{"gene":"RBMS3","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2007,"finding":"RBMS3 binds sequence-specifically to a 60-nt element located 1946 nt 3' of the stop codon in the Prx1 mRNA 3'UTR, stabilizing Prx1 mRNA, increasing its half-life, and thereby enhancing Prx1 protein synthesis and downstream collagen alpha1(I) expression in hepatic stellate cells.","method":"RNA immunoprecipitation followed by differential display to identify Prx1 mRNA as an RBMS3 target; reporter mRNA assays with and without the RBMS3 binding site; ectopic expression of RBMS3 in quiescent HSCs","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal RIP, sequence-specific binding site mapped, reporter assays with and without binding site, functional rescue in primary cells; single lab but multiple orthogonal methods","pmids":["17586524"],"is_preprint":false},{"year":2012,"finding":"Rbms3 (zebrafish ortholog) is transiently expressed in the cytoplasm of condensing cranial neural crest cells in pharyngeal arches; it stabilizes a reporter transcript containing the smad2 3'UTR, RNA immunoprecipitation shows enrichment for smad2/3 mRNAs, and rbms3 morphants display reduced pSmad2 levels, placing Rbms3 as a post-transcriptional positive regulator of TGF-β/Smad2/3 signaling required for chondrogenesis.","method":"Zebrafish protein-trap screen for localization; morpholino knockdown phenotype; RNA immunoprecipitation (RIP) with full-length Rbms3; reporter assay with smad2 3'UTR; pSmad2 immunoblotting in morphants","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RIP, reporter assay, morphant phenotype with signaling readout (pSmad2), live imaging for localization; multiple orthogonal methods in single study","pmids":["23091072"],"is_preprint":false},{"year":2012,"finding":"Rbms3 binds to the 3'UTR of Ptf1a mRNA (but not Pdx1 3'UTR) and stimulates translation of a reporter bearing the Ptf1a 3'UTR; knockdown of Rbms3 in AR42J-B13 pancreatic exocrine cells reduces Ptf1a expression, indicating RBMS3 post-transcriptionally promotes Ptf1a protein production during pancreas development.","method":"Differential screening assay for expression; RNA-binding assay (3'UTR binding specificity); reporter translation assay; siRNA knockdown of Rbms3 in AR42J-B13 cells with Ptf1a protein/mRNA readout","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter translation assay plus knockdown; single lab, two orthogonal methods","pmids":["22372950"],"is_preprint":false},{"year":2012,"finding":"RBMS3 tumor-suppressive function in nasopharyngeal carcinoma is mechanistically linked to: (a) G1/S cell cycle arrest via upregulation of p53 and p21 and downregulation of cyclin E and CDK2 with inhibition of Rb-Ser780 phosphorylation; (b) pro-apoptotic activity through mitochondrial pathway activation (caspase-9, PARP); and (c) inhibition of angiogenesis associated with downregulation of MMP2, β-catenin, and downstream targets cyclin-D1, c-Myc, MMP7, MMP9.","method":"Overexpression and RNAi suppression in NPC cell lines; cell cycle analysis; immunoblotting for p53, p21, cyclin E, CDK2, Rb phosphorylation, caspase-9, PARP, MMP2, β-catenin, cyclin-D1, c-Myc, MMP7, MMP9; microvessel formation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression/knockdown with multiple molecular readouts; single lab, multiple orthogonal assays","pmids":["22957092"],"is_preprint":false},{"year":2018,"finding":"RBMS3 directly binds (via CLIP-seq and RIP/EMSA) and stabilizes the mRNAs of multiple Wnt/β-catenin negative regulators — DKK3, AXIN1, BACH1, and NFAT5 — thereby inhibiting β-catenin/CBP signaling; this activity is competed by miR-126-5p, which otherwise represses these same transcripts. Loss of RBMS3 thus activates β-catenin/CBP signaling and confers platinum resistance in epithelial ovarian cancer.","method":"CLIP-seq, RNA immunoprecipitation (RIP), electrophoretic mobility shift assay (EMSA), immunoblotting, immunofluorescence, clone formation and Annexin V apoptosis assays in vitro; intraperitoneal tumor model in vivo","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — CLIP-seq plus RIP plus EMSA directly identify binding targets; functional rescue with pathway inhibitor in vivo; multiple orthogonal methods in single study","pmids":["30279231"],"is_preprint":false},{"year":2019,"finding":"RBMS3 directly binds the 3'UTR of Twist1 mRNA (confirmed by RNA immunoprecipitation and luciferase reporter assay), negatively regulating Twist1 expression and thereby reducing Twist1-induced MMP2 expression, migration, invasion, and lung metastasis of breast cancer cells.","method":"RNA immunoprecipitation (RIP), luciferase reporter assay with Twist1 3'UTR, Transwell migration/invasion assays, in vivo lung metastasis assay, transcriptome sequencing","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal RIP and reporter assay confirm direct 3'UTR binding; single lab, two orthogonal methods","pmids":["30819235"],"is_preprint":false},{"year":2021,"finding":"RBMS3 interacts with the mRNA of the EMT transcription factor PRRX1 and promotes PRRX1 mRNA stability; PRRX1 is required for RBMS3-mediated EMT and partially rescues RBMS3 knockdown phenotypes in triple-negative breast cancer cells. RBMS3 is sufficient to induce EMT in immortalized mammary epithelial cells and necessary for maintaining the mesenchymal phenotype and invasion/migration in TNBC.","method":"Genome-wide mRNA stability assay (actinomycin D transcriptional blockade), RIP demonstrating RBMS3 interaction with PRRX1 mRNA, PRRX1 rescue experiments, in vivo spontaneous metastasis model, loss-of-function RBMS3 knockdown","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide stability screen plus RIP plus genetic rescue in vitro and in vivo; multiple orthogonal methods in single study","pmids":["34608266"],"is_preprint":false},{"year":2022,"finding":"RBMS3 silencing cooperates with BRAFV600E to promote malignant lung tumorigenesis; RBMS3-null BRAFV600E lung tumors show elevated Ctnnb1, Ccnd1, Axin2, Lgr5, and c-Myc mRNAs, indicating RBMS3 suppresses the WNT/β-catenin signaling axis in lung cancer. RBMS3Null tumors are resistant to dabrafenib plus trametinib but sensitive to porcupine inhibition.","method":"Sleeping Beauty transposon mutagenesis screen in BRAFV600E GEM model; CRISPR/Cas9 RBMS3 knockout; lung organoid growth assay; GEM in vivo tumor development; qRT-PCR for Wnt target genes; drug treatment (dabrafenib+trametinib, porcupine inhibitor)","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — transposon screen plus CRISPR validation plus GEM in vivo models plus molecular pathway readout; multiple orthogonal methods with in vivo confirmation","pmids":["36112789"],"is_preprint":false},{"year":2022,"finding":"RBMS3 stabilizes CD274 (PD-L1) mRNA by interacting with its 3'UTR in TNBC cells, thereby increasing PD-L1 protein levels; RBMS3 depletion destabilizes CD274 mRNA and reduces PD-L1 expression, suppressing immune evasion.","method":"RIP demonstrating RBMS3 binding to CD274 mRNA 3'UTR; mRNA stability assays; immunoblotting for PD-L1; RBMS3 knockdown in MDA-MB-231 cells; in vivo T-cell immunity assays with RBMS3 ablation plus auranofin","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus mRNA stability assay confirm direct binding and stabilization; in vivo functional validation; single lab","pmids":["36414028"],"is_preprint":false},{"year":2023,"finding":"RBMS3 is a downstream effector of the LKB1/AMPK pathway: activation of AMPK promotes RBMS3 expression, and RBMS3 mediates AMPK's inhibitory effects on lung cancer cell invasion and migration; inhibiting RBMS3 reverses AMPK agonist-induced suppression of invasion.","method":"Immunohistochemistry for RBMS3/LKB1 co-expression in lung cancer tissues; AMPK agonist/inhibitor treatment in lung cancer cell lines; RBMS3 knockdown rescue of AMPK-mediated invasion inhibition; Transwell migration/invasion assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological epistasis (AMPK agonist/inhibitor + RBMS3 KD) with functional rescue; single lab, pathway placement via genetic/chemical epistasis","pmids":["37781074"],"is_preprint":false},{"year":2024,"finding":"RBMS3 modulates the stability of LIMS1 mRNA in colon cancer cells; knockdown of LIMS1 rescues the inhibitory effect of RBMS3 overexpression on colon cancer cell proliferation, migration, and invasion, placing LIMS1 downstream of RBMS3.","method":"RBMS3 overexpression and knockdown in colon cancer cells; mRNA stability assays for LIMS1; RIP (implied by 'molecular biology methods'); LIMS1 knockdown rescue experiment; animal xenograft models","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability assay plus genetic rescue (LIMS1 KD reversal); single lab, two orthogonal methods","pmids":["38618967"],"is_preprint":false},{"year":2025,"finding":"RBMS3 physically recruits the ubiquitin E3 ligase TRIM21 to ANGPT2 protein in an RNA-independent manner, facilitating K48-linked polyubiquitination and proteasomal degradation of ANGPT2; loss of RBMS3 in HCC prevents this ubiquitination, leading to ANGPT2 accumulation, increased angiogenesis, and sorafenib resistance.","method":"Immunoprecipitation mass spectrometry (IP-MS) and co-immunoprecipitation (co-IP) to identify RBMS3–TRIM21–ANGPT2 complex; K48-ubiquitination assays; RBMS3 overexpression/knockdown with ANGPT2 protein level and secretion readouts; RNA-independence confirmed; in vitro and in vivo functional assays; ANGPT2 antibody combination rescue","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — IP-MS plus co-IP plus K48-ubiquitination biochemical assay confirm RNA-independent protein complex and ubiquitination mechanism; functional in vivo rescue; multiple orthogonal methods","pmids":["40069332"],"is_preprint":false},{"year":2025,"finding":"RBMS3 forms a protein complex with ELAVL1 and UPF1; RBMS3 reduces ELAVL1 mRNA stability at the post-transcriptional level, leading to downregulation of downstream VEGF-A and IL-6; restoring ELAVL1 reverses RBMS3-mediated suppression of angiogenesis, invasion, and STAT3 phosphorylation in ovarian cancer. Additionally, RBMS3 inhibits UPF1 methylation (functional consequences not yet fully characterized).","method":"Immunoprecipitation, immunofluorescence, mRNA stability assays, methylation assays, Western blotting, angiogenesis and migration assays in vitro, in vivo nude mouse tumor models, ELAVL1 rescue experiments","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifies RBMS3–ELAVL1–UPF1 complex; mRNA stability assay confirms ELAVL1 mRNA destabilization; genetic rescue (ELAVL1 re-expression) confirms pathway; single lab","pmids":["42002122"],"is_preprint":false},{"year":2025,"finding":"RBMS3 regulates TXNIP mRNA stability as a metastasis-suppressive mechanism in breast cancer; RBMS3 depletion destabilizes TXNIP transcripts, and in vivo epistasis studies confirm that RBMS3 suppression of metastasis is mediated through TXNIP mRNA stabilization.","method":"Genome-wide mRNA stability measurements across breast cancer models; deep-learning RBP regulon inference (GreyHound); RBMS3 knockdown with TXNIP mRNA stability readout; in vivo epistasis (xenograft models with RBMS3 depletion and TXNIP manipulation)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mRNA stability profiling plus in vivo epistasis; preprint, not yet peer-reviewed; single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"RBMS3 acts downstream of miRNA-21a-5p: miR-21a-5p targets RBMS3 (validated by dual luciferase reporter), and suppression of RBMS3 reverses miR-21a-5p knockdown-mediated inhibition of angiogenesis after transient ischemic attack. RBMS3 modulation of angiogenesis in this context is linked to the TGFBR1/SMAD2/3 pathway downstream.","method":"Dual luciferase reporter assay validating miR-21a-5p binding to RBMS3; adeno-associated virus-mediated RBMS3 knockdown in TIA mouse model; in vitro OGD/reoxygenation model; angiogenesis readouts; TGFBR1/SMAD2/3 pathway analysis","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirms direct miR-21a-5p/RBMS3 interaction; in vivo AAV knockdown with pathway rescue; single lab, two orthogonal methods","pmids":["40820584"],"is_preprint":false},{"year":2025,"finding":"Rbms3 upregulation in mesenchymal stem cells under T2DM conditions impairs osteogenic differentiation and fracture healing by modulating the MAPK signaling pathway, as demonstrated by in vitro transduction experiments and in vivo micro-CT/histological analysis.","method":"scRNA-seq and transcriptomic integration; lentiviral Rbms3 overexpression/knockdown in MSCs; ALP staining, ARS, qPCR, Western blotting for osteogenic markers and MAPK pathway components; in vivo fracture healing model with micro-CT and histological staining","journal":"Journal of inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with MAPK pathway readout in vitro and in vivo; single lab, multiple methods","pmids":["40718133"],"is_preprint":false}],"current_model":"RBMS3 is an RNA-binding protein that acts predominantly as a post-transcriptional regulator: it binds 3'UTRs of specific target mRNAs (including Prx1, Smad2/3, Ptf1a, Twist1, PRRX1, TXNIP, DKK3, AXIN1, BACH1, NFAT5, CD274/PD-L1, ELAVL1, and LIMS1) to modulate their stability or translation, thereby suppressing EMT, the Wnt/β-catenin axis, and pro-tumorigenic signaling; in addition, RBMS3 can function in an RNA-independent manner by recruiting the E3 ubiquitin ligase TRIM21 to promote K48-linked ubiquitination and degradation of ANGPT2, placing it as a dual-mode regulator acting both post-transcriptionally and post-translationally."},"narrative":{"mechanistic_narrative":"RBMS3 is a sequence-specific RNA-binding protein that acts as a post-transcriptional regulator of gene expression by binding the 3'UTRs of target mRNAs to control their stability and translation [PMID:17586524, PMID:30279231, PMID:34608266]. Its earliest characterized activity is mRNA stabilization: it binds a defined element in the Prx1 3'UTR to extend transcript half-life and drive Prx1-dependent collagen expression in hepatic stellate cells [PMID:17586524], and analogous 3'UTR binding stabilizes smad2/3 transcripts to support TGF-β/Smad2/3 signaling during chondrogenesis and stimulates Ptf1a translation during pancreatic development [PMID:23091072, PMID:22372950]. In cancer, RBMS3 functions predominantly as a tumor suppressor by stabilizing transcripts encoding negative regulators of the Wnt/β-catenin axis—DKK3, AXIN1, BACH1, and NFAT5—thereby restraining β-catenin/CBP signaling, an activity antagonized by miR-126-5p [PMID:30279231], and by suppressing the same axis in BRAFV600E-driven lung tumors [PMID:36112789]. It additionally limits EMT and metastasis by destabilizing or restraining EMT effectors and metastasis-linked transcripts including Twist1, PRRX1, and TXNIP [PMID:30819235, PMID:34608266]. Beyond its RNA-dependent roles, RBMS3 also acts post-translationally: it physically recruits the E3 ubiquitin ligase TRIM21 to ANGPT2 in an RNA-independent manner to promote K48-linked polyubiquitination and proteasomal degradation, restraining angiogenesis [PMID:40069332]. RBMS3 is itself positioned downstream of upstream regulatory inputs, being induced by LKB1/AMPK signaling and targeted by miR-21a-5p [PMID:37781074, PMID:40820584].","teleology":[{"year":2007,"claim":"Established that RBMS3 is a sequence-specific 3'UTR-binding protein that stabilizes a target mRNA, defining its core molecular activity.","evidence":"RIP/differential display identifying Prx1 mRNA, reporter assays with and without the mapped binding site, and ectopic expression in primary hepatic stellate cells","pmids":["17586524"],"confidence":"High","gaps":["Mechanism of stabilization (decay machinery engaged) not defined","Generality of the 60-nt binding element to other targets unknown"]},{"year":2012,"claim":"Showed RBMS3 acts in developmental signaling by stabilizing smad2/3 transcripts and promoting Ptf1a translation, extending its role from stabilization to translational control in distinct tissues.","evidence":"Zebrafish protein-trap localization, morpholino knockdown with pSmad2 readout, RIP and 3'UTR reporter assays; separately, 3'UTR binding specificity and reporter translation assays in pancreatic exocrine cells","pmids":["23091072","22372950"],"confidence":"High","gaps":["How RBMS3 distinguishes stabilization versus translational stimulation among targets is unresolved","Direct binding partners mediating these outputs not identified"]},{"year":2012,"claim":"Linked RBMS3 to tumor suppression through cell-cycle arrest, apoptosis, and anti-angiogenic phenotypes, broadening its physiological significance.","evidence":"Overexpression/RNAi in nasopharyngeal carcinoma lines with cell-cycle analysis, immunoblotting of p53/p21/cyclin E/CDK2/β-catenin targets, and microvessel assays","pmids":["22957092"],"confidence":"Medium","gaps":["Phenotypes are correlative; direct mRNA targets driving these outputs not mapped","Whether β-catenin downregulation is post-transcriptional unaddressed at this stage"]},{"year":2018,"claim":"Defined the mechanism by which RBMS3 restrains Wnt/β-catenin signaling: direct stabilization of multiple negative regulator mRNAs, with competition by miR-126-5p.","evidence":"CLIP-seq, RIP, and EMSA mapping direct binding to DKK3/AXIN1/BACH1/NFAT5; in vitro functional assays and intraperitoneal tumor model with pathway inhibitor rescue","pmids":["30279231"],"confidence":"High","gaps":["Relative contribution of each target transcript not dissected","Structural basis of multi-target recognition unknown"]},{"year":2019,"claim":"Demonstrated RBMS3 negatively regulates the EMT transcription factor Twist1 via direct 3'UTR binding, connecting RBMS3 to metastasis suppression.","evidence":"Reciprocal RIP, luciferase reporter with Twist1 3'UTR, Transwell assays, and in vivo lung metastasis model in breast cancer","pmids":["30819235"],"confidence":"Medium","gaps":["Whether RBMS3 destabilizes versus represses translation of Twist1 not clarified","Single-lab validation"]},{"year":2021,"claim":"Showed RBMS3 controls the EMT program through PRRX1 mRNA stability and can both induce and maintain mesenchymal states, refining its context-dependent role.","evidence":"Genome-wide mRNA stability profiling, RIP for PRRX1 mRNA, PRRX1 genetic rescue, and in vivo spontaneous metastasis model in TNBC","pmids":["34608266"],"confidence":"High","gaps":["Reconciling EMT-promoting activity here with metastasis-suppressive roles elsewhere remains open","Determinants of cell-context-specific output not defined"]},{"year":2022,"claim":"Validated RBMS3 as a Wnt/β-catenin suppressor and tumor suppressor in vivo, and identified RBMS3 loss as conferring resistance to BRAF/MEK inhibition but sensitivity to porcupine inhibition.","evidence":"Sleeping Beauty transposon screen, CRISPR knockout, lung organoid and GEM models, qRT-PCR of Wnt targets, and drug treatments","pmids":["36112789"],"confidence":"High","gaps":["Direct mRNA targets mediating Wnt suppression in lung not mapped in this system","Mechanism connecting RBMS3 loss to drug resistance not biochemically resolved"]},{"year":2022,"claim":"Revealed a context where RBMS3 stabilizes a pro-tumorigenic transcript (CD274/PD-L1), showing its 3'UTR-stabilization activity is not uniformly tumor-suppressive.","evidence":"RIP, mRNA stability assays, immunoblotting, RBMS3 knockdown in MDA-MB-231 cells, and in vivo T-cell immunity assays","pmids":["36414028"],"confidence":"Medium","gaps":["What dictates stabilizing versus destabilizing outcomes on different targets is unknown","Single-lab finding"]},{"year":2023,"claim":"Placed RBMS3 downstream of the LKB1/AMPK pathway as an effector of AMPK-mediated suppression of invasion, integrating it into upstream metabolic signaling.","evidence":"IHC co-expression, AMPK agonist/inhibitor treatments, RBMS3 knockdown rescue, and Transwell assays in lung cancer cells","pmids":["37781074"],"confidence":"Medium","gaps":["Mechanism by which AMPK induces RBMS3 (transcriptional vs post-transcriptional) unknown","Pharmacological epistasis only"]},{"year":2024,"claim":"Identified LIMS1 as an RBMS3-regulated transcript in colon cancer mediating its anti-proliferative and anti-invasive effects.","evidence":"RBMS3 gain/loss with LIMS1 mRNA stability assays and LIMS1 knockdown rescue, plus xenograft models","pmids":["38618967"],"confidence":"Medium","gaps":["Direct binding (RIP) only implied","Direction of LIMS1 mRNA regulation not fully resolved"]},{"year":2025,"claim":"Uncovered an RNA-independent function: RBMS3 scaffolds TRIM21 onto ANGPT2 to drive its K48-ubiquitination and degradation, establishing RBMS3 as a dual post-transcriptional/post-translational regulator.","evidence":"IP-MS and co-IP defining the RBMS3–TRIM21–ANGPT2 complex, K48-ubiquitination assays, RNA-independence confirmation, and in vivo functional rescue in HCC","pmids":["40069332"],"confidence":"High","gaps":["Structural basis of TRIM21/ANGPT2 bridging not defined","Whether other substrates use this RNA-independent mode unknown"]},{"year":2025,"claim":"Showed RBMS3 forms a complex with ELAVL1 and UPF1 and destabilizes ELAVL1 mRNA to suppress angiogenic signaling, adding a complex-based regulatory layer.","evidence":"Co-IP, immunofluorescence, mRNA stability and methylation assays, and ELAVL1 rescue in ovarian cancer models","pmids":["42002122"],"confidence":"Medium","gaps":["Functional consequence of RBMS3-mediated UPF1 methylation inhibition uncharacterized","Direct vs indirect ELAVL1 mRNA targeting not separated"]},{"year":2025,"claim":"Positioned RBMS3 within upstream miRNA control and downstream TGF-β signaling in a vascular/ischemic context, and in MSC osteogenesis via MAPK signaling, extending its roles beyond cancer.","evidence":"Dual luciferase reporter for miR-21a-5p/RBMS3, AAV knockdown in a TIA model with TGFBR1/SMAD2/3 analysis; and lentiviral Rbms3 perturbation in MSCs with MAPK readouts and in vivo fracture healing","pmids":["40820584","40718133"],"confidence":"Medium","gaps":["Direct mRNA targets in these non-cancer contexts not mapped","Mechanistic link between RBMS3 and MAPK components unresolved"]},{"year":null,"claim":"What determines whether RBMS3 stabilizes versus destabilizes a given target, and how its RNA-dependent and RNA-independent (TRIM21-scaffold) activities are coordinated, remains unresolved.","evidence":"No single study reconciles the bidirectional mRNA outcomes or the dual-mode regulation across contexts","pmids":[],"confidence":"Low","gaps":["No structural model of RBMS3 target/partner recognition","Rules governing stabilizing vs destabilizing fate of bound transcripts unknown","Interplay between post-transcriptional and post-translational modes uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,4,5,6,8]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,4,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,12]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,7,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,7,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11]}],"complexes":["RBMS3–TRIM21–ANGPT2 complex","RBMS3–ELAVL1–UPF1 complex"],"partners":["TRIM21","ANGPT2","ELAVL1","UPF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6XE24","full_name":"RNA-binding motif, single-stranded-interacting protein 3","aliases":[],"length_aa":437,"mass_kda":47.8,"function":"Binds poly(A) and poly(U) oligoribonucleotides","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6XE24/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBMS3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RBMS3","total_profiled":1310},"omim":[{"mim_id":"605786","title":"RNA-BINDING MOTIF PROTEIN, SINGLE STRAND-INTERACTING, 3; RBMS3","url":"https://www.omim.org/entry/605786"},{"mim_id":"601267","title":"CHEMOKINE, CC MOTIF, RECEPTOR 2; CCR2","url":"https://www.omim.org/entry/601267"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBMS3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q6XE24","domains":[{"cath_id":"3.30.70.330","chopping":"57-132","consensus_level":"high","plddt":95.2013,"start":57,"end":132},{"cath_id":"3.30.70.330","chopping":"140-221","consensus_level":"high","plddt":91.1323,"start":140,"end":221}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6XE24","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6XE24-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6XE24-F1-predicted_aligned_error_v6.png","plddt_mean":63.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBMS3","jax_strain_url":"https://www.jax.org/strain/search?query=RBMS3"},"sequence":{"accession":"Q6XE24","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6XE24.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6XE24/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6XE24"}},"corpus_meta":[{"pmid":"22267851","id":"PMC_22267851","title":"Genomewide pharmacogenetics of bisphosphonate-induced osteonecrosis of the jaw: the role of RBMS3.","date":"2012","source":"The oncologist","url":"https://pubmed.ncbi.nlm.nih.gov/22267851","citation_count":77,"is_preprint":false},{"pmid":"17586524","id":"PMC_17586524","title":"RNA-binding protein RBMS3 is expressed in activated hepatic stellate cells and liver fibrosis and increases expression of transcription factor Prx1.","date":"2007","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17586524","citation_count":55,"is_preprint":false},{"pmid":"30279231","id":"PMC_30279231","title":"Loss of RBMS3 Confers Platinum Resistance in Epithelial Ovarian Cancer via Activation of miR-126-5p/β-catenin/CBP signaling.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30279231","citation_count":54,"is_preprint":false},{"pmid":"33845141","id":"PMC_33845141","title":"LncRNA MEG3 regulates breast cancer proliferation and apoptosis through miR-141-3p/RBMS3 axis.","date":"2021","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33845141","citation_count":49,"is_preprint":false},{"pmid":"30819235","id":"PMC_30819235","title":"The RNA binding protein RBMS3 inhibits the metastasis of breast cancer by regulating Twist1 expression.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30819235","citation_count":46,"is_preprint":false},{"pmid":"22957092","id":"PMC_22957092","title":"RBMS3 at 3p24 inhibits nasopharyngeal carcinoma development via inhibiting cell proliferation, angiogenesis, and inducing apoptosis.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22957092","citation_count":44,"is_preprint":false},{"pmid":"23091072","id":"PMC_23091072","title":"Rbms3 functions in craniofacial development by posttranscriptionally modulating TGF-β signaling.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23091072","citation_count":40,"is_preprint":false},{"pmid":"34608266","id":"PMC_34608266","title":"RNA binding protein RBMS3 is a common EMT effector that modulates triple-negative breast cancer progression via stabilizing PRRX1 mRNA.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34608266","citation_count":34,"is_preprint":false},{"pmid":"28409548","id":"PMC_28409548","title":"RBMS3 Inhibits the Proliferation and Metastasis of Breast Cancer Cells.","date":"2017","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/28409548","citation_count":32,"is_preprint":false},{"pmid":"36112789","id":"PMC_36112789","title":"Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis.","date":"2022","source":"Cancer 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enhances ferroptosis and suppresses ovarian cancer progression.","date":"2024","source":"Reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/39689458","citation_count":10,"is_preprint":false},{"pmid":"37781074","id":"PMC_37781074","title":"RBMS3, a downstream target of AMPK, Exerts Inhibitory Effects on Invasion and Metastasis of Lung Cancer.","date":"2023","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37781074","citation_count":10,"is_preprint":false},{"pmid":"38618967","id":"PMC_38618967","title":"The RNA-binding protein RBMS3 inhibits the progression of colon cancer by regulating the stability of LIMS1 mRNA.","date":"2024","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38618967","citation_count":9,"is_preprint":false},{"pmid":"38726149","id":"PMC_38726149","title":"Tumor suppressor function of RBMS3 overexpression in EOC associated with immune cell infiltration.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38726149","citation_count":9,"is_preprint":false},{"pmid":"40471105","id":"PMC_40471105","title":"Metformin Enhances PD-L1 Inhibitor Efficacy in Ovarian Cancer by Modulating the Immune Microenvironment and RBMS3 Expression.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40471105","citation_count":7,"is_preprint":false},{"pmid":"35743677","id":"PMC_35743677","title":"Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury.","date":"2022","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35743677","citation_count":7,"is_preprint":false},{"pmid":"38472166","id":"PMC_38472166","title":"Serum exosomal miR-3662 down-regulates the expression of RBMS3 to promote malignant progression and gemcitabine resistance of breast cancer cells.","date":"2024","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/38472166","citation_count":6,"is_preprint":false},{"pmid":"40069332","id":"PMC_40069332","title":"RBMS3-loss impedes TRIM21-induced ubiquitination of ANGPT2 in an RNA-independent manner and drives sorafenib resistance in hepatocellular carcinoma.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40069332","citation_count":3,"is_preprint":false},{"pmid":"39392600","id":"PMC_39392600","title":"Identification of RNA-binding protein RBMS3 as a potential biomarker for immunotherapy in bladder cancer.","date":"2025","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/39392600","citation_count":2,"is_preprint":false},{"pmid":"40820584","id":"PMC_40820584","title":"MicroRNA-21a-5p Promotes Cerebral Angiogenesis in Transient Ischemic Attack by Targeting RBMS3 and Subsequently Modulating the TGFBR1/SMAD2/3 Pathway.","date":"2025","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/40820584","citation_count":2,"is_preprint":false},{"pmid":"38822975","id":"PMC_38822975","title":"To investigate the role and potential mechanism of has_circ_RBMS3 in bone metastasis of breast cancer based on bioinformatics.","date":"2024","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/38822975","citation_count":2,"is_preprint":false},{"pmid":"31987045","id":"PMC_31987045","title":"Correction to: The RNA binding protein RBMS3 inhibits the metastasis of breast cancer by regulating Twist1 expression.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31987045","citation_count":2,"is_preprint":false},{"pmid":"41249383","id":"PMC_41249383","title":"M6A-ALKBH5-dependent RBMS3-AS3 down-regulation suppresses ferroptosis to promote lung adenocarcinoma progression through HNRNPDL/ZEB1/GPX4 axis.","date":"2025","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41249383","citation_count":1,"is_preprint":false},{"pmid":"40718133","id":"PMC_40718133","title":"Rbms3 Upregulation in Mesenchymal Stem Cells Impairs Fracture Healing in Type 2 Diabetes Mellitus.","date":"2025","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/40718133","citation_count":0,"is_preprint":false},{"pmid":"42002122","id":"PMC_42002122","title":"RBMS3 synergistically suppresses ovarian cancer progression at the post-transcriptional level by destabilizing ELAVL1 mRNA and inhibiting UPF1 methylation.","date":"2026","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/42002122","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.19.25338331","title":"Novel Epistatic Interaction Between RBMS3 and CDKN2B-AS1 in Coronary Artery Disease Risk Identified by Machine Learning Tool VariantSpark","date":"2025-10-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.19.25338331","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.06.658309","title":"Integrative analysis of mRNA stability regulation uncovers a metastasis-suppressive program in breast cancer","date":"2025-06-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.06.658309","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20555,"output_tokens":4953,"usd":0.06798,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13168,"output_tokens":4750,"usd":0.092295,"stage2_stop_reason":"end_turn"},"total_usd":0.160275,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"RBMS3 binds sequence-specifically to a 60-nt element located 1946 nt 3' of the stop codon in the Prx1 mRNA 3'UTR, stabilizing Prx1 mRNA, increasing its half-life, and thereby enhancing Prx1 protein synthesis and downstream collagen alpha1(I) expression in hepatic stellate cells.\",\n      \"method\": \"RNA immunoprecipitation followed by differential display to identify Prx1 mRNA as an RBMS3 target; reporter mRNA assays with and without the RBMS3 binding site; ectopic expression of RBMS3 in quiescent HSCs\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal RIP, sequence-specific binding site mapped, reporter assays with and without binding site, functional rescue in primary cells; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17586524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rbms3 (zebrafish ortholog) is transiently expressed in the cytoplasm of condensing cranial neural crest cells in pharyngeal arches; it stabilizes a reporter transcript containing the smad2 3'UTR, RNA immunoprecipitation shows enrichment for smad2/3 mRNAs, and rbms3 morphants display reduced pSmad2 levels, placing Rbms3 as a post-transcriptional positive regulator of TGF-β/Smad2/3 signaling required for chondrogenesis.\",\n      \"method\": \"Zebrafish protein-trap screen for localization; morpholino knockdown phenotype; RNA immunoprecipitation (RIP) with full-length Rbms3; reporter assay with smad2 3'UTR; pSmad2 immunoblotting in morphants\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, reporter assay, morphant phenotype with signaling readout (pSmad2), live imaging for localization; multiple orthogonal methods in single study\",\n      \"pmids\": [\"23091072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rbms3 binds to the 3'UTR of Ptf1a mRNA (but not Pdx1 3'UTR) and stimulates translation of a reporter bearing the Ptf1a 3'UTR; knockdown of Rbms3 in AR42J-B13 pancreatic exocrine cells reduces Ptf1a expression, indicating RBMS3 post-transcriptionally promotes Ptf1a protein production during pancreas development.\",\n      \"method\": \"Differential screening assay for expression; RNA-binding assay (3'UTR binding specificity); reporter translation assay; siRNA knockdown of Rbms3 in AR42J-B13 cells with Ptf1a protein/mRNA readout\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter translation assay plus knockdown; single lab, two orthogonal methods\",\n      \"pmids\": [\"22372950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RBMS3 tumor-suppressive function in nasopharyngeal carcinoma is mechanistically linked to: (a) G1/S cell cycle arrest via upregulation of p53 and p21 and downregulation of cyclin E and CDK2 with inhibition of Rb-Ser780 phosphorylation; (b) pro-apoptotic activity through mitochondrial pathway activation (caspase-9, PARP); and (c) inhibition of angiogenesis associated with downregulation of MMP2, β-catenin, and downstream targets cyclin-D1, c-Myc, MMP7, MMP9.\",\n      \"method\": \"Overexpression and RNAi suppression in NPC cell lines; cell cycle analysis; immunoblotting for p53, p21, cyclin E, CDK2, Rb phosphorylation, caspase-9, PARP, MMP2, β-catenin, cyclin-D1, c-Myc, MMP7, MMP9; microvessel formation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression/knockdown with multiple molecular readouts; single lab, multiple orthogonal assays\",\n      \"pmids\": [\"22957092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBMS3 directly binds (via CLIP-seq and RIP/EMSA) and stabilizes the mRNAs of multiple Wnt/β-catenin negative regulators — DKK3, AXIN1, BACH1, and NFAT5 — thereby inhibiting β-catenin/CBP signaling; this activity is competed by miR-126-5p, which otherwise represses these same transcripts. Loss of RBMS3 thus activates β-catenin/CBP signaling and confers platinum resistance in epithelial ovarian cancer.\",\n      \"method\": \"CLIP-seq, RNA immunoprecipitation (RIP), electrophoretic mobility shift assay (EMSA), immunoblotting, immunofluorescence, clone formation and Annexin V apoptosis assays in vitro; intraperitoneal tumor model in vivo\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — CLIP-seq plus RIP plus EMSA directly identify binding targets; functional rescue with pathway inhibitor in vivo; multiple orthogonal methods in single study\",\n      \"pmids\": [\"30279231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RBMS3 directly binds the 3'UTR of Twist1 mRNA (confirmed by RNA immunoprecipitation and luciferase reporter assay), negatively regulating Twist1 expression and thereby reducing Twist1-induced MMP2 expression, migration, invasion, and lung metastasis of breast cancer cells.\",\n      \"method\": \"RNA immunoprecipitation (RIP), luciferase reporter assay with Twist1 3'UTR, Transwell migration/invasion assays, in vivo lung metastasis assay, transcriptome sequencing\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal RIP and reporter assay confirm direct 3'UTR binding; single lab, two orthogonal methods\",\n      \"pmids\": [\"30819235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBMS3 interacts with the mRNA of the EMT transcription factor PRRX1 and promotes PRRX1 mRNA stability; PRRX1 is required for RBMS3-mediated EMT and partially rescues RBMS3 knockdown phenotypes in triple-negative breast cancer cells. RBMS3 is sufficient to induce EMT in immortalized mammary epithelial cells and necessary for maintaining the mesenchymal phenotype and invasion/migration in TNBC.\",\n      \"method\": \"Genome-wide mRNA stability assay (actinomycin D transcriptional blockade), RIP demonstrating RBMS3 interaction with PRRX1 mRNA, PRRX1 rescue experiments, in vivo spontaneous metastasis model, loss-of-function RBMS3 knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide stability screen plus RIP plus genetic rescue in vitro and in vivo; multiple orthogonal methods in single study\",\n      \"pmids\": [\"34608266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBMS3 silencing cooperates with BRAFV600E to promote malignant lung tumorigenesis; RBMS3-null BRAFV600E lung tumors show elevated Ctnnb1, Ccnd1, Axin2, Lgr5, and c-Myc mRNAs, indicating RBMS3 suppresses the WNT/β-catenin signaling axis in lung cancer. RBMS3Null tumors are resistant to dabrafenib plus trametinib but sensitive to porcupine inhibition.\",\n      \"method\": \"Sleeping Beauty transposon mutagenesis screen in BRAFV600E GEM model; CRISPR/Cas9 RBMS3 knockout; lung organoid growth assay; GEM in vivo tumor development; qRT-PCR for Wnt target genes; drug treatment (dabrafenib+trametinib, porcupine inhibitor)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transposon screen plus CRISPR validation plus GEM in vivo models plus molecular pathway readout; multiple orthogonal methods with in vivo confirmation\",\n      \"pmids\": [\"36112789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBMS3 stabilizes CD274 (PD-L1) mRNA by interacting with its 3'UTR in TNBC cells, thereby increasing PD-L1 protein levels; RBMS3 depletion destabilizes CD274 mRNA and reduces PD-L1 expression, suppressing immune evasion.\",\n      \"method\": \"RIP demonstrating RBMS3 binding to CD274 mRNA 3'UTR; mRNA stability assays; immunoblotting for PD-L1; RBMS3 knockdown in MDA-MB-231 cells; in vivo T-cell immunity assays with RBMS3 ablation plus auranofin\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus mRNA stability assay confirm direct binding and stabilization; in vivo functional validation; single lab\",\n      \"pmids\": [\"36414028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBMS3 is a downstream effector of the LKB1/AMPK pathway: activation of AMPK promotes RBMS3 expression, and RBMS3 mediates AMPK's inhibitory effects on lung cancer cell invasion and migration; inhibiting RBMS3 reverses AMPK agonist-induced suppression of invasion.\",\n      \"method\": \"Immunohistochemistry for RBMS3/LKB1 co-expression in lung cancer tissues; AMPK agonist/inhibitor treatment in lung cancer cell lines; RBMS3 knockdown rescue of AMPK-mediated invasion inhibition; Transwell migration/invasion assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological epistasis (AMPK agonist/inhibitor + RBMS3 KD) with functional rescue; single lab, pathway placement via genetic/chemical epistasis\",\n      \"pmids\": [\"37781074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBMS3 modulates the stability of LIMS1 mRNA in colon cancer cells; knockdown of LIMS1 rescues the inhibitory effect of RBMS3 overexpression on colon cancer cell proliferation, migration, and invasion, placing LIMS1 downstream of RBMS3.\",\n      \"method\": \"RBMS3 overexpression and knockdown in colon cancer cells; mRNA stability assays for LIMS1; RIP (implied by 'molecular biology methods'); LIMS1 knockdown rescue experiment; animal xenograft models\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability assay plus genetic rescue (LIMS1 KD reversal); single lab, two orthogonal methods\",\n      \"pmids\": [\"38618967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBMS3 physically recruits the ubiquitin E3 ligase TRIM21 to ANGPT2 protein in an RNA-independent manner, facilitating K48-linked polyubiquitination and proteasomal degradation of ANGPT2; loss of RBMS3 in HCC prevents this ubiquitination, leading to ANGPT2 accumulation, increased angiogenesis, and sorafenib resistance.\",\n      \"method\": \"Immunoprecipitation mass spectrometry (IP-MS) and co-immunoprecipitation (co-IP) to identify RBMS3–TRIM21–ANGPT2 complex; K48-ubiquitination assays; RBMS3 overexpression/knockdown with ANGPT2 protein level and secretion readouts; RNA-independence confirmed; in vitro and in vivo functional assays; ANGPT2 antibody combination rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — IP-MS plus co-IP plus K48-ubiquitination biochemical assay confirm RNA-independent protein complex and ubiquitination mechanism; functional in vivo rescue; multiple orthogonal methods\",\n      \"pmids\": [\"40069332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBMS3 forms a protein complex with ELAVL1 and UPF1; RBMS3 reduces ELAVL1 mRNA stability at the post-transcriptional level, leading to downregulation of downstream VEGF-A and IL-6; restoring ELAVL1 reverses RBMS3-mediated suppression of angiogenesis, invasion, and STAT3 phosphorylation in ovarian cancer. Additionally, RBMS3 inhibits UPF1 methylation (functional consequences not yet fully characterized).\",\n      \"method\": \"Immunoprecipitation, immunofluorescence, mRNA stability assays, methylation assays, Western blotting, angiogenesis and migration assays in vitro, in vivo nude mouse tumor models, ELAVL1 rescue experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifies RBMS3–ELAVL1–UPF1 complex; mRNA stability assay confirms ELAVL1 mRNA destabilization; genetic rescue (ELAVL1 re-expression) confirms pathway; single lab\",\n      \"pmids\": [\"42002122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBMS3 regulates TXNIP mRNA stability as a metastasis-suppressive mechanism in breast cancer; RBMS3 depletion destabilizes TXNIP transcripts, and in vivo epistasis studies confirm that RBMS3 suppression of metastasis is mediated through TXNIP mRNA stabilization.\",\n      \"method\": \"Genome-wide mRNA stability measurements across breast cancer models; deep-learning RBP regulon inference (GreyHound); RBMS3 knockdown with TXNIP mRNA stability readout; in vivo epistasis (xenograft models with RBMS3 depletion and TXNIP manipulation)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mRNA stability profiling plus in vivo epistasis; preprint, not yet peer-reviewed; single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBMS3 acts downstream of miRNA-21a-5p: miR-21a-5p targets RBMS3 (validated by dual luciferase reporter), and suppression of RBMS3 reverses miR-21a-5p knockdown-mediated inhibition of angiogenesis after transient ischemic attack. RBMS3 modulation of angiogenesis in this context is linked to the TGFBR1/SMAD2/3 pathway downstream.\",\n      \"method\": \"Dual luciferase reporter assay validating miR-21a-5p binding to RBMS3; adeno-associated virus-mediated RBMS3 knockdown in TIA mouse model; in vitro OGD/reoxygenation model; angiogenesis readouts; TGFBR1/SMAD2/3 pathway analysis\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirms direct miR-21a-5p/RBMS3 interaction; in vivo AAV knockdown with pathway rescue; single lab, two orthogonal methods\",\n      \"pmids\": [\"40820584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rbms3 upregulation in mesenchymal stem cells under T2DM conditions impairs osteogenic differentiation and fracture healing by modulating the MAPK signaling pathway, as demonstrated by in vitro transduction experiments and in vivo micro-CT/histological analysis.\",\n      \"method\": \"scRNA-seq and transcriptomic integration; lentiviral Rbms3 overexpression/knockdown in MSCs; ALP staining, ARS, qPCR, Western blotting for osteogenic markers and MAPK pathway components; in vivo fracture healing model with micro-CT and histological staining\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with MAPK pathway readout in vitro and in vivo; single lab, multiple methods\",\n      \"pmids\": [\"40718133\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBMS3 is an RNA-binding protein that acts predominantly as a post-transcriptional regulator: it binds 3'UTRs of specific target mRNAs (including Prx1, Smad2/3, Ptf1a, Twist1, PRRX1, TXNIP, DKK3, AXIN1, BACH1, NFAT5, CD274/PD-L1, ELAVL1, and LIMS1) to modulate their stability or translation, thereby suppressing EMT, the Wnt/β-catenin axis, and pro-tumorigenic signaling; in addition, RBMS3 can function in an RNA-independent manner by recruiting the E3 ubiquitin ligase TRIM21 to promote K48-linked ubiquitination and degradation of ANGPT2, placing it as a dual-mode regulator acting both post-transcriptionally and post-translationally.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBMS3 is a sequence-specific RNA-binding protein that acts as a post-transcriptional regulator of gene expression by binding the 3'UTRs of target mRNAs to control their stability and translation [#0, #4, #6]. Its earliest characterized activity is mRNA stabilization: it binds a defined element in the Prx1 3'UTR to extend transcript half-life and drive Prx1-dependent collagen expression in hepatic stellate cells [#0], and analogous 3'UTR binding stabilizes smad2/3 transcripts to support TGF-\\u03b2/Smad2/3 signaling during chondrogenesis and stimulates Ptf1a translation during pancreatic development [#1, #2]. In cancer, RBMS3 functions predominantly as a tumor suppressor by stabilizing transcripts encoding negative regulators of the Wnt/\\u03b2-catenin axis\\u2014DKK3, AXIN1, BACH1, and NFAT5\\u2014thereby restraining \\u03b2-catenin/CBP signaling, an activity antagonized by miR-126-5p [#4], and by suppressing the same axis in BRAFV600E-driven lung tumors [#7]. It additionally limits EMT and metastasis by destabilizing or restraining EMT effectors and metastasis-linked transcripts including Twist1, PRRX1, and TXNIP [#5, #6, #13]. Beyond its RNA-dependent roles, RBMS3 also acts post-translationally: it physically recruits the E3 ubiquitin ligase TRIM21 to ANGPT2 in an RNA-independent manner to promote K48-linked polyubiquitination and proteasomal degradation, restraining angiogenesis [#11]. RBMS3 is itself positioned downstream of upstream regulatory inputs, being induced by LKB1/AMPK signaling and targeted by miR-21a-5p [#9, #14].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that RBMS3 is a sequence-specific 3'UTR-binding protein that stabilizes a target mRNA, defining its core molecular activity.\",\n      \"evidence\": \"RIP/differential display identifying Prx1 mRNA, reporter assays with and without the mapped binding site, and ectopic expression in primary hepatic stellate cells\",\n      \"pmids\": [\"17586524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of stabilization (decay machinery engaged) not defined\", \"Generality of the 60-nt binding element to other targets unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed RBMS3 acts in developmental signaling by stabilizing smad2/3 transcripts and promoting Ptf1a translation, extending its role from stabilization to translational control in distinct tissues.\",\n      \"evidence\": \"Zebrafish protein-trap localization, morpholino knockdown with pSmad2 readout, RIP and 3'UTR reporter assays; separately, 3'UTR binding specificity and reporter translation assays in pancreatic exocrine cells\",\n      \"pmids\": [\"23091072\", \"22372950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RBMS3 distinguishes stabilization versus translational stimulation among targets is unresolved\", \"Direct binding partners mediating these outputs not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked RBMS3 to tumor suppression through cell-cycle arrest, apoptosis, and anti-angiogenic phenotypes, broadening its physiological significance.\",\n      \"evidence\": \"Overexpression/RNAi in nasopharyngeal carcinoma lines with cell-cycle analysis, immunoblotting of p53/p21/cyclin E/CDK2/\\u03b2-catenin targets, and microvessel assays\",\n      \"pmids\": [\"22957092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phenotypes are correlative; direct mRNA targets driving these outputs not mapped\", \"Whether \\u03b2-catenin downregulation is post-transcriptional unaddressed at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the mechanism by which RBMS3 restrains Wnt/\\u03b2-catenin signaling: direct stabilization of multiple negative regulator mRNAs, with competition by miR-126-5p.\",\n      \"evidence\": \"CLIP-seq, RIP, and EMSA mapping direct binding to DKK3/AXIN1/BACH1/NFAT5; in vitro functional assays and intraperitoneal tumor model with pathway inhibitor rescue\",\n      \"pmids\": [\"30279231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each target transcript not dissected\", \"Structural basis of multi-target recognition unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated RBMS3 negatively regulates the EMT transcription factor Twist1 via direct 3'UTR binding, connecting RBMS3 to metastasis suppression.\",\n      \"evidence\": \"Reciprocal RIP, luciferase reporter with Twist1 3'UTR, Transwell assays, and in vivo lung metastasis model in breast cancer\",\n      \"pmids\": [\"30819235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RBMS3 destabilizes versus represses translation of Twist1 not clarified\", \"Single-lab validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed RBMS3 controls the EMT program through PRRX1 mRNA stability and can both induce and maintain mesenchymal states, refining its context-dependent role.\",\n      \"evidence\": \"Genome-wide mRNA stability profiling, RIP for PRRX1 mRNA, PRRX1 genetic rescue, and in vivo spontaneous metastasis model in TNBC\",\n      \"pmids\": [\"34608266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling EMT-promoting activity here with metastasis-suppressive roles elsewhere remains open\", \"Determinants of cell-context-specific output not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Validated RBMS3 as a Wnt/\\u03b2-catenin suppressor and tumor suppressor in vivo, and identified RBMS3 loss as conferring resistance to BRAF/MEK inhibition but sensitivity to porcupine inhibition.\",\n      \"evidence\": \"Sleeping Beauty transposon screen, CRISPR knockout, lung organoid and GEM models, qRT-PCR of Wnt targets, and drug treatments\",\n      \"pmids\": [\"36112789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mRNA targets mediating Wnt suppression in lung not mapped in this system\", \"Mechanism connecting RBMS3 loss to drug resistance not biochemically resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a context where RBMS3 stabilizes a pro-tumorigenic transcript (CD274/PD-L1), showing its 3'UTR-stabilization activity is not uniformly tumor-suppressive.\",\n      \"evidence\": \"RIP, mRNA stability assays, immunoblotting, RBMS3 knockdown in MDA-MB-231 cells, and in vivo T-cell immunity assays\",\n      \"pmids\": [\"36414028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What dictates stabilizing versus destabilizing outcomes on different targets is unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed RBMS3 downstream of the LKB1/AMPK pathway as an effector of AMPK-mediated suppression of invasion, integrating it into upstream metabolic signaling.\",\n      \"evidence\": \"IHC co-expression, AMPK agonist/inhibitor treatments, RBMS3 knockdown rescue, and Transwell assays in lung cancer cells\",\n      \"pmids\": [\"37781074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which AMPK induces RBMS3 (transcriptional vs post-transcriptional) unknown\", \"Pharmacological epistasis only\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified LIMS1 as an RBMS3-regulated transcript in colon cancer mediating its anti-proliferative and anti-invasive effects.\",\n      \"evidence\": \"RBMS3 gain/loss with LIMS1 mRNA stability assays and LIMS1 knockdown rescue, plus xenograft models\",\n      \"pmids\": [\"38618967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding (RIP) only implied\", \"Direction of LIMS1 mRNA regulation not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered an RNA-independent function: RBMS3 scaffolds TRIM21 onto ANGPT2 to drive its K48-ubiquitination and degradation, establishing RBMS3 as a dual post-transcriptional/post-translational regulator.\",\n      \"evidence\": \"IP-MS and co-IP defining the RBMS3\\u2013TRIM21\\u2013ANGPT2 complex, K48-ubiquitination assays, RNA-independence confirmation, and in vivo functional rescue in HCC\",\n      \"pmids\": [\"40069332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TRIM21/ANGPT2 bridging not defined\", \"Whether other substrates use this RNA-independent mode unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed RBMS3 forms a complex with ELAVL1 and UPF1 and destabilizes ELAVL1 mRNA to suppress angiogenic signaling, adding a complex-based regulatory layer.\",\n      \"evidence\": \"Co-IP, immunofluorescence, mRNA stability and methylation assays, and ELAVL1 rescue in ovarian cancer models\",\n      \"pmids\": [\"42002122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of RBMS3-mediated UPF1 methylation inhibition uncharacterized\", \"Direct vs indirect ELAVL1 mRNA targeting not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned RBMS3 within upstream miRNA control and downstream TGF-\\u03b2 signaling in a vascular/ischemic context, and in MSC osteogenesis via MAPK signaling, extending its roles beyond cancer.\",\n      \"evidence\": \"Dual luciferase reporter for miR-21a-5p/RBMS3, AAV knockdown in a TIA model with TGFBR1/SMAD2/3 analysis; and lentiviral Rbms3 perturbation in MSCs with MAPK readouts and in vivo fracture healing\",\n      \"pmids\": [\"40820584\", \"40718133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mRNA targets in these non-cancer contexts not mapped\", \"Mechanistic link between RBMS3 and MAPK components unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What determines whether RBMS3 stabilizes versus destabilizes a given target, and how its RNA-dependent and RNA-independent (TRIM21-scaffold) activities are coordinated, remains unresolved.\",\n      \"evidence\": \"No single study reconciles the bidirectional mRNA outcomes or the dual-mode regulation across contexts\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of RBMS3 target/partner recognition\", \"Rules governing stabilizing vs destabilizing fate of bound transcripts unknown\", \"Interplay between post-transcriptional and post-translational modes uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 4, 5, 6, 8]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 7, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 7, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\n      \"RBMS3\\u2013TRIM21\\u2013ANGPT2 complex\",\n      \"RBMS3\\u2013ELAVL1\\u2013UPF1 complex\"\n    ],\n    \"partners\": [\n      \"TRIM21\",\n      \"ANGPT2\",\n      \"ELAVL1\",\n      \"UPF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}