{"gene":"RPRM","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":2000,"finding":"Reprimo is a highly glycosylated cytoplasmic protein that, when ectopically expressed, induces G2 arrest of the cell cycle. In arrested cells, both Cdc2 kinase activity and nuclear translocation of cyclin B1 are inhibited, placing Reprimo in the Cdc2·cyclin B1 regulation pathway. Reprimo mRNA induction by X-irradiation is p53-dependent.","method":"Ectopic expression in cells, cell cycle analysis, Cdc2 kinase activity assay, cyclin B1 localization by immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — foundational paper with multiple orthogonal methods (ectopic expression, kinase assay, localization), replicated by subsequent work","pmids":["10930422"],"is_preprint":false},{"year":2009,"finding":"Estrogen repression of RPRM requires a tripartite interaction among estrogen receptor alpha (ERα), histone deacetylase 7 (HDAC7), and the chromatin pioneer factor FoxA1. HDAC7 binds ERα and represses its transcriptional activity independently of HDAC7's deacetylase activity. FoxA1 is recruited to the RPRM promoter, interacts with HDAC7, and is necessary for repression. Estrogen treatment causes decreases in H3K4me1/me2 marks and release of RNA Pol II from the RPRM proximal promoter.","method":"ChIP assays, Co-IP (ERα–HDAC7 interaction), siRNA knockdown, HDAC7 deacetylase-dead mutant, promoter reporter assays, histone mark analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, mutagenesis of HDAC7 catalytic domain, siRNA), single lab","pmids":["19917725"],"is_preprint":false},{"year":2012,"finding":"In pituitary tumor cells stably expressing RPRM mRNA, the RPRM protein is rapidly degraded via ubiquitination and proteasomal targeting, keeping steady-state protein levels low. Cellular stress (growth factor withdrawal) stabilizes RPRM protein. RPRM overexpression reduces cell proliferation and increases apoptosis (caspase-3 cleavage, nuclear condensation) in response to growth factor deprivation, and suppresses colony formation, without altering G2/M transition in these cells.","method":"Stable cell line expression, proteasome inhibitor treatment, ubiquitination assays, caspase-3 cleavage assay, clonogenic assay, cell cycle analysis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays and biochemical evidence for proteasomal degradation, single lab","pmids":["22562171"],"is_preprint":false},{"year":2016,"finding":"Overexpression of RPRM in MDA-MB-231 breast cancer cells decreased cell migration, wound healing, and invasion in vitro, without altering cell viability, phosphatidylserine translocation, or G2/M cell cycle transition, indicating a migration/invasion-suppressive function distinct from cell cycle arrest.","method":"Ectopic overexpression, wound-healing assay, Transwell invasion assay, flow cytometry, annexin V assay","journal":"Biological research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean overexpression with defined phenotypic readout, single lab, single cell line","pmids":["26796959"],"is_preprint":false},{"year":2022,"finding":"RPRM translocates from the cytoplasm to the nucleus shortly after X-irradiation, where it interacts with ATM and promotes ATM nuclear export and proteasomal degradation, thereby downregulating ATM protein levels and impairing DNA repair. Nuclear translocation requires phosphorylation of RPRM at serine 98 by CDK4/6, and depends on Importin-11 (IPO11). RPRM overexpression sensitizes cells to irradiation, whereas RPRM deficiency increases radioresistance.","method":"Co-IP (RPRM–ATM interaction), subcellular fractionation, phosphomutant analysis, CDK4/6 inhibitor treatment, IPO11 knockdown, nuclear export assays, in vivo irradiation model","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, phosphomutant, multiple inhibitors, in vitro and in vivo validation, single lab with orthogonal methods","pmids":["36185355"],"is_preprint":false},{"year":2022,"finding":"RPRM deletion preserves hematopoietic stem cell (HSC) regeneration after ionizing radiation. Mechanistically, RPRM loss increases EGFR expression and phosphorylation in HSCs, activating STAT3 and DNA-PKcs, which promotes HSC DNA repair and proliferation.","method":"RPRM-knockout mouse model, flow cytometry of HSC populations, EGFR/STAT3/DNA-PKcs pathway analysis by western blot, irradiation injury model","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined mechanistic pathway (EGFR-STAT3-DNA-PKcs), single lab","pmids":["36041213"],"is_preprint":false},{"year":2024,"finding":"RPRM mediates neuronal ferroptosis after irradiation via the CREB-Nrf2/SCD1 pathway. After irradiation, RPRM binds to CREB and promotes its degradation, reducing CREB protein levels, which in turn downregulates Nrf2 and SCD1, leading to iron accumulation and lipid peroxidation. RPRM deletion prevents this cascade: it restores Nrf2 and SCD1 expression, reverses dysregulation of iron storage proteins (Fth, Ftl) and transporters (Tfr1, Fpn), and maintains GPX4 levels.","method":"RPRM-knockout mouse model, Co-IP (RPRM–CREB interaction), whole-brain irradiation, mitochondrial morphology by EM, iron accumulation assay, lipid peroxidation assay, GPX4/Nrf2/SCD1 western blots","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with in vivo and in vitro mechanistic validation including Co-IP and multiple orthogonal endpoints, single lab","pmids":["38272326"],"is_preprint":false},{"year":2025,"finding":"Reprimo protein is secreted extracellularly and extrinsically induces apoptosis in recipient cells. FAT1, FAT4, CELSR1, CELSR2, and CELSR3 (protocadherin family members) were identified as receptors for secreted Reprimo. Reprimo acts upstream of the Hippo-YAP/TAZ-p73 axis to transactivate proapoptotic genes. In vivo analyses confirm tumor-suppressive effects of secreted Reprimo.","method":"Receptor identification (binding assays), co-immunoprecipitation, Hippo pathway reporter assays, proapoptotic gene transactivation assays, in vivo tumor suppression models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — receptor identification, pathway epistasis, in vitro and in vivo validation across multiple methods, single lab","pmids":["39913207"],"is_preprint":false},{"year":2019,"finding":"HspB2 binds mutant p53 and alters its DNA-binding site, subsequently upregulating RPRM (along with BAI-1 and TSAP6), which are downstream genes of wild-type p53, thereby inhibiting cell proliferation in pancreatic cancer cells.","method":"Co-IP (HspB2–p53 interaction), western blot for RPRM expression, cell proliferation assay in Panc-1 cells","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and expression measurement, single lab, RPRM is one of several targets studied","pmids":["31692031"],"is_preprint":false},{"year":2022,"finding":"LINC00467 (a long noncoding RNA) promotes methylation and decreased expression of the Reprimo promoter by recruiting DNA methyltransferase 1 (DNMT1) to the RPRM promoter in gastric cancer cells.","method":"RNA immunoprecipitation / chromatin binding assays showing LINC00467–DNMT1 recruitment to RPRM promoter, methylation sequencing, LINC00467 knockdown/overexpression","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct mechanistic demonstration of lncRNA recruiting DNMT1 to RPRM promoter, single lab, limited replication","pmids":["35549646"],"is_preprint":false},{"year":2012,"finding":"EBV-encoded LMP-1 expression upregulates Reprimo (and 14-3-3σ) and induces G2/M cell cycle arrest in HEK293T cells, suggesting LMP-1 engages the Reprimo pathway to cause G2/M arrest.","method":"Ectopic LMP-1 expression in HEK293T, real-time PCR for Reprimo transcription, flow cytometry for cell cycle","journal":"Comptes rendus biologies","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional measurement and cell cycle analysis, no direct mechanistic dissection of RPRM's role, single lab","pmids":["23312294"],"is_preprint":false},{"year":2025,"finding":"In female mice, ERα signaling in Rprm-lineage cells (identified in the mediobasal hypothalamus brain region) regulates thermoregulation, specifically modulating brown adipose tissue temperature and tail temperature. Ablation of Rprm-expressing cells in the mediobasal hypothalamus phenocopies the ERα-KO effect, indicating centrally mediated temperature regulation via this cell population.","method":"Reprimo-Cre mouse for conditional ERα knockout (RERKO), stereotaxic cell ablation in mediobasal hypothalamus, core temperature telemetry, BAT temperature measurement, lineage tracing","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO and cell ablation with defined thermoregulatory phenotype, single lab, mechanistic link to hypothalamic Rprm cells established","pmids":["41315012"],"is_preprint":false}],"current_model":"RPRM (Reprimo) is a p53-target, highly glycosylated cytoplasmic protein that acts as a tumor suppressor through multiple mechanisms: intracellularly, it induces G2/M arrest by inhibiting Cdc2 kinase activity and cyclin B1 nuclear translocation; after irradiation, it undergoes CDK4/6-phosphorylation at Ser98 and IPO11-dependent nuclear translocation where it binds ATM and promotes its proteasomal degradation, impairing DNA repair and sensitizing cells to radiation; it also binds CREB to promote its degradation, downregulating the Nrf2/SCD1 antioxidant axis and driving ferroptosis; extracellularly, secreted Reprimo binds protocadherin family receptors (FAT1/4, CELSR1-3) to activate the Hippo-YAP/TAZ-p73 apoptosis pathway; its transcription is repressed by an ERα–HDAC7–FoxA1 tripartite complex and by LINC00467-recruited DNMT1-mediated promoter methylation; and in the hypothalamus, Rprm-lineage cells mediate estrogen-dependent thermoregulation in female mice."},"narrative":{"mechanistic_narrative":"RPRM (Reprimo) is a p53-inducible, highly glycosylated cytoplasmic protein that functions as a tumor suppressor and cell-cycle/stress effector across multiple cellular contexts [PMID:10930422]. Its canonical activity is enforcement of G2 arrest: ectopic Reprimo inhibits Cdc2 kinase activity and blocks nuclear translocation of cyclin B1, situating it within the Cdc2·cyclin B1 regulatory axis downstream of p53 [PMID:10930422]. Beyond cell-cycle control, RPRM operates as an intracellular regulator of the DNA-damage and oxidative-stress response: after irradiation it is phosphorylated at Ser98 by CDK4/6 and imported into the nucleus via Importin-11, where it binds ATM and drives ATM nuclear export and proteasomal degradation, impairing DNA repair and sensitizing cells to radiation [PMID:36185355]. In neurons, post-irradiation RPRM binds CREB and promotes its degradation, collapsing the downstream Nrf2/SCD1 antioxidant axis and driving iron accumulation, lipid peroxidation, and ferroptosis [PMID:38272326]. RPRM is also secreted and acts extrinsically: secreted Reprimo binds protocadherin-family receptors (FAT1, FAT4, CELSR1-3) and acts upstream of the Hippo-YAP/TAZ-p73 axis to transactivate proapoptotic genes, suppressing tumors in vivo [PMID:39913207]. RPRM expression is itself tightly repressed at the promoter level, both by an ERα–HDAC7–FoxA1 tripartite complex that releases RNA Pol II and depletes H3K4 methylation [PMID:19917725] and by LINC00467-directed recruitment of DNMT1, which methylates and silences the RPRM promoter in gastric cancer [PMID:35549646]. A distinct physiological role is established in the brain, where ERα signaling in Rprm-lineage mediobasal hypothalamic cells governs estrogen-dependent thermoregulation in female mice [PMID:41315012].","teleology":[{"year":2000,"claim":"Established RPRM as a p53-responsive effector that enforces G2 arrest, defining its founding place in the cell-cycle checkpoint machinery.","evidence":"Ectopic expression with cell cycle analysis, Cdc2 kinase assay, and cyclin B1 localization in irradiated cells","pmids":["10930422"],"confidence":"High","gaps":["Direct molecular target through which RPRM inhibits Cdc2 not identified","Mechanism linking glycosylation to function unresolved"]},{"year":2009,"claim":"Resolved how RPRM transcription is silenced by hormonal signaling, identifying an ERα–HDAC7–FoxA1 complex as the repressive machinery at its promoter.","evidence":"ChIP, Co-IP, siRNA, HDAC7 deacetylase-dead mutant, and reporter assays with histone-mark analysis","pmids":["19917725"],"confidence":"High","gaps":["Does not address RPRM protein-level function downstream of repression","Generalizability beyond estrogen-responsive cells untested"]},{"year":2012,"claim":"Showed RPRM protein is constitutively destabilized by ubiquitin-proteasome turnover and that stress stabilizes it to promote apoptosis, extending its role beyond G2 arrest.","evidence":"Stable expression, proteasome inhibition, ubiquitination assays, caspase-3 cleavage, and clonogenic assays in pituitary tumor cells","pmids":["22562171"],"confidence":"Medium","gaps":["E3 ligase mediating RPRM ubiquitination not identified","Stress-dependent stabilization mechanism unknown"]},{"year":2012,"claim":"Linked viral oncoprotein LMP-1 to engagement of the Reprimo pathway during G2/M arrest, hinting at non-p53 routes to RPRM induction.","evidence":"Ectopic LMP-1 expression with RT-PCR and flow cytometry in HEK293T","pmids":["23312294"],"confidence":"Low","gaps":["Transcriptional correlation only; no direct test that RPRM is required for LMP-1-induced arrest","No mechanistic dissection of induction"]},{"year":2016,"claim":"Identified a migration/invasion-suppressive activity of RPRM distinct from its cell-cycle role, broadening its tumor-suppressor repertoire.","evidence":"Overexpression with wound-healing, Transwell invasion, and annexin V assays in MDA-MB-231 cells","pmids":["26796959"],"confidence":"Medium","gaps":["Molecular mediators of the anti-migratory effect not defined","Single cell line"]},{"year":2019,"claim":"Placed RPRM downstream of a mutant-p53-modulating chaperone, showing HspB2 can restore RPRM expression to restrain proliferation.","evidence":"Co-IP of HspB2–p53 and western blot for RPRM in Panc-1 cells","pmids":["31692031"],"confidence":"Low","gaps":["Single Co-IP and expression measurement; RPRM is one of several reported targets","Causal requirement for RPRM not isolated"]},{"year":2022,"claim":"Defined the regulated nuclear import of RPRM after irradiation and its action on ATM, establishing RPRM as a radiosensitizer that suppresses DNA repair.","evidence":"Reciprocal Co-IP, subcellular fractionation, Ser98 phosphomutant, CDK4/6 inhibitor, IPO11 knockdown, and in vivo irradiation","pmids":["36185355"],"confidence":"High","gaps":["Structural basis of RPRM–ATM binding unresolved","E3 ligase driving ATM degradation unidentified"]},{"year":2022,"claim":"Demonstrated in vivo that RPRM loss preserves hematopoietic stem cell regeneration via EGFR-STAT3-DNA-PKcs signaling, confirming RPRM restrains DNA repair physiologically.","evidence":"RPRM-knockout mice, HSC flow cytometry, pathway western blots, and irradiation injury model","pmids":["36041213"],"confidence":"Medium","gaps":["How RPRM loss elevates EGFR expression mechanistically unclear","Direct versus indirect link to DNA-PKcs not separated"]},{"year":2022,"claim":"Identified LINC00467-directed DNMT1 promoter methylation as an epigenetic silencing mechanism for RPRM in gastric cancer.","evidence":"RNA-IP/chromatin binding, methylation sequencing, and LINC00467 perturbation","pmids":["35549646"],"confidence":"Medium","gaps":["Generality across tumor types untested","Functional consequence of RPRM silencing not directly assayed here"]},{"year":2024,"claim":"Connected RPRM to neuronal ferroptosis after irradiation through CREB degradation and collapse of the Nrf2/SCD1 antioxidant axis, defining a new oxidative-stress effector function.","evidence":"RPRM-knockout mice, RPRM–CREB Co-IP, whole-brain irradiation, iron/lipid-peroxidation assays, and GPX4/Nrf2/SCD1 westerns","pmids":["38272326"],"confidence":"High","gaps":["Mechanism by which RPRM targets CREB for degradation unresolved","Whether ferroptotic role extends beyond neurons unknown"]},{"year":2025,"claim":"Revealed RPRM acts extracellularly as a secreted ligand for protocadherin receptors, coupling it to Hippo-YAP/TAZ-p73 proapoptotic signaling.","evidence":"Receptor-binding/Co-IP identification of FAT1/4 and CELSR1-3, Hippo reporter and proapoptotic transactivation assays, and in vivo tumor suppression","pmids":["39913207"],"confidence":"High","gaps":["How secretion of a cytoplasmic glycoprotein is achieved not defined","Receptor selectivity and ligand stoichiometry unresolved"]},{"year":2025,"claim":"Established a physiological neuroendocrine role for Rprm-lineage hypothalamic cells in estrogen-dependent thermoregulation, separate from tumor suppression.","evidence":"Reprimo-Cre conditional ERα knockout, mediobasal hypothalamic cell ablation, and core/BAT temperature telemetry in female mice","pmids":["41315012"],"confidence":"Medium","gaps":["Whether RPRM protein itself, versus the lineage marker, drives thermoregulation untested","Molecular output of these cells not defined"]},{"year":null,"claim":"How a single glycosylated protein coordinates its cytoplasmic cell-cycle role, regulated nuclear import, ferroptosis induction, and extracellular ligand activity into one coherent regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of RPRM","Mechanism of RPRM secretion and processing unknown","E3 ligases for RPRM-driven degradation of ATM and CREB unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]}],"complexes":[],"partners":["ATM","CREB","FAT1","FAT4","CELSR1","CELSR2","CELSR3","IPO11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NS64","full_name":"Protein reprimo","aliases":[],"length_aa":109,"mass_kda":11.8,"function":"May be involved in the regulation of p53-dependent G2 arrest of the cell cycle. Seems to induce cell cycle arrest by inhibiting CDK1 activity and nuclear translocation of the CDC2 cyclin B1 complex (By similarity)","subcellular_location":"Cytoplasm; Membrane","url":"https://www.uniprot.org/uniprotkb/Q9NS64/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RPRM","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/RPRM","total_profiled":1310},"omim":[{"mim_id":"612171","title":"REPRIMO; RPRM","url":"https://www.omim.org/entry/612171"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPRM"},"hgnc":{"alias_symbol":["FLJ90327","REPRIMO"],"prev_symbol":[]},"alphafold":{"accession":"Q9NS64","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NS64","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NS64-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NS64-F1-predicted_aligned_error_v6.png","plddt_mean":60.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPRM","jax_strain_url":"https://www.jax.org/strain/search?query=RPRM"},"sequence":{"accession":"Q9NS64","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NS64.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NS64/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NS64"}},"corpus_meta":[{"pmid":"10930422","id":"PMC_10930422","title":"Reprimo, a new candidate mediator of the p53-mediated cell cycle arrest at the G2 phase.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10930422","citation_count":166,"is_preprint":false},{"pmid":"18829507","id":"PMC_18829507","title":"Reprimo as a potential biomarker for early detection in gastric cancer.","date":"2008","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/18829507","citation_count":108,"is_preprint":false},{"pmid":"19917725","id":"PMC_19917725","title":"Histone deacetylase 7 and FoxA1 in estrogen-mediated repression of RPRM.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19917725","citation_count":68,"is_preprint":false},{"pmid":"15700311","id":"PMC_15700311","title":"Aberrant methylation of Reprimo in human malignancies.","date":"2005","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15700311","citation_count":58,"is_preprint":false},{"pmid":"22562171","id":"PMC_22562171","title":"Reprimo (RPRM) is a novel tumor suppressor in pituitary tumors and regulates survival, proliferation, and tumorigenicity.","date":"2012","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22562171","citation_count":42,"is_preprint":false},{"pmid":"17121882","id":"PMC_17121882","title":"Reprimo methylation is a potential biomarker of Barrett's-Associated esophageal neoplastic progression.","date":"2006","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/17121882","citation_count":41,"is_preprint":false},{"pmid":"23982217","id":"PMC_23982217","title":"DNA damage-inducible gene, reprimo functions as a tumor suppressor and is suppressed by promoter methylation in gastric cancer.","date":"2013","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/23982217","citation_count":39,"is_preprint":false},{"pmid":"25954972","id":"PMC_25954972","title":"Loss of Expression of Reprimo, a p53-induced Cell Cycle Arrest Gene, Correlates with Invasive Stage of Tumor Progression and p73 Expression in Gastric Cancer.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25954972","citation_count":32,"is_preprint":false},{"pmid":"15713514","id":"PMC_15713514","title":"Aberrant methylation of Reprimo in lung cancer.","date":"2005","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/15713514","citation_count":26,"is_preprint":false},{"pmid":"20949468","id":"PMC_20949468","title":"Loss of Reprimo and S100A2 expression in human gastric adenocarcinoma.","date":"2010","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/20949468","citation_count":24,"is_preprint":false},{"pmid":"26823831","id":"PMC_26823831","title":"Implication of Reprimo and hMLH1 gene methylation in early diagnosis of gastric carcinoma.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26823831","citation_count":23,"is_preprint":false},{"pmid":"31692031","id":"PMC_31692031","title":"Molecular chaperone HspB2 inhibited pancreatic cancer cell proliferation via activating p53 downstream gene RPRM, BAI1, and TSAP6.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31692031","citation_count":23,"is_preprint":false},{"pmid":"33322837","id":"PMC_33322837","title":"The Reprimo-Like Gene Is an Epigenetic-Mediated Tumor Suppressor and a Candidate Biomarker for the Non-Invasive Detection of Gastric Cancer.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33322837","citation_count":20,"is_preprint":false},{"pmid":"27432065","id":"PMC_27432065","title":"Evolutionary history of the reprimo tumor suppressor gene family in vertebrates with a description of a new reprimo gene lineage.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27432065","citation_count":18,"is_preprint":false},{"pmid":"26796959","id":"PMC_26796959","title":"Reprimo as a modulator of cell migration and invasion in the MDA-MB-231 breast cancer cell line.","date":"2016","source":"Biological research","url":"https://pubmed.ncbi.nlm.nih.gov/26796959","citation_count":17,"is_preprint":false},{"pmid":"32431794","id":"PMC_32431794","title":"Methylation Analysis of P16, RASSF1A, RPRM, and RUNX3 in Circulating Cell-Free DNA for Detection of Gastric Cancer: A Validation Study.","date":"2020","source":"Avicenna journal of medical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32431794","citation_count":17,"is_preprint":false},{"pmid":"29941787","id":"PMC_29941787","title":"The Reprimo Gene Family: A Novel Gene Lineage in Gastric Cancer with Tumor Suppressive 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lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/25629980","citation_count":6,"is_preprint":false},{"pmid":"31073223","id":"PMC_31073223","title":"The Reprimo gene family member, reprimo-like (rprml), is required for blood development in embryonic zebrafish.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31073223","citation_count":5,"is_preprint":false},{"pmid":"36855658","id":"PMC_36855658","title":"Value of Methylation Status of RPRM, SDC2, and TCF4 Genes in Plasma for Gastric Adenocarcinoma Screening.","date":"2023","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36855658","citation_count":5,"is_preprint":false},{"pmid":"36185355","id":"PMC_36185355","title":"RPRM negatively regulates ATM levels through its nuclear translocation on irradiation mediated by CDK4/6 and 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40244164","citation_count":3,"is_preprint":false},{"pmid":"40849852","id":"PMC_40849852","title":"SFRP2 and RPRM as methylation based serum biomarkers for the detection of gastric cancer.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40849852","citation_count":3,"is_preprint":false},{"pmid":"31069006","id":"PMC_31069006","title":"Prediction of onset of remnant gastric cancer by promoter DNA methylation of CDO1/HOPX/Reprimo/E-cadherin.","date":"2019","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/31069006","citation_count":3,"is_preprint":false},{"pmid":"23312294","id":"PMC_23312294","title":"Epstein-Barr virus-encoded latent membrane protein-1 upregulates 14-3-3σ and Reprimo to confer G(2)/M phase cell cycle arrest.","date":"2012","source":"Comptes rendus biologies","url":"https://pubmed.ncbi.nlm.nih.gov/23312294","citation_count":2,"is_preprint":false},{"pmid":"41315012","id":"PMC_41315012","title":"Sex-Specific Thermoregulatory Effects of Estrogen Signaling in Reprimo Lineage Cells.","date":"2025","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/41315012","citation_count":1,"is_preprint":false},{"pmid":"12395409","id":"PMC_12395409","title":"Identification of polymorphisms in the human Reprimo gene using public EST data.","date":"2002","source":"Teratogenesis, carcinogenesis, and mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/12395409","citation_count":1,"is_preprint":false},{"pmid":"41036848","id":"PMC_41036848","title":"Reprimo (RPRM): A Tumor Suppressor That Induces Extrinsic Apoptosis via YAP Signaling.","date":"2025","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/41036848","citation_count":0,"is_preprint":false},{"pmid":"39677630","id":"PMC_39677630","title":"Sex-specific thermoregulatory effects of estrogen signaling in Reprimo lineage cells.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39677630","citation_count":0,"is_preprint":false},{"pmid":"32111873","id":"PMC_32111873","title":"Author Correction: The Reprimo gene family member, reprimo-like (rprml), is required for blood development in embryonic zebrafish.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32111873","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.02.626488","title":"Sex-specific thermoregulatory effects of estrogen signaling in  <i>Reprimo</i>  lineage cells","date":"2024-12-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.02.626488","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23900,"output_tokens":3420,"usd":0.0615,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11025,"output_tokens":3987,"usd":0.0774,"stage2_stop_reason":"end_turn"},"total_usd":0.1389,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Reprimo is a highly glycosylated cytoplasmic protein that, when ectopically expressed, induces G2 arrest of the cell cycle. In arrested cells, both Cdc2 kinase activity and nuclear translocation of cyclin B1 are inhibited, placing Reprimo in the Cdc2·cyclin B1 regulation pathway. Reprimo mRNA induction by X-irradiation is p53-dependent.\",\n      \"method\": \"Ectopic expression in cells, cell cycle analysis, Cdc2 kinase activity assay, cyclin B1 localization by immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — foundational paper with multiple orthogonal methods (ectopic expression, kinase assay, localization), replicated by subsequent work\",\n      \"pmids\": [\"10930422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Estrogen repression of RPRM requires a tripartite interaction among estrogen receptor alpha (ERα), histone deacetylase 7 (HDAC7), and the chromatin pioneer factor FoxA1. HDAC7 binds ERα and represses its transcriptional activity independently of HDAC7's deacetylase activity. FoxA1 is recruited to the RPRM promoter, interacts with HDAC7, and is necessary for repression. Estrogen treatment causes decreases in H3K4me1/me2 marks and release of RNA Pol II from the RPRM proximal promoter.\",\n      \"method\": \"ChIP assays, Co-IP (ERα–HDAC7 interaction), siRNA knockdown, HDAC7 deacetylase-dead mutant, promoter reporter assays, histone mark analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, mutagenesis of HDAC7 catalytic domain, siRNA), single lab\",\n      \"pmids\": [\"19917725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In pituitary tumor cells stably expressing RPRM mRNA, the RPRM protein is rapidly degraded via ubiquitination and proteasomal targeting, keeping steady-state protein levels low. Cellular stress (growth factor withdrawal) stabilizes RPRM protein. RPRM overexpression reduces cell proliferation and increases apoptosis (caspase-3 cleavage, nuclear condensation) in response to growth factor deprivation, and suppresses colony formation, without altering G2/M transition in these cells.\",\n      \"method\": \"Stable cell line expression, proteasome inhibitor treatment, ubiquitination assays, caspase-3 cleavage assay, clonogenic assay, cell cycle analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays and biochemical evidence for proteasomal degradation, single lab\",\n      \"pmids\": [\"22562171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Overexpression of RPRM in MDA-MB-231 breast cancer cells decreased cell migration, wound healing, and invasion in vitro, without altering cell viability, phosphatidylserine translocation, or G2/M cell cycle transition, indicating a migration/invasion-suppressive function distinct from cell cycle arrest.\",\n      \"method\": \"Ectopic overexpression, wound-healing assay, Transwell invasion assay, flow cytometry, annexin V assay\",\n      \"journal\": \"Biological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean overexpression with defined phenotypic readout, single lab, single cell line\",\n      \"pmids\": [\"26796959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RPRM translocates from the cytoplasm to the nucleus shortly after X-irradiation, where it interacts with ATM and promotes ATM nuclear export and proteasomal degradation, thereby downregulating ATM protein levels and impairing DNA repair. Nuclear translocation requires phosphorylation of RPRM at serine 98 by CDK4/6, and depends on Importin-11 (IPO11). RPRM overexpression sensitizes cells to irradiation, whereas RPRM deficiency increases radioresistance.\",\n      \"method\": \"Co-IP (RPRM–ATM interaction), subcellular fractionation, phosphomutant analysis, CDK4/6 inhibitor treatment, IPO11 knockdown, nuclear export assays, in vivo irradiation model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, phosphomutant, multiple inhibitors, in vitro and in vivo validation, single lab with orthogonal methods\",\n      \"pmids\": [\"36185355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RPRM deletion preserves hematopoietic stem cell (HSC) regeneration after ionizing radiation. Mechanistically, RPRM loss increases EGFR expression and phosphorylation in HSCs, activating STAT3 and DNA-PKcs, which promotes HSC DNA repair and proliferation.\",\n      \"method\": \"RPRM-knockout mouse model, flow cytometry of HSC populations, EGFR/STAT3/DNA-PKcs pathway analysis by western blot, irradiation injury model\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined mechanistic pathway (EGFR-STAT3-DNA-PKcs), single lab\",\n      \"pmids\": [\"36041213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RPRM mediates neuronal ferroptosis after irradiation via the CREB-Nrf2/SCD1 pathway. After irradiation, RPRM binds to CREB and promotes its degradation, reducing CREB protein levels, which in turn downregulates Nrf2 and SCD1, leading to iron accumulation and lipid peroxidation. RPRM deletion prevents this cascade: it restores Nrf2 and SCD1 expression, reverses dysregulation of iron storage proteins (Fth, Ftl) and transporters (Tfr1, Fpn), and maintains GPX4 levels.\",\n      \"method\": \"RPRM-knockout mouse model, Co-IP (RPRM–CREB interaction), whole-brain irradiation, mitochondrial morphology by EM, iron accumulation assay, lipid peroxidation assay, GPX4/Nrf2/SCD1 western blots\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with in vivo and in vitro mechanistic validation including Co-IP and multiple orthogonal endpoints, single lab\",\n      \"pmids\": [\"38272326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Reprimo protein is secreted extracellularly and extrinsically induces apoptosis in recipient cells. FAT1, FAT4, CELSR1, CELSR2, and CELSR3 (protocadherin family members) were identified as receptors for secreted Reprimo. Reprimo acts upstream of the Hippo-YAP/TAZ-p73 axis to transactivate proapoptotic genes. In vivo analyses confirm tumor-suppressive effects of secreted Reprimo.\",\n      \"method\": \"Receptor identification (binding assays), co-immunoprecipitation, Hippo pathway reporter assays, proapoptotic gene transactivation assays, in vivo tumor suppression models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identification, pathway epistasis, in vitro and in vivo validation across multiple methods, single lab\",\n      \"pmids\": [\"39913207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HspB2 binds mutant p53 and alters its DNA-binding site, subsequently upregulating RPRM (along with BAI-1 and TSAP6), which are downstream genes of wild-type p53, thereby inhibiting cell proliferation in pancreatic cancer cells.\",\n      \"method\": \"Co-IP (HspB2–p53 interaction), western blot for RPRM expression, cell proliferation assay in Panc-1 cells\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and expression measurement, single lab, RPRM is one of several targets studied\",\n      \"pmids\": [\"31692031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LINC00467 (a long noncoding RNA) promotes methylation and decreased expression of the Reprimo promoter by recruiting DNA methyltransferase 1 (DNMT1) to the RPRM promoter in gastric cancer cells.\",\n      \"method\": \"RNA immunoprecipitation / chromatin binding assays showing LINC00467–DNMT1 recruitment to RPRM promoter, methylation sequencing, LINC00467 knockdown/overexpression\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct mechanistic demonstration of lncRNA recruiting DNMT1 to RPRM promoter, single lab, limited replication\",\n      \"pmids\": [\"35549646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EBV-encoded LMP-1 expression upregulates Reprimo (and 14-3-3σ) and induces G2/M cell cycle arrest in HEK293T cells, suggesting LMP-1 engages the Reprimo pathway to cause G2/M arrest.\",\n      \"method\": \"Ectopic LMP-1 expression in HEK293T, real-time PCR for Reprimo transcription, flow cytometry for cell cycle\",\n      \"journal\": \"Comptes rendus biologies\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional measurement and cell cycle analysis, no direct mechanistic dissection of RPRM's role, single lab\",\n      \"pmids\": [\"23312294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In female mice, ERα signaling in Rprm-lineage cells (identified in the mediobasal hypothalamus brain region) regulates thermoregulation, specifically modulating brown adipose tissue temperature and tail temperature. Ablation of Rprm-expressing cells in the mediobasal hypothalamus phenocopies the ERα-KO effect, indicating centrally mediated temperature regulation via this cell population.\",\n      \"method\": \"Reprimo-Cre mouse for conditional ERα knockout (RERKO), stereotaxic cell ablation in mediobasal hypothalamus, core temperature telemetry, BAT temperature measurement, lineage tracing\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO and cell ablation with defined thermoregulatory phenotype, single lab, mechanistic link to hypothalamic Rprm cells established\",\n      \"pmids\": [\"41315012\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPRM (Reprimo) is a p53-target, highly glycosylated cytoplasmic protein that acts as a tumor suppressor through multiple mechanisms: intracellularly, it induces G2/M arrest by inhibiting Cdc2 kinase activity and cyclin B1 nuclear translocation; after irradiation, it undergoes CDK4/6-phosphorylation at Ser98 and IPO11-dependent nuclear translocation where it binds ATM and promotes its proteasomal degradation, impairing DNA repair and sensitizing cells to radiation; it also binds CREB to promote its degradation, downregulating the Nrf2/SCD1 antioxidant axis and driving ferroptosis; extracellularly, secreted Reprimo binds protocadherin family receptors (FAT1/4, CELSR1-3) to activate the Hippo-YAP/TAZ-p73 apoptosis pathway; its transcription is repressed by an ERα–HDAC7–FoxA1 tripartite complex and by LINC00467-recruited DNMT1-mediated promoter methylation; and in the hypothalamus, Rprm-lineage cells mediate estrogen-dependent thermoregulation in female mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPRM (Reprimo) is a p53-inducible, highly glycosylated cytoplasmic protein that functions as a tumor suppressor and cell-cycle/stress effector across multiple cellular contexts [#0]. Its canonical activity is enforcement of G2 arrest: ectopic Reprimo inhibits Cdc2 kinase activity and blocks nuclear translocation of cyclin B1, situating it within the Cdc2·cyclin B1 regulatory axis downstream of p53 [#0]. Beyond cell-cycle control, RPRM operates as an intracellular regulator of the DNA-damage and oxidative-stress response: after irradiation it is phosphorylated at Ser98 by CDK4/6 and imported into the nucleus via Importin-11, where it binds ATM and drives ATM nuclear export and proteasomal degradation, impairing DNA repair and sensitizing cells to radiation [#4]. In neurons, post-irradiation RPRM binds CREB and promotes its degradation, collapsing the downstream Nrf2/SCD1 antioxidant axis and driving iron accumulation, lipid peroxidation, and ferroptosis [#6]. RPRM is also secreted and acts extrinsically: secreted Reprimo binds protocadherin-family receptors (FAT1, FAT4, CELSR1-3) and acts upstream of the Hippo-YAP/TAZ-p73 axis to transactivate proapoptotic genes, suppressing tumors in vivo [#7]. RPRM expression is itself tightly repressed at the promoter level, both by an ERα–HDAC7–FoxA1 tripartite complex that releases RNA Pol II and depletes H3K4 methylation [#1] and by LINC00467-directed recruitment of DNMT1, which methylates and silences the RPRM promoter in gastric cancer [#9]. A distinct physiological role is established in the brain, where ERα signaling in Rprm-lineage mediobasal hypothalamic cells governs estrogen-dependent thermoregulation in female mice [#11].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established RPRM as a p53-responsive effector that enforces G2 arrest, defining its founding place in the cell-cycle checkpoint machinery.\",\n      \"evidence\": \"Ectopic expression with cell cycle analysis, Cdc2 kinase assay, and cyclin B1 localization in irradiated cells\",\n      \"pmids\": [\"10930422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target through which RPRM inhibits Cdc2 not identified\", \"Mechanism linking glycosylation to function unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how RPRM transcription is silenced by hormonal signaling, identifying an ERα–HDAC7–FoxA1 complex as the repressive machinery at its promoter.\",\n      \"evidence\": \"ChIP, Co-IP, siRNA, HDAC7 deacetylase-dead mutant, and reporter assays with histone-mark analysis\",\n      \"pmids\": [\"19917725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address RPRM protein-level function downstream of repression\", \"Generalizability beyond estrogen-responsive cells untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed RPRM protein is constitutively destabilized by ubiquitin-proteasome turnover and that stress stabilizes it to promote apoptosis, extending its role beyond G2 arrest.\",\n      \"evidence\": \"Stable expression, proteasome inhibition, ubiquitination assays, caspase-3 cleavage, and clonogenic assays in pituitary tumor cells\",\n      \"pmids\": [\"22562171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating RPRM ubiquitination not identified\", \"Stress-dependent stabilization mechanism unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked viral oncoprotein LMP-1 to engagement of the Reprimo pathway during G2/M arrest, hinting at non-p53 routes to RPRM induction.\",\n      \"evidence\": \"Ectopic LMP-1 expression with RT-PCR and flow cytometry in HEK293T\",\n      \"pmids\": [\"23312294\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Transcriptional correlation only; no direct test that RPRM is required for LMP-1-induced arrest\", \"No mechanistic dissection of induction\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a migration/invasion-suppressive activity of RPRM distinct from its cell-cycle role, broadening its tumor-suppressor repertoire.\",\n      \"evidence\": \"Overexpression with wound-healing, Transwell invasion, and annexin V assays in MDA-MB-231 cells\",\n      \"pmids\": [\"26796959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mediators of the anti-migratory effect not defined\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed RPRM downstream of a mutant-p53-modulating chaperone, showing HspB2 can restore RPRM expression to restrain proliferation.\",\n      \"evidence\": \"Co-IP of HspB2–p53 and western blot for RPRM in Panc-1 cells\",\n      \"pmids\": [\"31692031\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP and expression measurement; RPRM is one of several reported targets\", \"Causal requirement for RPRM not isolated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the regulated nuclear import of RPRM after irradiation and its action on ATM, establishing RPRM as a radiosensitizer that suppresses DNA repair.\",\n      \"evidence\": \"Reciprocal Co-IP, subcellular fractionation, Ser98 phosphomutant, CDK4/6 inhibitor, IPO11 knockdown, and in vivo irradiation\",\n      \"pmids\": [\"36185355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RPRM–ATM binding unresolved\", \"E3 ligase driving ATM degradation unidentified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated in vivo that RPRM loss preserves hematopoietic stem cell regeneration via EGFR-STAT3-DNA-PKcs signaling, confirming RPRM restrains DNA repair physiologically.\",\n      \"evidence\": \"RPRM-knockout mice, HSC flow cytometry, pathway western blots, and irradiation injury model\",\n      \"pmids\": [\"36041213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How RPRM loss elevates EGFR expression mechanistically unclear\", \"Direct versus indirect link to DNA-PKcs not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified LINC00467-directed DNMT1 promoter methylation as an epigenetic silencing mechanism for RPRM in gastric cancer.\",\n      \"evidence\": \"RNA-IP/chromatin binding, methylation sequencing, and LINC00467 perturbation\",\n      \"pmids\": [\"35549646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality across tumor types untested\", \"Functional consequence of RPRM silencing not directly assayed here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected RPRM to neuronal ferroptosis after irradiation through CREB degradation and collapse of the Nrf2/SCD1 antioxidant axis, defining a new oxidative-stress effector function.\",\n      \"evidence\": \"RPRM-knockout mice, RPRM–CREB Co-IP, whole-brain irradiation, iron/lipid-peroxidation assays, and GPX4/Nrf2/SCD1 westerns\",\n      \"pmids\": [\"38272326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RPRM targets CREB for degradation unresolved\", \"Whether ferroptotic role extends beyond neurons unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed RPRM acts extracellularly as a secreted ligand for protocadherin receptors, coupling it to Hippo-YAP/TAZ-p73 proapoptotic signaling.\",\n      \"evidence\": \"Receptor-binding/Co-IP identification of FAT1/4 and CELSR1-3, Hippo reporter and proapoptotic transactivation assays, and in vivo tumor suppression\",\n      \"pmids\": [\"39913207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How secretion of a cytoplasmic glycoprotein is achieved not defined\", \"Receptor selectivity and ligand stoichiometry unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a physiological neuroendocrine role for Rprm-lineage hypothalamic cells in estrogen-dependent thermoregulation, separate from tumor suppression.\",\n      \"evidence\": \"Reprimo-Cre conditional ERα knockout, mediobasal hypothalamic cell ablation, and core/BAT temperature telemetry in female mice\",\n      \"pmids\": [\"41315012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RPRM protein itself, versus the lineage marker, drives thermoregulation untested\", \"Molecular output of these cells not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single glycosylated protein coordinates its cytoplasmic cell-cycle role, regulated nuclear import, ferroptosis induction, and extracellular ligand activity into one coherent regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of RPRM\", \"Mechanism of RPRM secretion and processing unknown\", \"E3 ligases for RPRM-driven degradation of ATM and CREB unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATM\", \"CREB\", \"FAT1\", \"FAT4\", \"CELSR1\", \"CELSR2\", \"CELSR3\", \"IPO11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}