cells with mobilizable iron stores (not copper transport).\",\n      \"method\": \"Review integrating biochemical assays of ferroxidase activity, aceruloplasminemia genetic studies, and multicopper oxidase family comparisons\",\n      \"journal\": \"Annual review of nutrition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — enzymatic characterization (ferroxidase) supported by multiple labs and genetic loss-of-function evidence; well-replicated\",\n      \"pmids\": [\"12055353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Interferon-gamma (IFN-γ) triggers phosphorylation of glutamyl-prolyl-tRNA synthetase (GluProRS), releasing it from the multisynthetase complex; phosphorylated GluProRS then assembles with three additional proteins into the GAIT (IFN-γ-activated inhibitor of translation) complex, which binds the ceruloplasmin (Cp) 3'-UTR GAIT element and silences Cp mRNA translation. GluProRS was identified as a GAIT complex component by RNA affinity chromatography using the Cp GAIT element as ligand.\",\n      \"method\": \"RNA affinity chromatography with Cp GAIT element; mass spectrometry identification; co-immunoprecipitation; in vitro translation assays; mutagenesis of GluProRS and GAIT element\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — RNA affinity purification, MS identification, reconstitution, and mutagenesis in a single study; highly cited foundational mechanism paper\",\n      \"pmids\": [\"15479637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Copper stabilizes HIF-1α under normoxic conditions by inhibiting prolyl-4-hydroxylase (PHD) activity, leading to HIF-1-dependent transcriptional induction of the ceruloplasmin (CP) gene. Hypoxia also induces hepatic ceruloplasmin in vivo in mice. Both copper and hypoxia drive CP promoter activity via hypoxia-response elements (HREs) in hepatoma cells, revealing that CP is a direct HIF-1 target gene regulated by oxygen, iron, and copper status.\",\n      \"method\": \"In vitro PHD hydroxylation assays with CuCl2; HRE-dependent reporter gene assays; real-time RT-PCR of CP mRNA in hepatoma cells and hypoxic mouse liver; CuCl2 treatment experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro enzyme assay + cell-based reporter + in vivo mouse model; orthogonal methods establishing HIF-1/CP regulatory axis\",\n      \"pmids\": [\"15741220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ceruloplasmin functions as a NO oxidase and nitrite synthase in plasma: it oxidizes nitric oxide (NO) to NO+, which is hydrated to nitrite, thereby maintaining endocrine NO homeostasis. Plasma NO oxidase activity was decreased after ceruloplasmin immunodepletion, in ceruloplasmin knockout (Cp−/−) mice, and in people with congenital aceruloplasminemia. Cp−/− mice had substantially reduced plasma nitrite and were more susceptible to hepatic ischemia-reperfusion injury, which was rescued by nitrite repletion.\",\n      \"method\": \"Ceruloplasmin immunodepletion from plasma; Cp knockout mice; aceruloplasminemia patient plasma; NO oxidase activity assays; plasma nitrite measurement; liver ischemia-reperfusion model with nitrite rescue\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal approaches (immunodepletion, KO mice, human genetic deficiency, in vivo rescue); identifies novel enzymatic function\",\n      \"pmids\": [\"16906150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ceruloplasmin (CP) suppresses ferroptosis in hepatocellular carcinoma (HCC) cells by regulating iron homeostasis: CP depletion promotes erastin- and RSL3-induced ferroptotic cell death with accumulation of intracellular Fe2+ and lipid ROS, while CP overexpression suppresses ferroptosis. A novel frameshift mutation in CP (c.1192-1196del) found in patients with iron accumulation and neurodegeneration abolishes CP's ability to regulate iron homeostasis and ferroptosis protection.\",\n      \"method\": \"siRNA knockdown and overexpression of CP in HCC cells; ferroptosis inducers (erastin, RSL3); Fe2+ and lipid ROS measurement; patient-derived CP frameshift mutation functional characterization\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KD/OE with specific ferroptotic phenotype, Fe2+/lipid ROS readouts, and pathogenic mutation validation; multiple orthogonal approaches\",\n      \"pmids\": [\"32283255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The m6A reader Igf2bp1 is upregulated in LPS-activated microglia and enhances m6A methylation and stability of Cp (ceruloplasmin) mRNA (and Gbp11 mRNA), thereby mediating LPS-induced microglial inflammatory activation. Perturbation of Igf2bp1 function reduces Cp mRNA stability and microglial activation.\",\n      \"method\": \"High-throughput m6A sequencing (MeRIP-seq); RNA-seq; Igf2bp1 knockdown/overexpression; qRT-PCR; mRNA stability assays in LPS-activated microglia\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function with m6A sequencing identifies Igf2bp1 as writer/reader stabilizing Cp mRNA; single lab, moderate mechanistic depth\",\n      \"pmids\": [\"35572575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In hepatocellular carcinoma, ionizing radiation reduces COMMD10 expression, causing intracellular copper accumulation, which stabilizes HIF1α (by impairing its ubiquitin-mediated degradation) and promotes HIF1α nuclear translocation. HIF1α then transcriptionally upregulates ceruloplasmin (CP) and SLC7A11, which jointly suppress ferroptosis and confer radioresistance. Elevated CP in turn reduces intracellular Fe2+ levels and further stabilizes HIF1α, forming a positive HIF1α/CP feedback loop.\",\n      \"method\": \"COMMD10 knockdown/overexpression; HIF1α nuclear translocation assays; ubiquitination assays; CP and SLC7A11 transcription analysis; ferroptosis markers (GSH, lipid peroxidation, MDA, Fe2+); in vivo lentivirus-modified mouse radiotherapy models\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vitro and in vivo methods; identifies mechanistic HIF1α/CP positive feedback loop with functional radioresistance phenotype\",\n      \"pmids\": [\"35101526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In cerebral ischemia/reperfusion injury (CIRI), HIF-1α nuclear translocation transcriptionally upregulates CP expression; elevated CP then reduces intracellular iron-dependent ferroptosis but also increases cytoplasmic HIF-1α expression while inhibiting its nuclear translocation, forming an HIF-1α/CP regulatory loop. Chrysin inhibits HIF-1α nuclear translocation, thereby suppressing CP transcription and downstream ferroptosis in CIRI. Overexpression of CP increased HIF-1α expression yet inhibited its nuclear translocation, while CP silencing promoted HIF-1α nuclear accumulation and worsened CIRI.\",\n      \"method\": \"tMCAO rat model; OGD/R in PC12 cells; transcriptomics; qRT-PCR; Western blot; HIF-1α nuclear/cytoplasmic fractionation; CP overexpression and siRNA silencing; ferroptosis marker assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vivo and in vitro models with genetic gain/loss of function; single lab; replicated mechanistic HIF1α/CP loop concept from PMID:35101526\",\n      \"pmids\": [\"38555815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In endometrial cancer, lncRNA LINC02936 interacts with the transcription factor SIX1 and recruits it to the CP (ceruloplasmin) promoter, upregulating CP expression, which suppresses ferroptosis and promotes cancer progression. SIX1 directly modulates CP transcription, and a small peptide blocking the LINC02936–SIX1 interaction reduces CP expression, promotes ferroptosis, and inhibits tumor growth.\",\n      \"method\": \"ChIP assay; Co-IP; promoter-reporter assays; LINC02936 and SIX1 KD/OE; ferroptosis assays; small peptide intervention; in vivo xenograft models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, co-IP, and functional rescue in vitro and in vivo establish SIX1 as a transcriptional regulator of CP; single lab\",\n      \"pmids\": [\"38385087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The ceruloplasmin 3'-UTR GAIT element mediates IFN-γ-induced translational silencing of Cp mRNA through a mechanism involving mRNA circularization: 3'-UTR-binding proteins (the GAIT complex) interact with translation initiation machinery, and mRNA loop formation is required for the repression. This represents a model for 3'-UTR-mediated translational control.\",\n      \"method\": \"In vitro translation assays; RNA-protein binding studies with Cp 3'-UTR; analysis of GAIT element structure\",\n      \"journal\": \"Trends in biochemical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — review synthesizing experimental evidence from multiple studies; mechanistic model supported by in vitro translation data\",\n      \"pmids\": [\"12575997\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Ceruloplasmin (CP) is a secreted/GPI-anchored multicopper ferroxidase that oxidizes Fe2+ to Fe3+ (and also oxidizes NO to nitrite) to regulate cellular and systemic iron efflux and homeostasis; its expression is transcriptionally induced by HIF-1α (activated by hypoxia, iron deficiency, or copper) and by SIX1 (recruited by lncRNA LINC02936), while its translation is post-transcriptionally silenced by the IFN-γ-activated GAIT complex (containing phosphorylated GluProRS) binding the Cp 3'-UTR, and its mRNA is stabilized by the m6A reader Igf2bp1; CP suppresses ferroptosis by maintaining iron homeostasis (loss of CP promotes Fe2+ accumulation and lipid ROS), and CP engages in a positive HIF-1α/CP feedback loop relevant to radioresistance and ischemia-reperfusion injury.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Ceruloplasmin (CP) is a multicopper ferroxidase that functions as a central regulator linking iron homeostasis, hypoxia signaling, and ferroptosis. HIF1α transcriptionally activates CP expression, and elevated CP reciprocally sustains HIF1α levels by reducing intracellular iron, forming a positive feedback loop that suppresses ferroptosis in hepatocellular carcinoma and cerebral ischemia/reperfusion injury; this loop is disrupted by COMMD10-mediated ubiquitin-dependent degradation of HIF1α [PMID:35101526, PMID:38555815]. CP transcription is also upregulated by the lncRNA LINC02936/SIX1 axis at its promoter in endometrial cancer, where elevated CP inhibits ferroptosis and promotes tumor progression [PMID:38385087], while CP mRNA stability in activated microglia is maintained by the m6A reader Igf2bp1 [PMID:35572575].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Initial evidence linked reduced CP mRNA in patient PBMCs to impaired iron export in Alzheimer's disease, raising the question of whether CP participates in disease-relevant iron dysregulation beyond its classical serum ferroxidase role.\",\n      \"evidence\": \"qPCR of CP, APP, and ACO1 in PBMCs from 73 AD patients vs. 74 controls\",\n      \"pmids\": [\"26209012\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Purely correlative expression data without functional perturbation of CP\",\n        \"No measurement of CP ferroxidase activity or iron flux\",\n        \"Peripheral blood cells may not reflect CNS-relevant mechanisms\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The discovery that HIF1α transcriptionally activates CP and that CP reciprocally sustains HIF1α by lowering intracellular iron established a positive feedback loop (HIF1α/CP) as a mechanism for ferroptosis suppression, answering how CP expression is regulated under stress and how it protects cancer cells from iron-dependent cell death.\",\n      \"evidence\": \"Western blot, ubiquitination assays, nuclear fractionation, lentiviral overexpression/knockdown, and in vivo mouse xenograft models in hepatocellular carcinoma; COMMD10 identified as loop disruptor via HIF1α ubiquitin-dependent degradation\",\n      \"pmids\": [\"35101526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the HIF1α/CP loop operates in non-malignant tissues under physiological hypoxia\",\n        \"Structural basis for CP-mediated intracellular iron reduction is undefined\",\n        \"Identity of the ferroxidase-independent vs. ferroxidase-dependent contribution of CP to ferroptosis suppression\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of Igf2bp1 as an m6A-dependent stabilizer of CP mRNA in microglia revealed a post-transcriptional layer of CP regulation, explaining how CP expression is sustained during neuroinflammation independently of transcriptional control.\",\n      \"evidence\": \"m6A-seq, MeRIP, RNA immunoprecipitation, knockdown/overexpression in LPS-activated primary microglia\",\n      \"pmids\": [\"35572575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Igf2bp1-mediated CP stabilization occurs in non-microglial cell types\",\n        \"Specific m6A sites on CP mRNA required for Igf2bp1 binding are not mapped\",\n        \"Functional consequence of this regulation on iron homeostasis or ferroptosis not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extension of the HIF1α/CP axis to cerebral ischemia/reperfusion confirmed that this loop operates beyond cancer, with the added nuance that CP sustains HIF1α expression while paradoxically inhibiting its nuclear translocation, establishing tissue-generalizable relevance of the feedback circuit.\",\n      \"evidence\": \"tMCAO rat model, OGD/R cell model, transcriptomics, nuclear/cytoplasmic fractionation, HIF1α inhibition and CP perturbation\",\n      \"pmids\": [\"38555815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which CP inhibits HIF1α nuclear translocation remains undefined\",\n        \"Single-lab finding not yet replicated independently\",\n        \"Relative contribution of CP ferroxidase activity vs. other CP domains to this ischemic loop unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that the lncRNA LINC02936 recruits SIX1 to the CP promoter revealed a transcription factor–lncRNA axis for CP upregulation in endometrial cancer, broadening the repertoire of CP transcriptional regulators beyond HIF1α and showing that CP-mediated ferroptosis suppression can be pharmacologically targeted.\",\n      \"evidence\": \"ChIP, co-immunoprecipitation, reporter assays, small peptide interference, and gain/loss-of-function experiments with ferroptosis markers in endometrial cancer cells\",\n      \"pmids\": [\"38385087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SIX1-dependent CP regulation operates in non-cancer tissues\",\n        \"No in vivo validation of the small peptide inhibitor efficacy\",\n        \"Whether LINC02936/SIX1 and HIF1α pathways converge or act independently on CP transcription\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis by which CP lowers intracellular iron to stabilize HIF1α, whether the ferroxidase enzymatic activity is required for ferroptosis suppression, and how the multiple transcriptional (HIF1α, SIX1) and post-transcriptional (Igf2bp1/m6A) inputs are integrated in vivo across tissue contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No catalytic-dead CP mutant studies to dissect ferroxidase-dependent from ferroxidase-independent functions\",\n        \"No structural model of CP interaction with intracellular iron substrates relevant to the HIF1α loop\",\n        \"Crosstalk between HIF1α, SIX1/LINC02936, and Igf2bp1 regulatory inputs on CP has not been examined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HIF1A\",\n      \"COMMD10\",\n      \"IGF2BP1\",\n      \"SIX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Ceruloplasmin (CP) is a multicopper ferroxidase that oxidizes Fe²⁺ to Fe³⁺ to regulate iron efflux from cells, and also functions as a plasma NO oxidase converting NO to nitrite, thereby maintaining both systemic iron and nitric oxide homeostasis [PMID:12055353, PMID:16906150]. Loss-of-function mutations cause aceruloplasminemia, an autosomal recessive disorder of iron accumulation in brain, liver, and retina, with CP expression in CNS localized to perivascular astrocytes via a GPI-anchored splice isoform [PMID:7708681, PMID:8968753, PMID:10660599]. CP transcription is induced by HIF-1α in response to hypoxia, iron depletion, and copper accumulation, and CP in turn modulates HIF-1α stability, forming a positive feedback loop that suppresses ferroptosis by limiting intracellular Fe²⁺ and lipid ROS accumulation [PMID:15741220, PMID:35101526, PMID:32283255]. CP mRNA translation is post-transcriptionally silenced by the IFN-γ-activated GAIT complex, in which phosphorylated GluProRS binds the CP 3′-UTR GAIT element to repress translation via mRNA circularization [PMID:15479637, PMID:12575997].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Establishing that ceruloplasmin is a single-chain glycoprotein resolved longstanding uncertainty about whether it comprised multiple subunits and provided the primary structure foundation for all subsequent functional studies.\",\n      \"evidence\": \"Complete protein sequencing of proteolytic fragments with overlap determination from purified human ceruloplasmin\",\n      \"pmids\": [\"6582496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional crystal structure not yet determined at this time\", \"Copper binding sites not mapped to the primary sequence\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of loss-of-function CP mutations as the cause of aceruloplasminemia established that CP is essential for iron efflux, not merely a copper transport protein, and linked its absence to tissue iron overload and neurodegeneration.\",\n      \"evidence\": \"PCR sequencing of all 19 CP exons in aceruloplasminemia patients; MRI and liver biopsy confirming iron deposition\",\n      \"pmids\": [\"7708681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CP mediates iron efflux at the molecular level remained unclear\", \"Whether brain-specific isoforms existed was unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Localizing CP expression to perivascular astrocytes and retinal cells explained the specific neurodegeneration pattern in aceruloplasminemia and indicated a non-hepatic, CNS-autonomous role for CP in iron homeostasis.\",\n      \"evidence\": \"In situ hybridization with CP cRNA probes in human brain and retinal tissue; RNase protection assays\",\n      \"pmids\": [\"8968753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CNS CP was membrane-anchored or secreted was unknown\", \"The mechanism of CP-dependent neuronal protection was not defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery of a GPI-anchored CP splice isoform predominant in brain astrocytes resolved how CP could function at the cell surface to mediate local iron efflux independently of secreted hepatic ceruloplasmin.\",\n      \"evidence\": \"cDNA cloning of alternatively spliced exon downstream of exon 18; RNase protection comparing brain and liver\",\n      \"pmids\": [\"10660599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GPI-CP and secreted CP have identical ferroxidase activity was not tested\", \"Regulation of alternative splicing not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Elucidation of the GAIT-element-mediated translational silencing mechanism showed that CP mRNA is post-transcriptionally regulated by IFN-γ through 3′-UTR-dependent mRNA circularization, establishing a paradigm for cytokine-regulated translational control.\",\n      \"evidence\": \"In vitro translation assays and RNA-protein binding studies with the CP 3′-UTR GAIT element\",\n      \"pmids\": [\"12575997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of all GAIT complex components not yet known\", \"Physiological significance of CP translational silencing during inflammation not demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of phosphorylated GluProRS as a core GAIT complex component defined the molecular machinery responsible for IFN-γ-induced CP translational silencing, linking aminoacyl-tRNA synthetase moonlighting to immune-regulated gene expression.\",\n      \"evidence\": \"RNA affinity chromatography with CP GAIT element; mass spectrometry; co-immunoprecipitation; reconstituted in vitro translation\",\n      \"pmids\": [\"15479637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of GAIT-mediated CP silencing in infection or inflammation not shown\", \"Whether other mRNAs are coordinately regulated by GAIT was unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that copper stabilizes HIF-1α by inhibiting prolyl hydroxylases, leading to HIF-1-dependent CP transcription, unified copper, oxygen, and iron sensing into a single transcriptional regulatory pathway for CP.\",\n      \"evidence\": \"In vitro PHD hydroxylation assays with CuCl₂; HRE-reporter assays; RT-PCR in hepatoma cells and hypoxic mouse liver\",\n      \"pmids\": [\"15741220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HIF-1α directly binds CP promoter HREs via ChIP was not shown\", \"Contribution of other HIF isoforms not assessed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery of CP's NO oxidase activity expanded its enzymatic repertoire beyond ferroxidase function and demonstrated a physiological role in maintaining plasma nitrite and protecting against ischemia-reperfusion injury.\",\n      \"evidence\": \"CP immunodepletion; Cp⁻/⁻ knockout mice; aceruloplasminemia patient plasma; NO oxidase assays; hepatic ischemia-reperfusion with nitrite rescue\",\n      \"pmids\": [\"16906150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NO oxidation versus ferroxidation not resolved\", \"Relative contribution of CP versus other NO oxidases in vivo unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connecting CP to ferroptosis suppression showed that CP's iron-regulatory function directly protects against a specific form of regulated cell death, explaining pathological consequences of CP loss beyond simple iron accumulation.\",\n      \"evidence\": \"CP knockdown/overexpression in HCC cells with erastin and RSL3; Fe²⁺ and lipid ROS quantification; pathogenic CP frameshift mutation characterization\",\n      \"pmids\": [\"32283255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CP suppresses ferroptosis in non-cancer cell types not tested\", \"Direct interaction between CP and ferroptosis machinery not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of a HIF-1α/CP positive feedback loop in radioresistant HCC, where radiation-induced copper accumulation stabilizes HIF-1α which upregulates CP to suppress ferroptosis, provided a mechanistic basis for CP's role in therapy resistance.\",\n      \"evidence\": \"COMMD10 KD/OE; HIF-1α ubiquitination and nuclear translocation assays; ferroptosis markers; in vivo mouse radiotherapy models\",\n      \"pmids\": [\"35101526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether COMMD10-HIF-1α-CP axis operates in non-hepatic cancers not established\", \"Direct physical interaction between CP and HIF-1α not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of Igf2bp1 as an m6A reader that stabilizes CP mRNA in activated microglia linked epitranscriptomic regulation to CP expression in neuroinflammation.\",\n      \"evidence\": \"MeRIP-seq; Igf2bp1 knockdown/overexpression with mRNA stability assays in LPS-activated microglia\",\n      \"pmids\": [\"35572575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether m6A modification of CP mRNA occurs in non-microglial cells not tested\", \"Specific m6A sites on CP mRNA not mapped\", \"Single-lab finding awaiting independent replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that lncRNA LINC02936 recruits SIX1 to the CP promoter to upregulate CP transcription and suppress ferroptosis in endometrial cancer revealed a tissue-specific transcriptional regulatory axis distinct from the HIF-1α pathway.\",\n      \"evidence\": \"ChIP; co-IP; promoter-reporter assays; KD/OE of LINC02936 and SIX1; small peptide intervention; xenograft models\",\n      \"pmids\": [\"38385087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SIX1 regulates CP in non-cancer contexts is unknown\", \"Single-lab study; independent validation needed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CP coordinates its ferroxidase and NO oxidase activities at the structural level, and whether the HIF-1α/CP feedback loop and ferroptosis suppression represent general mechanisms across tissues or are context-restricted to specific pathologies, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Structural basis distinguishing ferroxidase versus NO oxidase active sites not defined\", \"In vivo genetic validation of CP-ferroptosis axis outside liver/brain is lacking\", \"Relative contribution of GPI-anchored versus secreted CP isoforms to ferroptosis suppression unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 3, 5, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 11, 12, 13]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"complexes\": [\n      \"GAIT complex (mRNA target, not subunit)\"\n    ],\n    \"partners\": [\n      \"HIF1A\",\n      \"EPRS1\",\n      \"SIX1\",\n      \"IGF2BP1\",\n      \"COMMD10\",\n      \"SLC7A11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}