{"gene":"SCARA3","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":1998,"finding":"CSR (SCARA3) was identified as a novel macrophage scavenger receptor-like gene whose transcription is strongly induced in normal fibroblasts by UV irradiation or hydrogen peroxide. Overexpression of CSR in cells caused significant depletion of reactive oxygen species under oxidative stress conditions, indicating the CSR protein protects cells by scavenging oxidative molecules or harmful products of oxidation.","method":"Gene cloning, Northern blot for expression induction, and ROS measurement in CSR-overexpressing cells under oxidative stress","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression experiment with defined ROS readout, single lab, single study","pmids":["9580669"],"is_preprint":false},{"year":2006,"finding":"CSR1 (SCARA3) functions as a tumor suppressor in prostate cancer. Forced expression of CSR1 in prostate cancer cell lines DU145 and PC3 caused 2–3 fold decrease in colony formation, 10-fold reduction in anchorage-independent growth, and 3-fold decrease in invasion in vitro. In xenograft models, CSR1 expression in PC3 cells produced >8-fold reduction in tumor size and abolished invasion and mortality.","method":"Overexpression in prostate cancer cell lines (colony formation, soft agar, invasion assays), PC3 xenograft mouse model, methylation analysis of CSR1 promoter in clinical samples","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays (in vitro growth, invasion, in vivo xenograft) with consistent results, single lab","pmids":["16436673"],"is_preprint":false},{"year":2008,"finding":"CSR1 induces cell death by directly binding to CPSF3 (cleavage and polyadenylation-specific factor 3) via its C-terminus (amino acids 440–543). This interaction causes translocation of CPSF3 from the nucleus to the cytoplasm, resulting in inhibition of mRNA polyadenylation both in vitro and in vivo. A CSR1 mutant unable to bind CPSF3 did not alter CPSF3 subcellular distribution, did not inhibit polyadenylation, and did not induce cell death.","method":"Yeast two-hybrid screen of prostate cDNA library, co-immunoprecipitation, subcellular fractionation/localization, in vitro and in vivo polyadenylation assays, CSR1 binding-domain mutant analysis, siRNA knockdown of CPSF3","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — yeast two-hybrid discovery confirmed by co-IP, functional mutant rescue, in vitro and in vivo activity assays, multiple orthogonal methods in single rigorous study","pmids":["18806823"],"is_preprint":false},{"year":2012,"finding":"CSR1 interacts with X-linked Inhibitor of Apoptosis Protein (XIAP) via its C-terminus (amino acids 513–572). Binding of CSR1 to XIAP prevents XIAP from inhibiting caspase-9 and caspase-3, thereby enhancing their protease activities and accelerating cell death. A CSR1 mutant that cannot bind XIAP did not activate caspases or induce cell death; a XIAP mutant that cannot interact with caspase-9 also abolished CSR1-induced cell death.","method":"Yeast two-hybrid screening, in vitro recombinant protein-binding analyses, Co-IP, caspase-9 and caspase-3 activity assays, XIAP knockdown (siRNA), XIAP overexpression, domain-mapping mutants","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — yeast two-hybrid discovery, in vitro binding confirmation, functional mutant analysis, caspase activity assays; multiple orthogonal methods in one rigorous study","pmids":["22683311"],"is_preprint":false},{"year":2013,"finding":"SCARA3 expression is induced in multiple myeloma cells upon treatment with oxidative stressors (ionizing radiation and chemotherapeutic drugs). SCARA3 protects myeloma cells against oxidative stress-induced cell killing; SCARA3 knockdown sensitized myeloma cells to dexamethasone and bortezomib, while SCARA3 upregulation inhibited their cytotoxic effects.","method":"SCARA3 knockdown and overexpression in myeloma cell lines, drug treatment (dexamethasone, bortezomib), cell viability assays, epigenetic inactivation analysis","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined drug-response phenotype, single lab, two complementary approaches","pmids":["23537707"],"is_preprint":false},{"year":2014,"finding":"CSR (SCARA3) interacts with NADPH-P450 reductase (NPR) and acts as a new regulator of the hypoxic response. Overexpression of CSR enhanced induction of erythropoietin and hypoxia response element (HRE) activity under hypoxia in Hep3B cells, while knockdown of CSR suppressed these responses.","method":"Yeast two-hybrid identification of CSR-NPR interaction, overexpression and siRNA knockdown of CSR in Hep3B cells, erythropoietin and HRE reporter assays under hypoxia","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus gain- and loss-of-function with defined hypoxia readout, single lab","pmids":["24491563"],"is_preprint":false},{"year":2015,"finding":"miR-650 suppresses CSR1 (SCARA3) expression by directly targeting a site in the 3' UTR of CSR1 mRNA. Inhibition of miR-650 in prostate cancer cells increased CSR1 expression levels, suppressed colony formation, and blocked S-phase cell cycle entry. Mutation of the miR-650 target site in the CSR1 3' UTR completely abrogated miR-650's regulatory activity.","method":"Luciferase reporter assay with CSR1 3' UTR, 3' UTR target-site mutagenesis, miR-650 inhibitor treatment, qRT-PCR, colony formation and cell cycle assays, xenograft mouse model","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct target validation by luciferase reporter with site mutagenesis, functional rescue, in vivo xenograft confirmation; multiple orthogonal methods","pmids":["25956032"],"is_preprint":false},{"year":2017,"finding":"CSR1 (SCARA3) suppresses tumor growth and metastasis in hepatocellular carcinoma (HCC) by directly associating with hematopoietic PBX interacting protein (HPIP) and inhibiting downstream PI3K/AKT pathway activation. Overexpression of CSR1 inhibited HCC cell proliferation, migration, and invasion; CRISPR-Cas9 knockout of CSR1 had the opposite effects.","method":"Co-immunoprecipitation assay (CSR1–HPIP interaction), CRISPR-Cas9 knockout, overexpression, MTT proliferation assay, scratch wound and Matrigel invasion assays, Western blot for PI3K/AKT pathway","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for binding partner, CRISPR KO plus overexpression with defined cellular phenotype, pathway readout; single lab","pmids":["28975986"],"is_preprint":false},{"year":2018,"finding":"CSR1 (SCARA3) is SUMOylated at lysine 582 and subsequently rapidly ubiquitinated and degraded in prostate cancer cells. SENP1, a SUMO-specific protease, interacts with and deSUMOylates CSR1, preventing its degradation and enhancing CSR1-dependent prostate cancer cell death.","method":"Immunoprecipitation-based proteomics screen, GST pulldown assay, in vivo SUMOylation assay, CRISPR-based generation of Senp1-/- and CSR1-/- cells, FACS apoptosis assay","journal":"Cellular physiology and biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct SUMOylation site identification, GST pulldown for SENP1–CSR1 interaction, in vivo SUMOylation assay, CRISPR KO functional validation; multiple orthogonal methods in one study","pmids":["29705808"],"is_preprint":false},{"year":2021,"finding":"Scara3 regulates the fate switch of bone marrow mesenchymal stem cells (BMSCs) between osteoblast and adipocyte differentiation by promoting Foxo1 expression and autophagy flux. Deletion of Scara3 favored adipogenesis over osteogenesis, while overexpression promoted osteogenesis at the expense of adipogenesis. In vivo, adeno-associated virus-mediated Scara3 overexpression in bone marrow promoted bone formation and reduced bone marrow fat accumulation in ovariectomized and aged mice.","method":"siRNA knockdown and overexpression in BMSCs, qPCR and Western blot for differentiation markers, cell staining (Oil Red O, Alizarin Red), Western blot and immunofluorescence for Foxo1 and autophagy, intra-bone marrow AAV injection in OVX and aged mice, micro-CT and histology","journal":"Cell proliferation","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss- and gain-of-function in vitro plus in vivo AAV overexpression with mechanistic pathway (Foxo1/autophagy) identification; multiple orthogonal methods","pmids":["34254370"],"is_preprint":false},{"year":2022,"finding":"Overexpression of SCARA3 in lung cancer cells inhibited proliferation, migration, and invasion, reduced EMT markers (β-catenin, vimentin, MMP9), and enhanced sensitivity to cisplatin via the AKT and JNK signaling pathways. The anti-tumor effects were confirmed in a mouse xenograft model.","method":"SCARA3 overexpression in lung cancer cell lines, cell viability assay, Transwell migration/invasion, Western blot for EMT markers and AKT/JNK pathway, BALB/C nude mouse xenograft","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined phenotype (proliferation, EMT markers, signaling pathway) in vitro and in vivo, single lab","pmids":["35578316"],"is_preprint":false}],"current_model":"SCARA3 (CSR1) is a macrophage scavenger receptor-like transmembrane protein that protects cells from oxidative stress by scavenging reactive oxygen species; it functions as a tumor suppressor by inducing cell death through at least two mechanisms — (1) binding CPSF3 via its C-terminus to sequester it in the cytoplasm and inhibit mRNA polyadenylation, and (2) binding XIAP to prevent XIAP-mediated caspase-9/3 inhibition, thereby activating apoptosis; CSR1 protein stability is regulated by SUMOylation at K582 (which promotes ubiquitination and degradation) and by SENP1-mediated deSUMOylation; CSR1 expression is post-transcriptionally suppressed by miR-650 targeting its 3' UTR; and SCARA3 additionally controls bone marrow mesenchymal stem cell fate toward osteogenesis via Foxo1 and autophagy, and suppresses the PI3K/AKT pathway in hepatocellular carcinoma through interaction with HPIP."},"narrative":{"mechanistic_narrative":"SCARA3 (CSR1) is a macrophage scavenger receptor-like protein originally identified as a stress-inducible cytoprotective factor whose transcription is strongly induced by UV irradiation and hydrogen peroxide and whose overexpression depletes reactive oxygen species under oxidative stress [PMID:9580669], a protective role recapitulated in myeloma cells where SCARA3 buffers oxidative damage and modulates sensitivity to dexamethasone and bortezomib [PMID:23537707]. Beyond cytoprotection, SCARA3 acts as a tumor suppressor across prostate, hepatocellular, and lung cancers, reducing proliferation, anchorage-independent growth, invasion, and tumor formation in xenografts [PMID:16436673, PMID:28975986, PMID:35578316]. It promotes cell death through two distinct C-terminal protein interactions: binding CPSF3 (residues 440–543) to drive its nuclear-to-cytoplasmic translocation and inhibit mRNA polyadenylation [PMID:18806823], and binding XIAP (residues 513–572) to relieve XIAP-mediated inhibition of caspase-9 and caspase-3, thereby activating apoptosis [PMID:22683311]. SCARA3 abundance is tightly controlled: SUMOylation at K582 triggers ubiquitination and degradation, which is antagonized by SENP1-mediated deSUMOylation to stabilize the protein and enhance its pro-death activity [PMID:29705808], while miR-650 post-transcriptionally represses SCARA3 by targeting its 3' UTR [PMID:25956032]. SCARA3 additionally restrains PI3K/AKT signaling via association with HPIP in hepatocellular carcinoma [PMID:28975986] and directs bone marrow mesenchymal stem cell fate toward osteogenesis over adipogenesis through Foxo1 and autophagy [PMID:34254370].","teleology":[{"year":1998,"claim":"Established SCARA3's founding identity and function: an oxidative-stress-inducible scavenger receptor-like gene that protects cells by depleting reactive oxygen species, answering what this novel gene does under cellular stress.","evidence":"Gene cloning with Northern blot induction and ROS measurement in overexpressing cells under oxidative stress","pmids":["9580669"],"confidence":"Medium","gaps":["Molecular mechanism of ROS scavenging not defined","No identified ligand or substrate for the scavenger-like domain","Single lab, single study"]},{"year":2006,"claim":"Showed SCARA3 is a functional tumor suppressor, reframing the stress-response gene as a growth-and-invasion suppressor relevant to cancer.","evidence":"Overexpression in DU145/PC3 prostate cancer lines (colony, soft agar, invasion), PC3 xenografts, and promoter methylation analysis of clinical samples","pmids":["16436673"],"confidence":"High","gaps":["Molecular mechanism of growth suppression not yet identified","Limited to prostate cancer models"]},{"year":2008,"claim":"Identified the first molecular effector mechanism for SCARA3-induced death: C-terminal binding to CPSF3 that relocalizes it from nucleus to cytoplasm and inhibits mRNA polyadenylation.","evidence":"Yeast two-hybrid, co-IP, subcellular fractionation, in vitro/in vivo polyadenylation assays, and binding-domain mutant rescue","pmids":["18806823"],"confidence":"High","gaps":["Which polyadenylation targets drive cell death not defined","Link between scavenger function and CPSF3 binding unresolved"]},{"year":2012,"claim":"Defined a second pro-death mechanism: C-terminal binding to XIAP that derepresses caspase-9 and caspase-3, directly connecting SCARA3 to apoptotic execution.","evidence":"Yeast two-hybrid, recombinant protein binding, co-IP, caspase activity assays, and reciprocal domain-mapping mutants of SCARA3 and XIAP","pmids":["22683311"],"confidence":"High","gaps":["How CPSF3 and XIAP mechanisms are coordinated not established","Conditions selecting one death pathway over the other unknown"]},{"year":2013,"claim":"Extended the cytoprotective role to myeloma, showing SCARA3 sets the threshold for oxidative-stress-induced killing and modulates chemotherapy/radiation sensitivity.","evidence":"Knockdown and overexpression in myeloma lines with dexamethasone/bortezomib treatment and viability assays","pmids":["23537707"],"confidence":"Medium","gaps":["Apparent tension between pro-survival (oxidative) and pro-death (tumor suppressor) roles not reconciled","Single lab"]},{"year":2014,"claim":"Linked SCARA3 to hypoxic signaling via interaction with NADPH-P450 reductase, broadening its stress-response role beyond ROS scavenging.","evidence":"Yeast two-hybrid, overexpression and siRNA in Hep3B cells, erythropoietin and HRE reporter assays under hypoxia","pmids":["24491563"],"confidence":"Medium","gaps":["Mechanism connecting NPR binding to HRE activity unresolved","Single lab, not independently confirmed"]},{"year":2015,"claim":"Established post-transcriptional control of SCARA3 by miR-650, explaining how its tumor-suppressor levels are downregulated in cancer.","evidence":"3' UTR luciferase reporter with target-site mutagenesis, miR-650 inhibitor, qRT-PCR, functional and cell-cycle assays, and xenograft","pmids":["25956032"],"confidence":"High","gaps":["Upstream regulation of miR-650 not addressed","Other regulatory miRNAs not surveyed"]},{"year":2017,"claim":"Defined a signaling mechanism in hepatocellular carcinoma: SCARA3 binds HPIP and suppresses PI3K/AKT activation to restrain proliferation and metastasis.","evidence":"Co-IP for SCARA3–HPIP, CRISPR-Cas9 knockout plus overexpression, proliferation/migration/invasion assays, Western blot for PI3K/AKT","pmids":["28975986"],"confidence":"Medium","gaps":["SCARA3–HPIP binding interface not mapped","Single Co-IP without reciprocal structural validation","Single lab"]},{"year":2018,"claim":"Revealed SUMO-dependent control of SCARA3 stability: SUMOylation at K582 drives degradation and SENP1 deSUMOylation rescues the protein to enhance its pro-death activity.","evidence":"IP-proteomics, GST pulldown, in vivo SUMOylation assay, CRISPR Senp1-/- and CSR1-/- cells, FACS apoptosis","pmids":["29705808"],"confidence":"High","gaps":["E3 ligase mediating ubiquitination not identified","SUMO E3 for K582 not defined"]},{"year":2021,"claim":"Uncovered a developmental role distinct from cancer: SCARA3 directs bone marrow mesenchymal stem cell fate toward osteogenesis via Foxo1 and autophagy flux.","evidence":"siRNA/overexpression in BMSCs, differentiation marker assays, Foxo1/autophagy readouts, AAV overexpression in OVX and aged mice with micro-CT/histology","pmids":["34254370"],"confidence":"High","gaps":["How SCARA3 promotes Foxo1 expression mechanistically unknown","Relationship to its cancer/death functions unclear"]},{"year":2022,"claim":"Generalized the tumor-suppressor and chemosensitization roles to lung cancer through AKT/JNK signaling and EMT suppression.","evidence":"Overexpression in lung cancer lines, viability and Transwell assays, Western blot for EMT and AKT/JNK, nude mouse xenograft","pmids":["35578316"],"confidence":"Medium","gaps":["Direct binding partner in lung cancer not identified","Mechanistic link to AKT/JNK indirect","Single lab"]},{"year":null,"claim":"How SCARA3's scavenger-receptor-like architecture and oxidative cytoprotection mechanistically integrate with its cytoplasmic protein-interaction-driven apoptosis, stem cell fate, and signaling functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the protein or its interaction domains","Ligand/substrate of the scavenger-like domain unknown","Reconciliation of pro-survival and pro-death roles not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,8]},{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,10]}],"complexes":[],"partners":["CPSF3","XIAP","SENP1","HPIP","POR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6AZY7","full_name":"Scavenger receptor class A member 3","aliases":["Cellular stress response gene protein"],"length_aa":606,"mass_kda":65.1,"function":"Seems to protect cells by scavenging oxidative molecules or harmful products of oxidation","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q6AZY7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCARA3","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/SCARA3","total_profiled":1310},"omim":[{"mim_id":"602728","title":"SCAVENGER RECEPTOR CLASS A, MEMBER 3; SCARA3","url":"https://www.omim.org/entry/602728"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SCARA3"},"hgnc":{"alias_symbol":["CSR1","CSR","MSLR1","APC7","MSRL1"],"prev_symbol":[]},"alphafold":{"accession":"Q6AZY7","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6AZY7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6AZY7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6AZY7-F1-predicted_aligned_error_v6.png","plddt_mean":69.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCARA3","jax_strain_url":"https://www.jax.org/strain/search?query=SCARA3"},"sequence":{"accession":"Q6AZY7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6AZY7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6AZY7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6AZY7"}},"corpus_meta":[{"pmid":"19804758","id":"PMC_19804758","title":"The Argonaute CSR-1 and its 22G-RNA cofactors are required for holocentric chromosome 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biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24491563","citation_count":5,"is_preprint":false},{"pmid":"38743783","id":"PMC_38743783","title":"A role for the C. elegans Argonaute protein CSR-1 in small nuclear RNA 3' processing.","date":"2024","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38743783","citation_count":4,"is_preprint":false},{"pmid":"34959071","id":"PMC_34959071","title":"HomA and HomB, outer membrane proteins of Helicobacter pylori down-regulate activation-induced cytidine deaminase (AID) and Ig switch germline transcription and thereby affect class switch recombination (CSR) of Ig genes in human B-cells.","date":"2021","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34959071","citation_count":4,"is_preprint":false},{"pmid":"37451358","id":"PMC_37451358","title":"Proteomic analysis reveals the global effect of the BarA/SirA-Csr regulatory cascade in Salmonella Typhimurium grown in conditions that favor the expression of invasion genes.","date":"2023","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/37451358","citation_count":3,"is_preprint":false},{"pmid":"9747040","id":"PMC_9747040","title":"Dinucleotide repeat polymorphism in the first intron of the CSR gene.","date":"1998","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9747040","citation_count":3,"is_preprint":false},{"pmid":"34586953","id":"PMC_34586953","title":"DICER-AS1 functions as competing endogenous RNA that targets CSR1 by sponging microRNA-650 and suppresses gastric cancer progression.","date":"2021","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/34586953","citation_count":2,"is_preprint":false},{"pmid":"37115273","id":"PMC_37115273","title":"The catE gene of Bacillus licheniformis M2-7 is essential for growth in benzopyrene, and its expression is regulated by the Csr system.","date":"2023","source":"World journal of microbiology & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/37115273","citation_count":2,"is_preprint":false},{"pmid":"24859866","id":"PMC_24859866","title":"Identification of a Csr system in Serratia marcescens 2170.","date":"2014","source":"The Journal of general and applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24859866","citation_count":2,"is_preprint":false},{"pmid":"34539493","id":"PMC_34539493","title":"Embedded Philanthropic CSR in Digital China: Unified View of Prosocial and Pro-environmental Practices.","date":"2021","source":"Frontiers in psychology","url":"https://pubmed.ncbi.nlm.nih.gov/34539493","citation_count":2,"is_preprint":false},{"pmid":"40902003","id":"PMC_40902003","title":"hnRNPL-CstF64 complex: coordinating CSR and LSR in IgH locus recombination dynamics through eRNA and NHEJ regulation.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/40902003","citation_count":1,"is_preprint":false},{"pmid":"27058659","id":"PMC_27058659","title":"CSR-1 Slices a Balance.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27058659","citation_count":1,"is_preprint":false},{"pmid":"37404138","id":"PMC_37404138","title":"Precisely Controlling Csr sRNA Levels by MshH Enhances Vibrio cholerae Colonization in Adult Mice.","date":"2023","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37404138","citation_count":1,"is_preprint":false},{"pmid":"38233172","id":"PMC_38233172","title":"Identification of the Csr global regulatory system mediated by small RNA decay in Aeromonas salmonicida.","date":"2024","source":"The Journal of general and applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38233172","citation_count":1,"is_preprint":false},{"pmid":"40044903","id":"PMC_40044903","title":"Dynamic and intricate regulation by the Csr sRNAs in the Arctic Pseudoalteromonas fuliginea.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/40044903","citation_count":1,"is_preprint":false},{"pmid":"22960639","id":"PMC_22960639","title":"Birthing histone mRNAs by CSR-1 section.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22960639","citation_count":1,"is_preprint":false},{"pmid":"36251222","id":"PMC_36251222","title":"Validation of the CSRFENCE score for prediction of febrile neutropenia during chemotherapy cycles 2-6.","date":"2022","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36251222","citation_count":1,"is_preprint":false},{"pmid":"40036504","id":"PMC_40036504","title":"Argonaute CSR-1A promotes H3K9me3 maintenance to protect somatic development in offspring.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/40036504","citation_count":1,"is_preprint":false},{"pmid":"39037215","id":"PMC_39037215","title":"Argonaute protein CSR-1 restricts localization of holocentromere protein HCP-3, the C. elegans CENP-A homolog.","date":"2024","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/39037215","citation_count":0,"is_preprint":false},{"pmid":"40540580","id":"PMC_40540580","title":"Regulation of MORC-1 is key to the CSR-1-mediated germline gene licensing mechanism in C. elegans.","date":"2025","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/40540580","citation_count":0,"is_preprint":false},{"pmid":"40194751","id":"PMC_40194751","title":"The class A scavenger receptor member 3 (SCARA3) regulates cell apoptosis through X-linked apoptosis inhibitory protein (XIAP) in turbot (Scophthalmus maximus L.).","date":"2025","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40194751","citation_count":0,"is_preprint":false},{"pmid":"40433387","id":"PMC_40433387","title":"Potentiating T cell tumor targeting using a combination of TCR with a Siglec-7 based CSR.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40433387","citation_count":0,"is_preprint":false},{"pmid":"38991453","id":"PMC_38991453","title":"Geraniol (GER) attenuated chronic sleep restriction (CSR)-induced neuroinflammation in adolescent mice.","date":"2024","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/38991453","citation_count":0,"is_preprint":false},{"pmid":"41784692","id":"PMC_41784692","title":"Fruit weight regulation by a paralog of Cell Size Regulator (CSR) in tomato and other crops.","date":"2026","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/41784692","citation_count":0,"is_preprint":false},{"pmid":"40838118","id":"PMC_40838118","title":"Requirement of CSR-1 isoforms and catalytic activity for C. elegans lifespan.","date":"2025","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/40838118","citation_count":0,"is_preprint":false},{"pmid":"37639776","id":"PMC_37639776","title":"Pediatric myasthenia gravis with a combination of AChR and RyR is associated with an earlier onset and lower CSR rate: A cohort study in southwest China.","date":"2023","source":"European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society","url":"https://pubmed.ncbi.nlm.nih.gov/37639776","citation_count":0,"is_preprint":false},{"pmid":"40035896","id":"PMC_40035896","title":"Characterization of Fibrinolytic Enzyme from Bacillus altitudinis S-CSR 0020 and Its Clot-Degrading Capacity.","date":"2025","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40035896","citation_count":0,"is_preprint":false},{"pmid":"36570639","id":"PMC_36570639","title":"CSR-brand relationship, brand positioning, and investment risks driven towards climate change mitigation and next perspectives emerging from: \"Litigation, projections, pathway, and models\".","date":"2022","source":"SN business & economics","url":"https://pubmed.ncbi.nlm.nih.gov/36570639","citation_count":0,"is_preprint":false},{"pmid":"41071819","id":"PMC_41071819","title":"The chitin synthase regulator CSR-3 promotes cellular integrity during cell-cell fusion in the filamentous ascomycete fungus Neurospora crassa.","date":"2025","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41071819","citation_count":0,"is_preprint":false},{"pmid":"40927343","id":"PMC_40927343","title":"Unveiling the dual-pathway effect of CSR perception environmental on employee pro-environmental behavior: evidence from Chinese marine enterprises.","date":"2025","source":"Frontiers in psychology","url":"https://pubmed.ncbi.nlm.nih.gov/40927343","citation_count":0,"is_preprint":false},{"pmid":"41676647","id":"PMC_41676647","title":"Modeling binding of the conserved Csr/Rsm protein family across species of the γ-proteobacteria reveals niche-specific adaptation of the post-transcriptional regulon.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41676647","citation_count":0,"is_preprint":false},{"pmid":"40886513","id":"PMC_40886513","title":"Sowing the seeds of happiness, personal values, and creative behavior: The role of CSR perception in hospitality services.","date":"2025","source":"Acta psychologica","url":"https://pubmed.ncbi.nlm.nih.gov/40886513","citation_count":0,"is_preprint":false},{"pmid":"41175488","id":"PMC_41175488","title":"Top management's green inclusive leadership and sustainable competitive advantage in manufacturing firms: The enabling role of internal CSR communication.","date":"2025","source":"Journal of environmental management","url":"https://pubmed.ncbi.nlm.nih.gov/41175488","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.04.677290","title":"Isolation of region-specific factors assembled on the Immunoglobulin heavy chain locus during antibody class switch recombination","date":"2025-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.04.677290","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.24.684368","title":"The nuclear role of methionine adenosyltransferase 2A in immunoglobulin class switch recombination","date":"2025-10-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.24.684368","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44804,"output_tokens":4095,"usd":0.097919,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10950,"output_tokens":3871,"usd":0.075762,"stage2_stop_reason":"end_turn"},"total_usd":0.173681,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers about the human/mammalian gene SCARA3 (also known as CSR1, CSR, MSLR1, MSRL1 — the macrophage scavenger receptor-like protein involved in oxidative stress response and tumor suppression).\n\nThe vast majority of papers are about completely different genes:\n- C. elegans Argonaute CSR-1 (RNAi pathway) — different gene\n- Bacterial CsrA/CsrB/CsrC regulatory systems — different genes\n- Candida Csr1 (zinc transcription factor) — different gene\n- Drosophila Csr (foraging behavior) — different gene\n- Yeast CSR1 (Sec14 homolog, YLR380W) — different gene\n- Class switch recombination (CSR) — different process/acronym\n- Various other CSR acronyms\n\nPapers about SCARA3/CSR1 (human scavenger receptor-like protein):\n- PMID:9580669 — original CSR discovery (Han et al. 1998)\n- PMID:16436673 — CSR1 tumor suppressor in prostate cancer (Yu et al. 2006)\n- PMID:18806823 — CSR1 induces cell death via CPSF3 (Zhu et al. 2008)\n- PMID:22683311 — CSR1 interacts with XIAP (Zheng et al. 2012)\n- PMID:23537707 — SCARA3 in multiple myeloma (Brown et al. 2013)\n- PMID:25956032 — miR-650 suppresses CSR1 (Zuo et al. 2015)\n- PMID:24491563 — CSR interacts with NPR in hypoxic response (Oguro et al. 2014)\n- PMID:29705808 — SUMOylation of CSR1 (Luo et al. 2018)\n- PMID:34254370 — Scara3 regulates BMSC fate via Foxo1 (Chen et al. 2021)\n- PMID:33318306 — SCARA3 in metabolic disorders (Peng et al. 2020)\n- PMID:35578316 — SCARA3 inhibits proliferation via AKT in lung cancer (Kim et al. 2022)\n- PMID:28975986 — CSR1 suppresses HCC via HPIP (Jiang et al. 2017)\n- PMID:9747040 — CSR gene polymorphism (Han & Nakamura 1998)\n- PMID:40194751 — SmSCARA3 in turbot (fish ortholog study)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"CSR (SCARA3) was identified as a novel macrophage scavenger receptor-like gene whose transcription is strongly induced in normal fibroblasts by UV irradiation or hydrogen peroxide. Overexpression of CSR in cells caused significant depletion of reactive oxygen species under oxidative stress conditions, indicating the CSR protein protects cells by scavenging oxidative molecules or harmful products of oxidation.\",\n      \"method\": \"Gene cloning, Northern blot for expression induction, and ROS measurement in CSR-overexpressing cells under oxidative stress\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression experiment with defined ROS readout, single lab, single study\",\n      \"pmids\": [\"9580669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CSR1 (SCARA3) functions as a tumor suppressor in prostate cancer. Forced expression of CSR1 in prostate cancer cell lines DU145 and PC3 caused 2–3 fold decrease in colony formation, 10-fold reduction in anchorage-independent growth, and 3-fold decrease in invasion in vitro. In xenograft models, CSR1 expression in PC3 cells produced >8-fold reduction in tumor size and abolished invasion and mortality.\",\n      \"method\": \"Overexpression in prostate cancer cell lines (colony formation, soft agar, invasion assays), PC3 xenograft mouse model, methylation analysis of CSR1 promoter in clinical samples\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays (in vitro growth, invasion, in vivo xenograft) with consistent results, single lab\",\n      \"pmids\": [\"16436673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CSR1 induces cell death by directly binding to CPSF3 (cleavage and polyadenylation-specific factor 3) via its C-terminus (amino acids 440–543). This interaction causes translocation of CPSF3 from the nucleus to the cytoplasm, resulting in inhibition of mRNA polyadenylation both in vitro and in vivo. A CSR1 mutant unable to bind CPSF3 did not alter CPSF3 subcellular distribution, did not inhibit polyadenylation, and did not induce cell death.\",\n      \"method\": \"Yeast two-hybrid screen of prostate cDNA library, co-immunoprecipitation, subcellular fractionation/localization, in vitro and in vivo polyadenylation assays, CSR1 binding-domain mutant analysis, siRNA knockdown of CPSF3\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — yeast two-hybrid discovery confirmed by co-IP, functional mutant rescue, in vitro and in vivo activity assays, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"18806823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CSR1 interacts with X-linked Inhibitor of Apoptosis Protein (XIAP) via its C-terminus (amino acids 513–572). Binding of CSR1 to XIAP prevents XIAP from inhibiting caspase-9 and caspase-3, thereby enhancing their protease activities and accelerating cell death. A CSR1 mutant that cannot bind XIAP did not activate caspases or induce cell death; a XIAP mutant that cannot interact with caspase-9 also abolished CSR1-induced cell death.\",\n      \"method\": \"Yeast two-hybrid screening, in vitro recombinant protein-binding analyses, Co-IP, caspase-9 and caspase-3 activity assays, XIAP knockdown (siRNA), XIAP overexpression, domain-mapping mutants\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — yeast two-hybrid discovery, in vitro binding confirmation, functional mutant analysis, caspase activity assays; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"22683311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SCARA3 expression is induced in multiple myeloma cells upon treatment with oxidative stressors (ionizing radiation and chemotherapeutic drugs). SCARA3 protects myeloma cells against oxidative stress-induced cell killing; SCARA3 knockdown sensitized myeloma cells to dexamethasone and bortezomib, while SCARA3 upregulation inhibited their cytotoxic effects.\",\n      \"method\": \"SCARA3 knockdown and overexpression in myeloma cell lines, drug treatment (dexamethasone, bortezomib), cell viability assays, epigenetic inactivation analysis\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined drug-response phenotype, single lab, two complementary approaches\",\n      \"pmids\": [\"23537707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CSR (SCARA3) interacts with NADPH-P450 reductase (NPR) and acts as a new regulator of the hypoxic response. Overexpression of CSR enhanced induction of erythropoietin and hypoxia response element (HRE) activity under hypoxia in Hep3B cells, while knockdown of CSR suppressed these responses.\",\n      \"method\": \"Yeast two-hybrid identification of CSR-NPR interaction, overexpression and siRNA knockdown of CSR in Hep3B cells, erythropoietin and HRE reporter assays under hypoxia\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus gain- and loss-of-function with defined hypoxia readout, single lab\",\n      \"pmids\": [\"24491563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-650 suppresses CSR1 (SCARA3) expression by directly targeting a site in the 3' UTR of CSR1 mRNA. Inhibition of miR-650 in prostate cancer cells increased CSR1 expression levels, suppressed colony formation, and blocked S-phase cell cycle entry. Mutation of the miR-650 target site in the CSR1 3' UTR completely abrogated miR-650's regulatory activity.\",\n      \"method\": \"Luciferase reporter assay with CSR1 3' UTR, 3' UTR target-site mutagenesis, miR-650 inhibitor treatment, qRT-PCR, colony formation and cell cycle assays, xenograft mouse model\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct target validation by luciferase reporter with site mutagenesis, functional rescue, in vivo xenograft confirmation; multiple orthogonal methods\",\n      \"pmids\": [\"25956032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CSR1 (SCARA3) suppresses tumor growth and metastasis in hepatocellular carcinoma (HCC) by directly associating with hematopoietic PBX interacting protein (HPIP) and inhibiting downstream PI3K/AKT pathway activation. Overexpression of CSR1 inhibited HCC cell proliferation, migration, and invasion; CRISPR-Cas9 knockout of CSR1 had the opposite effects.\",\n      \"method\": \"Co-immunoprecipitation assay (CSR1–HPIP interaction), CRISPR-Cas9 knockout, overexpression, MTT proliferation assay, scratch wound and Matrigel invasion assays, Western blot for PI3K/AKT pathway\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for binding partner, CRISPR KO plus overexpression with defined cellular phenotype, pathway readout; single lab\",\n      \"pmids\": [\"28975986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CSR1 (SCARA3) is SUMOylated at lysine 582 and subsequently rapidly ubiquitinated and degraded in prostate cancer cells. SENP1, a SUMO-specific protease, interacts with and deSUMOylates CSR1, preventing its degradation and enhancing CSR1-dependent prostate cancer cell death.\",\n      \"method\": \"Immunoprecipitation-based proteomics screen, GST pulldown assay, in vivo SUMOylation assay, CRISPR-based generation of Senp1-/- and CSR1-/- cells, FACS apoptosis assay\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct SUMOylation site identification, GST pulldown for SENP1–CSR1 interaction, in vivo SUMOylation assay, CRISPR KO functional validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"29705808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Scara3 regulates the fate switch of bone marrow mesenchymal stem cells (BMSCs) between osteoblast and adipocyte differentiation by promoting Foxo1 expression and autophagy flux. Deletion of Scara3 favored adipogenesis over osteogenesis, while overexpression promoted osteogenesis at the expense of adipogenesis. In vivo, adeno-associated virus-mediated Scara3 overexpression in bone marrow promoted bone formation and reduced bone marrow fat accumulation in ovariectomized and aged mice.\",\n      \"method\": \"siRNA knockdown and overexpression in BMSCs, qPCR and Western blot for differentiation markers, cell staining (Oil Red O, Alizarin Red), Western blot and immunofluorescence for Foxo1 and autophagy, intra-bone marrow AAV injection in OVX and aged mice, micro-CT and histology\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss- and gain-of-function in vitro plus in vivo AAV overexpression with mechanistic pathway (Foxo1/autophagy) identification; multiple orthogonal methods\",\n      \"pmids\": [\"34254370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Overexpression of SCARA3 in lung cancer cells inhibited proliferation, migration, and invasion, reduced EMT markers (β-catenin, vimentin, MMP9), and enhanced sensitivity to cisplatin via the AKT and JNK signaling pathways. The anti-tumor effects were confirmed in a mouse xenograft model.\",\n      \"method\": \"SCARA3 overexpression in lung cancer cell lines, cell viability assay, Transwell migration/invasion, Western blot for EMT markers and AKT/JNK pathway, BALB/C nude mouse xenograft\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined phenotype (proliferation, EMT markers, signaling pathway) in vitro and in vivo, single lab\",\n      \"pmids\": [\"35578316\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCARA3 (CSR1) is a macrophage scavenger receptor-like transmembrane protein that protects cells from oxidative stress by scavenging reactive oxygen species; it functions as a tumor suppressor by inducing cell death through at least two mechanisms — (1) binding CPSF3 via its C-terminus to sequester it in the cytoplasm and inhibit mRNA polyadenylation, and (2) binding XIAP to prevent XIAP-mediated caspase-9/3 inhibition, thereby activating apoptosis; CSR1 protein stability is regulated by SUMOylation at K582 (which promotes ubiquitination and degradation) and by SENP1-mediated deSUMOylation; CSR1 expression is post-transcriptionally suppressed by miR-650 targeting its 3' UTR; and SCARA3 additionally controls bone marrow mesenchymal stem cell fate toward osteogenesis via Foxo1 and autophagy, and suppresses the PI3K/AKT pathway in hepatocellular carcinoma through interaction with HPIP.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCARA3 (CSR1) is a macrophage scavenger receptor-like protein originally identified as a stress-inducible cytoprotective factor whose transcription is strongly induced by UV irradiation and hydrogen peroxide and whose overexpression depletes reactive oxygen species under oxidative stress [#0], a protective role recapitulated in myeloma cells where SCARA3 buffers oxidative damage and modulates sensitivity to dexamethasone and bortezomib [#4]. Beyond cytoprotection, SCARA3 acts as a tumor suppressor across prostate, hepatocellular, and lung cancers, reducing proliferation, anchorage-independent growth, invasion, and tumor formation in xenografts [#1, #7, #10]. It promotes cell death through two distinct C-terminal protein interactions: binding CPSF3 (residues 440–543) to drive its nuclear-to-cytoplasmic translocation and inhibit mRNA polyadenylation [#2], and binding XIAP (residues 513–572) to relieve XIAP-mediated inhibition of caspase-9 and caspase-3, thereby activating apoptosis [#3]. SCARA3 abundance is tightly controlled: SUMOylation at K582 triggers ubiquitination and degradation, which is antagonized by SENP1-mediated deSUMOylation to stabilize the protein and enhance its pro-death activity [#8], while miR-650 post-transcriptionally represses SCARA3 by targeting its 3' UTR [#6]. SCARA3 additionally restrains PI3K/AKT signaling via association with HPIP in hepatocellular carcinoma [#7] and directs bone marrow mesenchymal stem cell fate toward osteogenesis over adipogenesis through Foxo1 and autophagy [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established SCARA3's founding identity and function: an oxidative-stress-inducible scavenger receptor-like gene that protects cells by depleting reactive oxygen species, answering what this novel gene does under cellular stress.\",\n      \"evidence\": \"Gene cloning with Northern blot induction and ROS measurement in overexpressing cells under oxidative stress\",\n      \"pmids\": [\"9580669\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism of ROS scavenging not defined\", \"No identified ligand or substrate for the scavenger-like domain\", \"Single lab, single study\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed SCARA3 is a functional tumor suppressor, reframing the stress-response gene as a growth-and-invasion suppressor relevant to cancer.\",\n      \"evidence\": \"Overexpression in DU145/PC3 prostate cancer lines (colony, soft agar, invasion), PC3 xenografts, and promoter methylation analysis of clinical samples\",\n      \"pmids\": [\"16436673\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism of growth suppression not yet identified\", \"Limited to prostate cancer models\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the first molecular effector mechanism for SCARA3-induced death: C-terminal binding to CPSF3 that relocalizes it from nucleus to cytoplasm and inhibits mRNA polyadenylation.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, subcellular fractionation, in vitro/in vivo polyadenylation assays, and binding-domain mutant rescue\",\n      \"pmids\": [\"18806823\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Which polyadenylation targets drive cell death not defined\", \"Link between scavenger function and CPSF3 binding unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a second pro-death mechanism: C-terminal binding to XIAP that derepresses caspase-9 and caspase-3, directly connecting SCARA3 to apoptotic execution.\",\n      \"evidence\": \"Yeast two-hybrid, recombinant protein binding, co-IP, caspase activity assays, and reciprocal domain-mapping mutants of SCARA3 and XIAP\",\n      \"pmids\": [\"22683311\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How CPSF3 and XIAP mechanisms are coordinated not established\", \"Conditions selecting one death pathway over the other unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the cytoprotective role to myeloma, showing SCARA3 sets the threshold for oxidative-stress-induced killing and modulates chemotherapy/radiation sensitivity.\",\n      \"evidence\": \"Knockdown and overexpression in myeloma lines with dexamethasone/bortezomib treatment and viability assays\",\n      \"pmids\": [\"23537707\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Apparent tension between pro-survival (oxidative) and pro-death (tumor suppressor) roles not reconciled\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked SCARA3 to hypoxic signaling via interaction with NADPH-P450 reductase, broadening its stress-response role beyond ROS scavenging.\",\n      \"evidence\": \"Yeast two-hybrid, overexpression and siRNA in Hep3B cells, erythropoietin and HRE reporter assays under hypoxia\",\n      \"pmids\": [\"24491563\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism connecting NPR binding to HRE activity unresolved\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established post-transcriptional control of SCARA3 by miR-650, explaining how its tumor-suppressor levels are downregulated in cancer.\",\n      \"evidence\": \"3' UTR luciferase reporter with target-site mutagenesis, miR-650 inhibitor, qRT-PCR, functional and cell-cycle assays, and xenograft\",\n      \"pmids\": [\"25956032\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Upstream regulation of miR-650 not addressed\", \"Other regulatory miRNAs not surveyed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a signaling mechanism in hepatocellular carcinoma: SCARA3 binds HPIP and suppresses PI3K/AKT activation to restrain proliferation and metastasis.\",\n      \"evidence\": \"Co-IP for SCARA3–HPIP, CRISPR-Cas9 knockout plus overexpression, proliferation/migration/invasion assays, Western blot for PI3K/AKT\",\n      \"pmids\": [\"28975986\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"SCARA3–HPIP binding interface not mapped\", \"Single Co-IP without reciprocal structural validation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed SUMO-dependent control of SCARA3 stability: SUMOylation at K582 drives degradation and SENP1 deSUMOylation rescues the protein to enhance its pro-death activity.\",\n      \"evidence\": \"IP-proteomics, GST pulldown, in vivo SUMOylation assay, CRISPR Senp1-/- and CSR1-/- cells, FACS apoptosis\",\n      \"pmids\": [\"29705808\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"E3 ligase mediating ubiquitination not identified\", \"SUMO E3 for K582 not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a developmental role distinct from cancer: SCARA3 directs bone marrow mesenchymal stem cell fate toward osteogenesis via Foxo1 and autophagy flux.\",\n      \"evidence\": \"siRNA/overexpression in BMSCs, differentiation marker assays, Foxo1/autophagy readouts, AAV overexpression in OVX and aged mice with micro-CT/histology\",\n      \"pmids\": [\"34254370\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How SCARA3 promotes Foxo1 expression mechanistically unknown\", \"Relationship to its cancer/death functions unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized the tumor-suppressor and chemosensitization roles to lung cancer through AKT/JNK signaling and EMT suppression.\",\n      \"evidence\": \"Overexpression in lung cancer lines, viability and Transwell assays, Western blot for EMT and AKT/JNK, nude mouse xenograft\",\n      \"pmids\": [\"35578316\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct binding partner in lung cancer not identified\", \"Mechanistic link to AKT/JNK indirect\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SCARA3's scavenger-receptor-like architecture and oxidative cytoprotection mechanistically integrate with its cytoplasmic protein-interaction-driven apoptosis, stem cell fate, and signaling functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of the protein or its interaction domains\", \"Ligand/substrate of the scavenger-like domain unknown\", \"Reconciliation of pro-survival and pro-death roles not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CPSF3\", \"XIAP\", \"SENP1\", \"HPIP\", \"POR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}