{"gene":"RBM38","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2006,"finding":"RNPC1a (RBM38 isoform) directly binds to the 3' UTR of p21 mRNA and stabilizes it, maintaining basal and stress-induced p21 transcript levels; RNPC1a but not RNPC1b induces G1 cell cycle arrest and stabilizes p21 transcript, despite both isoforms being expressed in nucleus and cytoplasm and both binding p21 3' UTR.","method":"RNA binding assays, knockdown/overexpression with mRNA stability assays, cell cycle analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct RNA binding demonstrated, isoform-specific functional dissection, replicated with knockdown and overexpression, multiple orthogonal methods","pmids":["17050675"],"is_preprint":false},{"year":2010,"finding":"RNPC1 (RBM38) and HuR physically interact via the RRM domain of RNPC1 and RRM3 of HuR; RNPC1 and HuR preferentially bind upstream and downstream AU-rich elements (AREs) in p21 3'-UTR respectively; RNPC1 enhances HuR's RNA-binding activity to p21 transcript in vitro and in vivo, and RNPC1's ability to stabilize p21 mRNA is dependent on HuR.","method":"Co-immunoprecipitation, RNA immunoprecipitation, in vitro RNA binding assays, domain-mapping experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein interaction mapping, domain-level mutagenesis, in vitro and in vivo RNA binding assays in single study","pmids":["20064878"],"is_preprint":false},{"year":2010,"finding":"RNPC1 (RBM38) binds AU-/U-rich elements in p63 3' UTR via its RRM domain and destabilizes p63 transcript, reducing p63 expression; RNPC1 RRM domain is required for binding and regulating p63 mRNA stability; RNPC1 promotes keratinocyte differentiation by repressing p63 expression.","method":"RNA immunoprecipitation, in vitro RNA binding (EMSA), overexpression/knockdown with mRNA stability assays, RRM mutant analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct RNA binding with domain mapping, functional consequence in differentiation, multiple orthogonal methods","pmids":["20457941"],"is_preprint":false},{"year":2011,"finding":"RNPC1 (RBM38) represses p53 mRNA translation by preventing eIF4E from binding to p53 mRNA; RNPC1 uses its C-terminal domain to physically interact with eIF4E and its N-terminal domain to bind p53 mRNA 5' and 3' UTRs; loss of RNPC1 in MEFs increases p53 protein, leading to enhanced premature senescence in a p53-dependent manner.","method":"Overexpression/knockdown translation assays, domain-mapping Co-IP with eIF4E, RNA-binding assays with p53 5'/3' UTR, polysome profiling, MEF senescence assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-level dissection of eIF4E interaction and RNA binding, multiple orthogonal methods, in vivo MEF validation","pmids":["21764855"],"is_preprint":false},{"year":2011,"finding":"RBM38 selectively blocks miRNA access to target mRNAs by interacting with uridine-rich regions near miRNA target sequences; RBM38 is induced by p53 and its ability to modulate miRNA-mediated repression is required for proper p53 function; RBM38 shows lower propensity to block p53-controlled miR-34a action on SIRT1.","method":"Genetic screen for RBPs controlling miRNA activity, luciferase reporter assays, RNA binding assays, RBM38 overexpression/knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic screen plus mechanistic follow-up with RNA binding assays and reporter assays, multiple targets examined","pmids":["22027593"],"is_preprint":false},{"year":2012,"finding":"RNPC1 (RBM38) destabilizes MDM2 transcript via binding to multiple AU-/U-rich elements in MDM2 3' UTR, reducing MDM2 expression independent of p53; RNA-binding activity of RNPC1 (RRM domain) is required for binding MDM2 transcript and inhibiting MDM2 expression.","method":"Overexpression/knockdown/knockout mRNA stability assays, RNA immunoprecipitation, EMSA, reporter assays with MDM2 3' UTR, RRM mutant analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct RNA binding with domain requirement, multiple orthogonal methods, KO corroboration","pmids":["22710720"],"is_preprint":false},{"year":2012,"finding":"RNPC1 (RBM38) post-transcriptionally stabilizes HuR mRNA via binding to its 3' UTR; RNA-binding-deficient RNPC1 mutant fails to stabilize HuR transcript; HuR, by repressing c-Myc expression, mediates RNPC1-induced growth suppression.","method":"Overexpression/knockdown/knockout mRNA stability assays, RNA immunoprecipitation, RNA-binding mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA-binding mutant used, KO corroboration, epistasis (HuR → c-Myc → growth suppression), multiple methods","pmids":["22371495"],"is_preprint":false},{"year":2012,"finding":"p73 mRNA stability is regulated by RNPC1 (RBM38) via a CU-rich element in the p73 3' UTR; loss of RNPC1 in p53-null MEFs reduces p73 expression along with p21 and p130, decreasing senescent cell number; combined knockdown of TAp73 and p21 completely abolishes RNPC1-mediated growth suppression and senescence.","method":"Overexpression/knockdown mRNA stability assays, RNA immunoprecipitation, EMSA, siRNA epistasis in MEFs","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct RNA binding, epistasis experiments, multiple orthogonal methods","pmids":["22508983"],"is_preprint":false},{"year":2012,"finding":"RBM38 is a direct transcriptional target of E2F1; endogenous E2F1 binds the RBM38 promoter; RBM38 and E2F1 constitute a negative feedback loop limiting E2F1-induced cell-cycle progression.","method":"ChIP demonstrating E2F1 binding to RBM38 promoter, siRNA knockdown of E2F1, cell-cycle analysis with RBM38 inhibition","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional cell-cycle assay, single lab, two orthogonal methods","pmids":["22798430"],"is_preprint":false},{"year":2013,"finding":"RNPC1 (RBM38) binds to an AU-rich element in MIC-1 3' UTR and stabilizes MIC-1 mRNA, increasing MIC-1 expression; knockdown of MIC-1 decreases RNPC1-induced cell growth suppression.","method":"Overexpression/knockdown/knockout mRNA stability assays, RNA immunoprecipitation, siRNA epistasis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding, functional epistasis, single lab","pmids":["23836903"],"is_preprint":false},{"year":2013,"finding":"RBM38 regulates alternative splicing during late erythroid differentiation, including activation of Protein 4.1R (EPB41) exon 16 splicing; RBM38 directly activates splicing when recruited to a downstream intron (tethering assay); SELEX-Seq identified a GU-rich RBM38 binding motif.","method":"Exon junction splicing microarray, minigene splicing assays, SELEX-Seq for binding motif, tethering assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SELEX-Seq motif identification, minigene validation, tethering assay, multiple orthogonal methods","pmids":["24250749"],"is_preprint":false},{"year":2013,"finding":"GSK3 phosphorylates RNPC1 (RBM38) at Ser195; phosphorylation at Ser195 (mimicked by S195D mutant) abolishes RNPC1's interaction with eIF4E on p53 mRNA and instead promotes interaction with eIF4G, facilitating assembly of the eIF4F complex on p53 mRNA and thereby promoting p53 mRNA translation; PI3K-Akt pathway inhibition activates GSK3, increases RNPC1 phosphorylation, and increases p53 expression in an RNPC1-dependent manner.","method":"In vitro kinase assay, phosphomimetic/deletion mutant analysis, Co-IP with eIF4E and eIF4G, polysome/cap-binding assays, PI3K inhibitor treatment","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus multiple mutants, Co-IP with translation factors, pathway intervention, multiple orthogonal methods","pmids":["24142875"],"is_preprint":false},{"year":2014,"finding":"Rbm38-null mice exhibit accelerated aging, hematopoietic defects, and spontaneous tumors; Rbm38 deficiency enhances IR-induced p53 accumulation and sensitizes mice to IR-induced lethality in a p53-dependent manner; Rbm38 deficiency markedly decreases tumor penetrance in p53 heterozygous mice via enhanced p53 expression; providing in vivo genetic evidence for the p53-Rbm38 autoregulatory loop.","method":"Knockout mouse model, ionizing radiation challenge, epistasis with p53-heterozygous mice, tumor monitoring","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with null mice and p53 compound mutants, replicated phenotypes","pmids":["25512531"],"is_preprint":false},{"year":2015,"finding":"PPM1D phosphatase directly interacts with RBM38 and dephosphorylates it at Ser195; dephosphorylated RBM38 represses p53 mRNA translation; RBM38 in turn promotes PPM1D mRNA translation by binding to PPM1D 3' UTR; creating a PPM1D-RBM38-p53 regulatory axis.","method":"Co-IP, in vitro dephosphorylation assay, RNA immunoprecipitation, reporter assays with PPM1D 3' UTR, translation/growth suppression assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro dephosphorylation, direct RNA binding, reciprocal regulatory loop with multiple orthogonal methods","pmids":["25823026"],"is_preprint":false},{"year":2015,"finding":"RBM38 (RNPC1) regulates HIF1α expression via mRNA translation under hypoxia by directly binding HIF1α 5' and 3' UTRs and preventing eIF4E binding to HIF1α mRNA; knockdown of RBM38 increases de novo HIF1α protein synthesis rate.","method":"Overexpression/knockdown, de novo protein synthesis assays, RNA immunoprecipitation, cap-binding assay with eIF4E, reporter assays with HIF1α UTRs","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding plus eIF4E cap-binding assay, single lab, multiple methods","pmids":["25622105"],"is_preprint":false},{"year":2017,"finding":"RBM38 stabilizes PTEN mRNA by binding to multiple AU/U-rich elements in PTEN 3' UTR; PTEN inhibition partially reverses RBM38-mediated growth suppression in breast cancer cells.","method":"RNA immunoprecipitation, EMSA, dual-luciferase reporter assay, overexpression/knockdown mRNA stability assays, PTEN inhibitor/siRNA epistasis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding with multiple methods, functional epistasis, single lab","pmids":["29052531"],"is_preprint":false},{"year":2017,"finding":"TGF-β induces Snail, which directly represses RBM38 transcription via E-box elements in the RBM38 promoter; RBM38 in turn stabilizes ZO-1 mRNA by binding AU/U-rich elements in ZO-1 3' UTR, and RBM38 overexpression reverses ZO-1 knockdown-mediated cell migration and invasion.","method":"ChIP assay (Snail on RBM38 promoter), luciferase reporter assay, RNA immunoprecipitation, EMSA, Transwell migration/invasion assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus direct RNA binding plus functional rescue, single lab","pmids":["28683467"],"is_preprint":false},{"year":2017,"finding":"RBM38 destabilizes c-Myc mRNA by directly targeting AU-rich elements in c-Myc 3' UTR; c-Myc transcription factor suppresses RBM38 gene expression by binding E-box motifs in the RBM38 promoter, forming a mutually antagonistic RBM38–c-Myc feedback loop.","method":"ChIP assay (c-Myc on RBM38 promoter), RNA immunoprecipitation, dual-luciferase reporter assay, overexpression/knockdown with mRNA stability","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus direct RNA binding, single lab, two orthogonal methods","pmids":["28399911"],"is_preprint":false},{"year":2017,"finding":"RNPC1 (RBM38) stabilizes ESR1 (ERα) mRNA by binding to AREs in ERα 3' UTR, increasing ERα expression; reciprocally, ERα overexpression decreases RNPC1 transcript and protein levels, forming a feedback loop.","method":"RNA immunoprecipitation, overexpression/knockdown mRNA stability assays","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/RIP, no domain mutagenesis, single lab","pmids":["25881544"],"is_preprint":false},{"year":2017,"finding":"RNPC1 (RBM38) stabilizes progesterone receptor (PR) mRNA by binding AU-rich elements in PR 3' UTR; RBM38 overexpression increases PR mRNA and protein and enhances progesterone-dependent proliferation in vitro and in vivo.","method":"RNA immunoprecipitation, mRNA stability assays, overexpression/knockdown, in vivo xenograft","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP, no domain mutagenesis, single lab","pmids":["27634883"],"is_preprint":false},{"year":2017,"finding":"RBM38 (RNPC1) stabilizes mRNAs of STARD13, CDH5, HOXD10, and HOXD1 in breast cancer cells, promoting a ceRNA network that inhibits cancer cell metastasis.","method":"Overexpression/knockdown with mRNA stability assays, functional invasion assays","journal":"Molecular pharmaceutics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mRNA stability with overexpression/knockdown, limited mechanistic detail in abstract, single lab","pmids":["29733656"],"is_preprint":false},{"year":2018,"finding":"RBM38 destabilizes MDM2 mRNA through binding AU/U-rich elements in MDM2 3' UTR in HCC, restoring wild-type p53 expression and suppressing HCC cell proliferation, migration, invasion, and tumor growth in vivo.","method":"Luciferase reporter assay with MDM2 3' UTR, overexpression/knockdown, functional assays in vitro and in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding shown by reporter assay, functional assays with in vivo validation, single lab","pmids":["30176896"],"is_preprint":false},{"year":2018,"finding":"An 8-amino acid peptide (Pep8) derived from the eIF4E-binding interface of RBM38 disrupts the RBM38-eIF4E complex; molecular simulations identified Ser-6 in Pep8 forms a hydrogen bond with Asp-202 in eIF4E; Pep8 relieves RBM38-mediated repression of p53 translation and suppresses tumor growth in RBM38- and p53-dependent manners.","method":"Molecular simulation, peptide competition assays, p53 translation assays, colony/tumor sphere formation, xenograft assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structure-guided peptide design with molecular simulation, in vitro translation assays, in vivo xenograft, multiple orthogonal methods","pmids":["30591552"],"is_preprint":false},{"year":2018,"finding":"Rbm38 is required for Pten mRNA stabilization through an AU-rich element in Pten 3' UTR; genetic ablation of Rbm38 in mutant p53 knock-in mice decreases PTEN expression, enhances mutant p53 expression, and promotes T-cell lymphomagenesis.","method":"Rbm38 knockout in mutant p53 knock-in mice, mRNA stability assays, 3' UTR binding assays, tumor monitoring","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model, direct RNA binding, compound mutant epistasis","pmids":["29330147"],"is_preprint":false},{"year":2018,"finding":"The Rbm38-p63 negative feedback loop operates in vivo: Rbm38 deficiency reduces tumor penetrance in TAp63+/- mice, extends lifespan of tumor-free TAp63+/- mice, reduces senescence markers and inflammatory cytokines (IL17D, Tnfsf15), while Rbm38-/-;TAp63+/- MEFs are resistant to cellular senescence.","method":"Compound knockout/heterozygous mouse model, lifespan monitoring, MEF senescence assays, cytokine expression analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with compound mutants, MEF functional assays, multiple phenotypic readouts","pmids":["29520104"],"is_preprint":false},{"year":2018,"finding":"Ser-195 phosphorylation of Rbm38 by GSK3β increases p63α expression by disrupting the association of Rbm38 with the Ago2-miR203 complex; unphosphorylated WT Rbm38 associates with Ago2 and facilitates miR203-mediated p63 mRNA degradation; S195D phosphomimetic Rbm38 shows reduced Ago2 association and fails to promote p63 mRNA degradation.","method":"Phosphomimetic/phospho-null mutant knock-in MEFs, Co-IP of Rbm38 with Ago2, miR203-dependent mRNA degradation assays, GSK3β activation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphomimetic knock-in MEF system, Rbm38-Ago2 Co-IP, functional miRNA degradation assays, multiple orthogonal methods","pmids":["30567739"],"is_preprint":false},{"year":2018,"finding":"RBM38 promotes B19V pre-mRNA splicing at the D2 donor site by binding the intronic splicing enhancer 2 (ISE2) element containing the consensus 5'-UGUGUG-3' motif; this promotes 11-kDa viral protein expression that in turn facilitates viral DNA replication and virion release.","method":"In vitro RNA binding assay confirming RBM38-ISE2 interaction, siRNA knockdown of RBM38 in erythroid cells with measurement of spliced mRNA and viral replication","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro RNA binding plus functional knockdown showing splicing and replication consequences, single lab","pmids":["29437973"],"is_preprint":false},{"year":2019,"finding":"Rbm38 silencing improves migratory capacity and proliferation of endothelial cells; local silencing of Rbm38 in vivo improved re-endothelialization of denuded carotid arteries; miR-98 and let-7f regulate Rbm38 (identified by luciferase reporter assay) and their overexpression mimics Rbm38 silencing effects.","method":"siRNA knockdown in HUVECs, in vivo carotid artery injury model with local Rbm38 silencing, luciferase reporter assays for miRNA regulation of Rbm38","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo vascular model plus in vitro functional assays, single lab","pmids":["30843048"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the RRM domain of human RBM38 in complex with single-stranded RNA revealed that RBM38 recognizes G(U/C/A)GUG sequence in a sequence- and structure-specific manner; two phenylalanine residues stack with RNA bases and are crucial for binding; hydrogen bonds between RNA bases and RBM38 main-chain/side-chain atoms determine sequence specificity.","method":"X-ray crystallography of RRM domain–RNA complex, mutagenesis of key residues, RNA binding assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation, defines sequence-specific recognition mechanism","pmids":["31860021"],"is_preprint":false},{"year":2020,"finding":"Alternative splicing of Cdh23 exon 68 is positively regulated by RBM38 (and RBM24) and negatively regulated by PTBP1; RBM38 identified in a cell-based screen as an enhancer of Cdh23 exon 68 inclusion.","method":"Cell-based splicing screen, minigene splicing assays, siRNA knockdown of splicing factors","journal":"Neural plasticity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based screen with functional minigene follow-up, single lab","pmids":["32774357"],"is_preprint":false},{"year":2020,"finding":"Rbm38 reduces the transcription elongation defect of the SMEK2 gene caused by splicing deficiency; this requires the N- and C-terminal regions as well as the RNA recognition motif of Rbm38.","method":"Transcription elongation assays under splicing-deficient conditions, domain deletion analysis of Rbm38","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain dissection with functional transcription elongation assay, single lab","pmids":["33233740"],"is_preprint":false},{"year":2021,"finding":"RBM38 acts as a dual regulator of survivin mRNA: it suppresses let-7b from binding and degrading survivin mRNA (increasing survivin), while also facilitating Ago2-miR-203a-mediated survivin mRNA degradation (decreasing survivin); Ser-195 in RBM38 interacts with Glu-73/-76 in AGO2, and Pep8 blocks the RBM38-AGO2 interaction, inhibiting miR-203a-mediated degradation.","method":"RNA immunoprecipitation, Co-IP of RBM38 with AGO2, miRNA competition assays, Pep8 peptide disruption, tumor spheroid viability assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with AGO2, domain-level interaction mapping, functional miRNA assays, peptide disruption, multiple orthogonal methods","pmids":["33472892"],"is_preprint":false},{"year":2021,"finding":"Fine-tuning of p53 expression by RBM38-eIF4E interaction: KI of RBM38-S195D or -Y192C enhances eIF4E binding to p53 mRNA and increases p53; KI of RBM38-S195K/R/L weakens eIF4E binding and decreases p53; KI of eIF4E-D202K reduces RBM38 interaction and enhances p53; Rbm38-S193D KI mice show enhanced p53-dependent cellular senescence, shortened lifespan, and spontaneous tumors.","method":"Multiple knock-in cell lines (RBM38 and eIF4E point mutants), cap-binding assays, Rbm38-S193D KI mouse model, senescence assays, lifespan monitoring","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KI mouse model plus multiple KI cell lines, cap-binding assays, in vivo lifespan data, multiple orthogonal approaches","pmids":["33664057"],"is_preprint":false},{"year":2021,"finding":"RNPC1 (RBM38) stabilizes MST1/2 mRNA by directly binding to it, activating the Hippo pathway; inhibition of MST1/2 rescues RNPC1-mediated attenuation of endometrial cancer sphere stemness.","method":"RNA immunoprecipitation, overexpression with stemness assays, MST1/2 inhibitor epistasis","journal":"Medical science monitor","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP without EMSA or domain mutagenesis, functional epistasis, single lab","pmids":["32088727"],"is_preprint":false},{"year":2021,"finding":"RBM38 stabilizes AURKB (aurora kinase B) mRNA by directly binding to the AURKB 3' UTR; RNPC1 overexpression increases AURKB mRNA and protein, promotes proliferation, migration and invasion, and causes mitotic defects and chromosomal instability in gastric cancer.","method":"RNA immunoprecipitation, EMSA, dual-luciferase reporter assay, mRNA stability assay, overexpression/knockdown, in vivo xenograft","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding shown by RIP/EMSA/reporter, functional assays, single lab","pmids":["34302858"],"is_preprint":false},{"year":2021,"finding":"RBM38 competes with miR-92a-3p for binding to PTEN 3' UTR, stabilizing PTEN transcript and inhibiting colorectal cancer progression; PTEN overexpression attenuates the effects of RBM38 depletion on CRC.","method":"RNA immunoprecipitation, luciferase reporter assay, competition binding assay, overexpression/knockdown, in vivo xenograft","journal":"Environmental toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive binding shown by RIP and reporter assay, functional epistasis, single lab","pmids":["34453780"],"is_preprint":false},{"year":2021,"finding":"SPRR2A/2D expression is regulated by an RBM38-p73 axis; RBM38 knockout reduces SPRR2A/2D expression; compound Rbm38/Trp73 double-null mice exhibit weak SPRR2A/2D expression in multiple tissues and susceptibility to systemic chronic inflammation, leading to shortened lifespan.","method":"Compound knockout mouse model, gene expression analysis, lifespan and tumor monitoring","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo compound genetic model with functional phenotype, single lab","pmids":["34204113"],"is_preprint":false},{"year":2022,"finding":"RBM38 directly binds to the lower bulge of the HBV epsilon (ε) stem loop via RNA recognition submotifs (RNPs) and interacts with HBV Pol in an RNA-independent manner; RBM38 forms heterogeneous oligomers with RBM24 to mediate Pol-ε binding; RBM38 also binds HBV core via its C-terminal region (ARD domain), facilitating Pol-ε–core combination and triggering pgRNA packaging for reverse transcription.","method":"Co-immunoprecipitation (RBM38 with ε, Pol, RBM24, HBV core), RNA binding assays, domain mapping (RNPs for RNA binding, C-terminal ARD for core interaction), pgRNA packaging assays","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP domain mapping, RNA binding assays, functional pgRNA packaging, single lab","pmids":["35041910"],"is_preprint":false},{"year":2023,"finding":"TRIM17 interacts with RBM38 and promotes K48-linked ubiquitination and proteasomal degradation of RBM38; TRIM17-mediated cisplatin resistance in NSCLC is markedly reversed by RBM38 restoration; RBM38 enhances cisplatin-induced ROS production.","method":"Co-IP of TRIM17 with RBM38, ubiquitination assay (K48-linked), overexpression/knockdown, in vitro and in vivo cisplatin resistance assays","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay, functional rescue, in vivo xenograft, single lab","pmids":["37219768"],"is_preprint":false},{"year":2023,"finding":"CBX7 interacts with TARDBP (TDP-43) and positively regulates RBM38 expression in a TARDBP-dependent manner; overexpression of RBM38 inhibits proliferation of CBX7-depleted neonatal cardiomyocytes, placing RBM38 downstream of the CBX7-TARDBP axis in controlling cardiomyocyte cell cycle exit.","method":"Co-immunoprecipitation (CBX7-TARDBP), mass spectrometry, adenoviral overexpression of CBX7/RBM38, conditional Cbx7 knockout mice, cardiomyocyte proliferation marker immunostaining","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mass spectrometry plus genetic epistasis with KO mice and overexpression rescue, single lab","pmids":["37158107"],"is_preprint":false},{"year":2023,"finding":"Small molecule compound 094 interacts with eIF4E via the same pocket as Pep8, dissociates RBM38 from eIF4E, and enhances TP53 mRNA translation in RBM38- and eIF4E-dependent manners; fluorobenzene and ethyl benzamide moieties are necessary for compound 094-eIF4E interaction; compound 094 suppresses tumor spheroid growth in RBM38- and TP53-dependent manners.","method":"Structure-activity relationship studies, eIF4E binding assays, p53 translation assays (polysome profiling/reporter), tumor spheroid assays, combination assays with doxorubicin/4EGI-1","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SAR studies, direct binding assays, translation assays, in vitro tumor models, multiple orthogonal methods","pmids":["36940176"],"is_preprint":false},{"year":2023,"finding":"RBM38 binds and stabilizes lncRNA GAS5 in sorafenib-resistant HCC cells; RBM38 reverses sorafenib resistance in HCC both in vitro and in vivo in a GAS5-dependent manner.","method":"RNA immunoprecipitation, overexpression/knockdown, drug resistance assays, in vivo xenograft, GAS5 knockdown epistasis","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP without detailed binding characterization, functional epistasis, single lab","pmids":["37296859"],"is_preprint":false},{"year":2025,"finding":"CDK4 phosphorylates RBM38 at Ser195; CDK4/6 inhibitors suppress mutant p53 mRNA translation through RBM38 by reducing Ser195 phosphorylation, which shifts RBM38 interaction from eIF4G (translation promotion) to eIF4E (translation repression) on p53 mRNA.","method":"CDK4/6 inhibitor treatment with RBM38 phosphorylation analysis, translation assays with p53 mRNA, RBM38 overexpression/knockdown, cell survival assays in RB-proficient and -deficient TNBC cells","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-substrate relationship with translation assays and functional cell survival, single lab","pmids":["41154395"],"is_preprint":false},{"year":2025,"finding":"Rbm38 regulates terminal erythropoiesis and heme biosynthesis by modulating alternative splicing, mRNA decay, and translation of Ferrochelatase (Fech); Rbm38-deficient mice develop microcytic hypochromic anemia, erythropoietic protoporphyria-like disease with PPIX accumulation; enforced Fech expression largely restores erythroid differentiation in Rbm38-null transplants.","method":"Conditional and whole-body knockout mouse models, transcriptome/splicing analysis, Fech rescue experiments (reconstitution transplant), erythroid differentiation assays, heme biosynthesis measurements","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mice, in vivo epistasis rescue with Fech, multiple regulatory mechanisms (splicing/stability/translation) identified, functional heme biosynthesis measurements","pmids":["40961234"],"is_preprint":false},{"year":2026,"finding":"In zebrafish, Rbm38 destabilizes pdx1 mRNA by binding to its 3' UTR and regulates alternative splicing of isl1a, smad2, and nkx2.2a; loss of Rbm38 leads to abnormal pancreatic enlargement.","method":"Zebrafish rbm38 loss-of-function, mRNA stability assays for pdx1 3' UTR binding, alternative splicing analysis for isl1a/smad2/nkx2.2a, pancreatic morphology assessment","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish KO model, direct RNA binding for pdx1, splicing analysis, single lab","pmids":["40796306"],"is_preprint":false}],"current_model":"RBM38 (RNPC1) is an RNA-binding protein that uses its RRM domain (preferentially recognizing GU/U-rich and AU-rich elements in target 3' and 5' UTRs) to regulate mRNA stability, alternative splicing, and translation of numerous targets including p21, p53, MDM2, p63, p73, HuR, PTEN, HIF1α, and Ferrochelatase; it represses p53 mRNA translation by physically blocking eIF4E from the p53 mRNA cap, a mechanism regulated by phosphorylation at Ser195 (by GSK3 or CDK4, reversed by PPM1D), which switches RBM38 from an eIF4E-interacting repressor to an eIF4G-recruiting activator of translation; RBM38 also controls miRNA accessibility to target mRNAs through association with Ago2, and its own expression is controlled transcriptionally by p53 family members and E2F1, post-translationally by ubiquitin ligases TRIM17 and RNF26, and upstream by TARDBP/CBX7 signaling in cardiomyocytes."},"narrative":{"mechanistic_narrative":"RBM38 (RNPC1) is an RRM-domain RNA-binding protein that governs post-transcriptional gene expression—mRNA stability, alternative splicing, translation, and miRNA accessibility—within a regulatory hub centered on the p53 family and cell-cycle/senescence control [PMID:17050675, PMID:21764855, PMID:24250749]. Its RRM recognizes G(U/C/A)GUG and AU/U-rich elements through two stacking phenylalanine residues and sequence-specific hydrogen bonds, as resolved by crystallography [PMID:31860021]. Through these elements RBM38 stabilizes a set of growth-suppressive transcripts (p21, p73, PTEN, HuR, MIC-1) while destabilizing others (p63, MDM2, c-Myc), thereby coupling p53-family output to differentiation, growth arrest, and senescence [PMID:17050675, PMID:20457941, PMID:22710720, PMID:22371495, PMID:22508983, PMID:29052531]. A central node is translational repression of p53: RBM38 uses its N-terminus to bind p53 mRNA 5'/3' UTRs and its C-terminus to bind eIF4E, blocking cap recognition; this repression is converted to activation when Ser195 phosphorylation (by GSK3 or CDK4, reversed by PPM1D) switches RBM38 from an eIF4E-interacting repressor to an eIF4G-recruiting promoter of eIF4F assembly [PMID:21764855, PMID:24142875, PMID:25823026, PMID:41154395]. The same Ser195 switch governs RBM38's association with Ago2, tuning miRNA-mediated decay of targets such as p63 and survivin [PMID:30567739, PMID:33472892]. The p53-RBM38 loop and the RBM38-p63 loop operate in vivo, where Rbm38 loss accelerates aging, causes hematopoietic defects and tumors, and modulates p53/p63-dependent senescence [PMID:25512531, PMID:29520104]. Beyond the p53 axis, RBM38 controls alternative splicing during erythroid differentiation, regulating Protein 4.1R and Ferrochelatase to support heme biosynthesis—its loss producing microcytic anemia and an erythropoietic protoporphyria-like phenotype [PMID:24250749, PMID:40961234]. The eIF4E-binding interface is druggable: a derived peptide (Pep8) and small molecule 094 dissociate RBM38 from eIF4E to relieve p53 translational repression and suppress tumor growth [PMID:30591552, PMID:36940176].","teleology":[{"year":2006,"claim":"Established RBM38 as a direct, isoform-specific regulator of mRNA stability, linking it to p21 and cell-cycle arrest.","evidence":"RNA binding assays plus knockdown/overexpression mRNA stability and cell-cycle analysis of RNPC1a vs RNPC1b","pmids":["17050675"],"confidence":"High","gaps":["Mechanism distinguishing isoform a from b activity not defined","binding-site element on p21 3' UTR not mapped at residue level"]},{"year":2010,"claim":"Showed RBM38 acts cooperatively with HuR and can both stabilize (p21) and destabilize (p63) transcripts through its RRM, broadening its target logic.","evidence":"Reciprocal Co-IP/domain mapping with HuR, RNA-IP, EMSA, and RRM-mutant stability assays in keratinocyte differentiation","pmids":["20064878","20457941"],"confidence":"High","gaps":["What determines whether RBM38 stabilizes versus destabilizes a given target is unresolved","no structural basis for HuR cooperativity"]},{"year":2011,"claim":"Defined RBM38's translational-repression mechanism—blocking eIF4E from the p53 mRNA cap—and its miRNA-gating role, embedding it in a p53 autoregulatory circuit.","evidence":"Domain-mapped Co-IP with eIF4E, polysome profiling, MEF senescence assays, and a genetic screen for RBP control of miRNA activity","pmids":["21764855","22027593"],"confidence":"High","gaps":["Stoichiometry of RBM38-eIF4E-mRNA complex unknown","rules governing which miRNA target sites RBM38 occludes not generalized"]},{"year":2012,"claim":"Expanded the target network (MDM2, HuR, p73, MIC-1) and identified E2F1 as a transcriptional input, positioning RBM38 in multiple feedback loops controlling growth suppression and senescence.","evidence":"RNA-IP/EMSA stability assays with RRM mutants, KO corroboration, siRNA epistasis in MEFs, and E2F1 promoter ChIP","pmids":["22710720","22371495","22508983","23836903","22798430"],"confidence":"High","gaps":["Hierarchy among competing targets in a single cell unclear","E2F1 regulation is Medium-confidence and single-lab"]},{"year":2013,"claim":"Resolved how RBM38's regulatory mode is switched and defined a splicing-activator role, with SELEX-Seq fixing a GU-rich binding motif.","evidence":"In vitro GSK3 kinase assay, phosphomimetic S195D mutants, Co-IP with eIF4E/eIF4G, and minigene/tethering splicing assays with SELEX-Seq","pmids":["24142875","24250749"],"confidence":"High","gaps":["How Ser195 phosphorylation physically remodels the eIF4E vs eIF4G interface not structurally defined","splicing target repertoire incomplete"]},{"year":2014,"claim":"Provided in vivo genetic proof of the p53-Rbm38 autoregulatory loop through aging, tumor, and radiation-sensitivity phenotypes.","evidence":"Rbm38-null mice, IR challenge, and compound epistasis with p53-heterozygous mice","pmids":["25512531"],"confidence":"High","gaps":["Tissue-specific contributions of individual targets to phenotypes not dissected"]},{"year":2015,"claim":"Identified PPM1D as the phosphatase reversing the Ser195 switch and extended translational control to HIF1α, defining bidirectional regulatory axes.","evidence":"In vitro dephosphorylation assay, Co-IP, RNA-IP, cap-binding assays, and reporter assays for PPM1D and HIF1α UTRs","pmids":["25823026","25622105"],"confidence":"Medium","gaps":["HIF1α regulation single-lab and Medium-confidence","kinetics of phosphorylation/dephosphorylation cycling in vivo unknown"]},{"year":2017,"claim":"Embedded RBM38 in multiple cancer feedback loops (c-Myc, Snail/ZO-1, ER/PR, PTEN, ceRNA network) controlling proliferation and metastasis.","evidence":"ChIP, RNA-IP, EMSA, reporter assays, and migration/invasion assays across breast and other cancer models","pmids":["28399911","28683467","29052531","25881544","27634883","29733656"],"confidence":"Medium","gaps":["Several of these (ER, PR, ceRNA) are Low-confidence single-RIP studies without domain mutagenesis","in vivo relevance of many target loops untested"]},{"year":2018,"claim":"Demonstrated druggability of the eIF4E interface and provided in vivo confirmation of Rbm38-PTEN and Rbm38-p63 loops in tumor suppression, plus a viral splicing role.","evidence":"Structure-guided Pep8 peptide with xenografts, compound-mutant mouse models (mutant-p53 KI, TAp63+/-), Ago2 Co-IP in phosphomimetic MEFs, and B19V splicing assays","pmids":["30591552","29330147","29520104","30567739","29437973"],"confidence":"High","gaps":["Therapeutic window of eIF4E-disrupting agents unknown","generality of the Ser195-Ago2 switch beyond p63 not yet broad"]},{"year":2020,"claim":"Delivered the structural basis of sequence-specific RNA recognition and expanded the splicing/transcription-coupling repertoire.","evidence":"X-ray crystallography of the RRM-ssRNA complex with mutagenesis, plus cell-based splicing screens (Cdh23) and transcription-elongation assays (SMEK2)","pmids":["31860021","32774357","33233740"],"confidence":"High","gaps":["Structure of full-length RBM38 or its complexes with eIF4E/Ago2 not solved","how single RRM achieves diverse target outcomes unexplained"]},{"year":2021,"claim":"Refined the Ser195 fine-tuning of p53 in vivo and clarified RBM38's dual, opposing control of miRNA-mediated decay via direct AGO2 contacts.","evidence":"Multiple RBM38/eIF4E knock-in cell lines and Rbm38-S193D KI mice with cap-binding/senescence/lifespan data, plus reciprocal AGO2 Co-IP and Pep8 disruption on survivin","pmids":["33664057","33472892","34302858","34453780","32088727","34204113"],"confidence":"High","gaps":["How RBM38 chooses between protective and decay-promoting miRNA modes on one transcript is unclear","several downstream cancer targets remain Low/Medium-confidence single-lab"]},{"year":2023,"claim":"Identified upstream regulators of RBM38 protein and expression (TRIM17 ubiquitination, CBX7-TARDBP axis) and a small-molecule eIF4E disruptor, linking RBM38 to drug resistance and cardiomyocyte cell-cycle exit.","evidence":"TRIM17 Co-IP/K48-ubiquitination assays, CBX7-TARDBP Co-IP/MS with conditional KO mice, and SAR-driven compound 094 binding/translation assays","pmids":["37219768","37158107","36940176","37296859"],"confidence":"Medium","gaps":["RNF26 ubiquitin-ligase regulation not represented by a discovery in this timeline","mechanism coupling CBX7-TARDBP to RBM38 transcription incompletely defined"]},{"year":2025,"claim":"Established a dedicated developmental/physiological role in erythropoiesis and heme biosynthesis through multi-modal regulation of Ferrochelatase, and identified CDK4 as a second Ser195 kinase.","evidence":"Conditional/whole-body Rbm38 KO mice with Fech rescue transplants and heme measurements, and CDK4/6-inhibitor translation assays in TNBC","pmids":["40961234","41154395"],"confidence":"High","gaps":["Coordination of splicing, decay, and translation of Fech by a single RBP not mechanistically integrated","CDK4 phosphorylation data are Medium-confidence single-lab"]},{"year":null,"claim":"How a single RRM with one defined RNA motif selects between stabilizing, destabilizing, splicing-activating, translation-repressing, and miRNA-gating outcomes on different targets remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of RBM38 in its eIF4E/eIF4G/Ago2 complexes","no global rule predicting target outcome from binding-site context","interplay of competing trans-acting partners (HuR, Ago2, eIF4E/4G) on a shared transcript not quantitatively defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,3,5,28,37]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[10,29,43,44]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[3,11,14,32]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,25,31]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,10,43]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,8,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,24]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,11,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,10,43,44]}],"complexes":["eIF4F (eIF4E/eIF4G on p53 mRNA cap)","RBM38-Ago2 miRNA complex"],"partners":["EIF4E","EIF4G","ELAVL1","AGO2","PPM1D","GSK3B","TRIM17","RBM24"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H0Z9","full_name":"RNA-binding protein 38","aliases":["CLL-associated antigen KW-5","HSRNASEB","RNA-binding motif protein 38","RNA-binding region-containing protein 1","ssDNA-binding protein SEB4"],"length_aa":239,"mass_kda":25.5,"function":"RNA-binding protein that specifically bind the 3'-UTR of CDKN1A transcripts, leading to maintain the stability of CDKN1A transcripts, thereby acting as a mediator of the p53/TP53 family to regulate CDKN1A. CDKN1A is a cyclin-dependent kinase inhibitor transcriptionally regulated by the p53/TP53 family to induce cell cycle arrest. Isoform 1, but not isoform 2, has the ability to induce cell cycle arrest in G1 and maintain the stability of CDKN1A transcripts induced by p53/TP53. Also acts as a mRNA splicing factor. Specifically regulates the expression of FGFR2-IIIb, an epithelial cell-specific isoform of FGFR2. Plays a role in myogenic differentiation (Microbial infection) Essential factor for the splicing of the pre-mRNAs of human parvovirus B19 (B19V) and for the expression of B19V 11-kDa protein, which enhances viral replication","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H0Z9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM38","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000132819","cell_line_id":"CID001483","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"RBM38;RBM24","stoichiometry":10.0},{"gene":"RAF1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001483","total_profiled":1310},"omim":[{"mim_id":"617603","title":"RNA-BINDING MOTIF PROTEIN 24; RBM24","url":"https://www.omim.org/entry/617603"},{"mim_id":"612428","title":"RNA-BINDING MOTIF PROTEIN 38; RBM38","url":"https://www.omim.org/entry/612428"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":251.7},{"tissue":"skeletal muscle","ntpm":261.1}],"url":"https://www.proteinatlas.org/search/RBM38"},"hgnc":{"alias_symbol":["HSRNASEB","SEB4D","seb4B","dJ800J21.2"],"prev_symbol":["RNPC1"]},"alphafold":{"accession":"Q9H0Z9","domains":[{"cath_id":"3.30.70.330","chopping":"34-109","consensus_level":"high","plddt":94.2104,"start":34,"end":109}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0Z9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0Z9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0Z9-F1-predicted_aligned_error_v6.png","plddt_mean":67.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM38","jax_strain_url":"https://www.jax.org/strain/search?query=RBM38"},"sequence":{"accession":"Q9H0Z9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H0Z9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H0Z9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0Z9"}},"corpus_meta":[{"pmid":"17050675","id":"PMC_17050675","title":"RNPC1, 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/34868364","citation_count":8,"is_preprint":false},{"pmid":"31966462","id":"PMC_31966462","title":"RNA-binding protein RBM38 acts as a tumor suppressor in gastric cancer.","date":"2017","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31966462","citation_count":7,"is_preprint":false},{"pmid":"37296859","id":"PMC_37296859","title":"RBM38 Reverses Sorafenib Resistance in Hepatocellular Carcinoma Cells by Combining and Promoting lncRNA-GAS5.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37296859","citation_count":7,"is_preprint":false},{"pmid":"36940176","id":"PMC_36940176","title":"Identification of a First-in-Class Small-Molecule Inhibitor of the EIF4E-RBM38 Complex That Enhances Wild-type TP53 Protein Translation for Tumor Growth Suppression.","date":"2023","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/36940176","citation_count":7,"is_preprint":false},{"pmid":"31760527","id":"PMC_31760527","title":"RBM38 induces SIRT1 expression during hypoxia in non-small cell lung cancer cells by suppressing MIR34A expression.","date":"2019","source":"Biotechnology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31760527","citation_count":7,"is_preprint":false},{"pmid":"32862581","id":"PMC_32862581","title":"Roles of ZEB2 and RBM38 in liver cancer stem cell proliferation.","date":"2020","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32862581","citation_count":6,"is_preprint":false},{"pmid":"33472892","id":"PMC_33472892","title":"Survivin Expression Is Differentially Regulated by a Selective Cross-talk between RBM38 and miRNAs let-7b or miR-203a.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33472892","citation_count":6,"is_preprint":false},{"pmid":"34302858","id":"PMC_34302858","title":"RNA-binding protein RNPC1 acts as an oncogene in gastric cancer by stabilizing aurora kinase B mRNA.","date":"2021","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34302858","citation_count":5,"is_preprint":false},{"pmid":"34204113","id":"PMC_34204113","title":"Small Proline-Rich Protein 2A and 2D Are Regulated by the RBM38-p73 Axis and Associated with p73-Dependent Suppression of Chronic Inflammation.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34204113","citation_count":4,"is_preprint":false},{"pmid":"37099788","id":"PMC_37099788","title":"RNF26 Promotes Pancreatic Cancer Proliferation by Enhancing RBM38 Degradation.","date":"2023","source":"Pancreas","url":"https://pubmed.ncbi.nlm.nih.gov/37099788","citation_count":3,"is_preprint":false},{"pmid":"35574389","id":"PMC_35574389","title":"Optimization of eIF4E-Binding Peptide Pep8 to Disrupt the RBM38-eIF4E Complex for Induction of p53 and Tumor Suppression.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35574389","citation_count":3,"is_preprint":false},{"pmid":"33233740","id":"PMC_33233740","title":"Rbm38 Reduces the Transcription Elongation Defect of the SMEK2 Gene Caused by Splicing Deficiency.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33233740","citation_count":3,"is_preprint":false},{"pmid":"40961234","id":"PMC_40961234","title":"Rbm38 deficiency impairs erythroid heme biosynthesis and induces porphyria via reduced ferrochelatase expression.","date":"2025","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/40961234","citation_count":2,"is_preprint":false},{"pmid":"26988821","id":"PMC_26988821","title":"[RNPC1 induces sensitivity of HER-2-positive breast cancer BT474 cells to trastuzumab through upregulation of HER2].","date":"2016","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/26988821","citation_count":2,"is_preprint":false},{"pmid":"40796306","id":"PMC_40796306","title":"RNA-binding protein Rbm38 as a multifaceted post-transcriptional regulator in zebrafish pancreatic development.","date":"2026","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/40796306","citation_count":0,"is_preprint":false},{"pmid":"34893109","id":"PMC_34893109","title":"[RBM38 Mediates the Proliferation of Acute Myeloid Leukemia Cells HL-60 by Regulating FZD1 mRNA Stability].","date":"2021","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/34893109","citation_count":0,"is_preprint":false},{"pmid":"41154395","id":"PMC_41154395","title":"CDK4/6 Inhibitors Suppress RB-Null Triple-Negative Breast Cancer by Inhibiting Mutant P53 Expression via RBM38 RNA-Binding Protein.","date":"2025","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/41154395","citation_count":0,"is_preprint":false},{"pmid":"40527976","id":"PMC_40527976","title":"EIF4A3-Mediated downregulation of circPTEN promotes hepatocellular carcinoma progression through the miR-1289/RBM38 Axis.","date":"2025","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/40527976","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.10.632466","title":"Identification and classification of abundant RNA-binding proteins in the mouse lens and interactions of Carhsp1, Igf2bp1/ZBP1, and Ybx1 with crystallin and β-actin mRNAs","date":"2025-01-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.10.632466","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35992,"output_tokens":10865,"usd":0.135475,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21562,"output_tokens":4987,"usd":0.116242,"stage2_stop_reason":"end_turn"},"total_usd":0.251717,"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\": 2006,\n      \"finding\": \"RNPC1a (RBM38 isoform) directly binds to the 3' UTR of p21 mRNA and stabilizes it, maintaining basal and stress-induced p21 transcript levels; RNPC1a but not RNPC1b induces G1 cell cycle arrest and stabilizes p21 transcript, despite both isoforms being expressed in nucleus and cytoplasm and both binding p21 3' UTR.\",\n      \"method\": \"RNA binding assays, knockdown/overexpression with mRNA stability assays, cell cycle analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct RNA binding demonstrated, isoform-specific functional dissection, replicated with knockdown and overexpression, multiple orthogonal methods\",\n      \"pmids\": [\"17050675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNPC1 (RBM38) and HuR physically interact via the RRM domain of RNPC1 and RRM3 of HuR; RNPC1 and HuR preferentially bind upstream and downstream AU-rich elements (AREs) in p21 3'-UTR respectively; RNPC1 enhances HuR's RNA-binding activity to p21 transcript in vitro and in vivo, and RNPC1's ability to stabilize p21 mRNA is dependent on HuR.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, in vitro RNA binding assays, domain-mapping experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein interaction mapping, domain-level mutagenesis, in vitro and in vivo RNA binding assays in single study\",\n      \"pmids\": [\"20064878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNPC1 (RBM38) binds AU-/U-rich elements in p63 3' UTR via its RRM domain and destabilizes p63 transcript, reducing p63 expression; RNPC1 RRM domain is required for binding and regulating p63 mRNA stability; RNPC1 promotes keratinocyte differentiation by repressing p63 expression.\",\n      \"method\": \"RNA immunoprecipitation, in vitro RNA binding (EMSA), overexpression/knockdown with mRNA stability assays, RRM mutant analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct RNA binding with domain mapping, functional consequence in differentiation, multiple orthogonal methods\",\n      \"pmids\": [\"20457941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RNPC1 (RBM38) represses p53 mRNA translation by preventing eIF4E from binding to p53 mRNA; RNPC1 uses its C-terminal domain to physically interact with eIF4E and its N-terminal domain to bind p53 mRNA 5' and 3' UTRs; loss of RNPC1 in MEFs increases p53 protein, leading to enhanced premature senescence in a p53-dependent manner.\",\n      \"method\": \"Overexpression/knockdown translation assays, domain-mapping Co-IP with eIF4E, RNA-binding assays with p53 5'/3' UTR, polysome profiling, MEF senescence assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-level dissection of eIF4E interaction and RNA binding, multiple orthogonal methods, in vivo MEF validation\",\n      \"pmids\": [\"21764855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RBM38 selectively blocks miRNA access to target mRNAs by interacting with uridine-rich regions near miRNA target sequences; RBM38 is induced by p53 and its ability to modulate miRNA-mediated repression is required for proper p53 function; RBM38 shows lower propensity to block p53-controlled miR-34a action on SIRT1.\",\n      \"method\": \"Genetic screen for RBPs controlling miRNA activity, luciferase reporter assays, RNA binding assays, RBM38 overexpression/knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic screen plus mechanistic follow-up with RNA binding assays and reporter assays, multiple targets examined\",\n      \"pmids\": [\"22027593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RNPC1 (RBM38) destabilizes MDM2 transcript via binding to multiple AU-/U-rich elements in MDM2 3' UTR, reducing MDM2 expression independent of p53; RNA-binding activity of RNPC1 (RRM domain) is required for binding MDM2 transcript and inhibiting MDM2 expression.\",\n      \"method\": \"Overexpression/knockdown/knockout mRNA stability assays, RNA immunoprecipitation, EMSA, reporter assays with MDM2 3' UTR, RRM mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct RNA binding with domain requirement, multiple orthogonal methods, KO corroboration\",\n      \"pmids\": [\"22710720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RNPC1 (RBM38) post-transcriptionally stabilizes HuR mRNA via binding to its 3' UTR; RNA-binding-deficient RNPC1 mutant fails to stabilize HuR transcript; HuR, by repressing c-Myc expression, mediates RNPC1-induced growth suppression.\",\n      \"method\": \"Overexpression/knockdown/knockout mRNA stability assays, RNA immunoprecipitation, RNA-binding mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA-binding mutant used, KO corroboration, epistasis (HuR → c-Myc → growth suppression), multiple methods\",\n      \"pmids\": [\"22371495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p73 mRNA stability is regulated by RNPC1 (RBM38) via a CU-rich element in the p73 3' UTR; loss of RNPC1 in p53-null MEFs reduces p73 expression along with p21 and p130, decreasing senescent cell number; combined knockdown of TAp73 and p21 completely abolishes RNPC1-mediated growth suppression and senescence.\",\n      \"method\": \"Overexpression/knockdown mRNA stability assays, RNA immunoprecipitation, EMSA, siRNA epistasis in MEFs\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct RNA binding, epistasis experiments, multiple orthogonal methods\",\n      \"pmids\": [\"22508983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RBM38 is a direct transcriptional target of E2F1; endogenous E2F1 binds the RBM38 promoter; RBM38 and E2F1 constitute a negative feedback loop limiting E2F1-induced cell-cycle progression.\",\n      \"method\": \"ChIP demonstrating E2F1 binding to RBM38 promoter, siRNA knockdown of E2F1, cell-cycle analysis with RBM38 inhibition\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional cell-cycle assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"22798430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RNPC1 (RBM38) binds to an AU-rich element in MIC-1 3' UTR and stabilizes MIC-1 mRNA, increasing MIC-1 expression; knockdown of MIC-1 decreases RNPC1-induced cell growth suppression.\",\n      \"method\": \"Overexpression/knockdown/knockout mRNA stability assays, RNA immunoprecipitation, siRNA epistasis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding, functional epistasis, single lab\",\n      \"pmids\": [\"23836903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBM38 regulates alternative splicing during late erythroid differentiation, including activation of Protein 4.1R (EPB41) exon 16 splicing; RBM38 directly activates splicing when recruited to a downstream intron (tethering assay); SELEX-Seq identified a GU-rich RBM38 binding motif.\",\n      \"method\": \"Exon junction splicing microarray, minigene splicing assays, SELEX-Seq for binding motif, tethering assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SELEX-Seq motif identification, minigene validation, tethering assay, multiple orthogonal methods\",\n      \"pmids\": [\"24250749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GSK3 phosphorylates RNPC1 (RBM38) at Ser195; phosphorylation at Ser195 (mimicked by S195D mutant) abolishes RNPC1's interaction with eIF4E on p53 mRNA and instead promotes interaction with eIF4G, facilitating assembly of the eIF4F complex on p53 mRNA and thereby promoting p53 mRNA translation; PI3K-Akt pathway inhibition activates GSK3, increases RNPC1 phosphorylation, and increases p53 expression in an RNPC1-dependent manner.\",\n      \"method\": \"In vitro kinase assay, phosphomimetic/deletion mutant analysis, Co-IP with eIF4E and eIF4G, polysome/cap-binding assays, PI3K inhibitor treatment\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus multiple mutants, Co-IP with translation factors, pathway intervention, multiple orthogonal methods\",\n      \"pmids\": [\"24142875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rbm38-null mice exhibit accelerated aging, hematopoietic defects, and spontaneous tumors; Rbm38 deficiency enhances IR-induced p53 accumulation and sensitizes mice to IR-induced lethality in a p53-dependent manner; Rbm38 deficiency markedly decreases tumor penetrance in p53 heterozygous mice via enhanced p53 expression; providing in vivo genetic evidence for the p53-Rbm38 autoregulatory loop.\",\n      \"method\": \"Knockout mouse model, ionizing radiation challenge, epistasis with p53-heterozygous mice, tumor monitoring\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with null mice and p53 compound mutants, replicated phenotypes\",\n      \"pmids\": [\"25512531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PPM1D phosphatase directly interacts with RBM38 and dephosphorylates it at Ser195; dephosphorylated RBM38 represses p53 mRNA translation; RBM38 in turn promotes PPM1D mRNA translation by binding to PPM1D 3' UTR; creating a PPM1D-RBM38-p53 regulatory axis.\",\n      \"method\": \"Co-IP, in vitro dephosphorylation assay, RNA immunoprecipitation, reporter assays with PPM1D 3' UTR, translation/growth suppression assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro dephosphorylation, direct RNA binding, reciprocal regulatory loop with multiple orthogonal methods\",\n      \"pmids\": [\"25823026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBM38 (RNPC1) regulates HIF1α expression via mRNA translation under hypoxia by directly binding HIF1α 5' and 3' UTRs and preventing eIF4E binding to HIF1α mRNA; knockdown of RBM38 increases de novo HIF1α protein synthesis rate.\",\n      \"method\": \"Overexpression/knockdown, de novo protein synthesis assays, RNA immunoprecipitation, cap-binding assay with eIF4E, reporter assays with HIF1α UTRs\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding plus eIF4E cap-binding assay, single lab, multiple methods\",\n      \"pmids\": [\"25622105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM38 stabilizes PTEN mRNA by binding to multiple AU/U-rich elements in PTEN 3' UTR; PTEN inhibition partially reverses RBM38-mediated growth suppression in breast cancer cells.\",\n      \"method\": \"RNA immunoprecipitation, EMSA, dual-luciferase reporter assay, overexpression/knockdown mRNA stability assays, PTEN inhibitor/siRNA epistasis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding with multiple methods, functional epistasis, single lab\",\n      \"pmids\": [\"29052531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TGF-β induces Snail, which directly represses RBM38 transcription via E-box elements in the RBM38 promoter; RBM38 in turn stabilizes ZO-1 mRNA by binding AU/U-rich elements in ZO-1 3' UTR, and RBM38 overexpression reverses ZO-1 knockdown-mediated cell migration and invasion.\",\n      \"method\": \"ChIP assay (Snail on RBM38 promoter), luciferase reporter assay, RNA immunoprecipitation, EMSA, Transwell migration/invasion assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus direct RNA binding plus functional rescue, single lab\",\n      \"pmids\": [\"28683467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM38 destabilizes c-Myc mRNA by directly targeting AU-rich elements in c-Myc 3' UTR; c-Myc transcription factor suppresses RBM38 gene expression by binding E-box motifs in the RBM38 promoter, forming a mutually antagonistic RBM38–c-Myc feedback loop.\",\n      \"method\": \"ChIP assay (c-Myc on RBM38 promoter), RNA immunoprecipitation, dual-luciferase reporter assay, overexpression/knockdown with mRNA stability\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus direct RNA binding, single lab, two orthogonal methods\",\n      \"pmids\": [\"28399911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RNPC1 (RBM38) stabilizes ESR1 (ERα) mRNA by binding to AREs in ERα 3' UTR, increasing ERα expression; reciprocally, ERα overexpression decreases RNPC1 transcript and protein levels, forming a feedback loop.\",\n      \"method\": \"RNA immunoprecipitation, overexpression/knockdown mRNA stability assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/RIP, no domain mutagenesis, single lab\",\n      \"pmids\": [\"25881544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RNPC1 (RBM38) stabilizes progesterone receptor (PR) mRNA by binding AU-rich elements in PR 3' UTR; RBM38 overexpression increases PR mRNA and protein and enhances progesterone-dependent proliferation in vitro and in vivo.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assays, overexpression/knockdown, in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP, no domain mutagenesis, single lab\",\n      \"pmids\": [\"27634883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM38 (RNPC1) stabilizes mRNAs of STARD13, CDH5, HOXD10, and HOXD1 in breast cancer cells, promoting a ceRNA network that inhibits cancer cell metastasis.\",\n      \"method\": \"Overexpression/knockdown with mRNA stability assays, functional invasion assays\",\n      \"journal\": \"Molecular pharmaceutics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mRNA stability with overexpression/knockdown, limited mechanistic detail in abstract, single lab\",\n      \"pmids\": [\"29733656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBM38 destabilizes MDM2 mRNA through binding AU/U-rich elements in MDM2 3' UTR in HCC, restoring wild-type p53 expression and suppressing HCC cell proliferation, migration, invasion, and tumor growth in vivo.\",\n      \"method\": \"Luciferase reporter assay with MDM2 3' UTR, overexpression/knockdown, functional assays in vitro and in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding shown by reporter assay, functional assays with in vivo validation, single lab\",\n      \"pmids\": [\"30176896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"An 8-amino acid peptide (Pep8) derived from the eIF4E-binding interface of RBM38 disrupts the RBM38-eIF4E complex; molecular simulations identified Ser-6 in Pep8 forms a hydrogen bond with Asp-202 in eIF4E; Pep8 relieves RBM38-mediated repression of p53 translation and suppresses tumor growth in RBM38- and p53-dependent manners.\",\n      \"method\": \"Molecular simulation, peptide competition assays, p53 translation assays, colony/tumor sphere formation, xenograft assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structure-guided peptide design with molecular simulation, in vitro translation assays, in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"30591552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rbm38 is required for Pten mRNA stabilization through an AU-rich element in Pten 3' UTR; genetic ablation of Rbm38 in mutant p53 knock-in mice decreases PTEN expression, enhances mutant p53 expression, and promotes T-cell lymphomagenesis.\",\n      \"method\": \"Rbm38 knockout in mutant p53 knock-in mice, mRNA stability assays, 3' UTR binding assays, tumor monitoring\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model, direct RNA binding, compound mutant epistasis\",\n      \"pmids\": [\"29330147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The Rbm38-p63 negative feedback loop operates in vivo: Rbm38 deficiency reduces tumor penetrance in TAp63+/- mice, extends lifespan of tumor-free TAp63+/- mice, reduces senescence markers and inflammatory cytokines (IL17D, Tnfsf15), while Rbm38-/-;TAp63+/- MEFs are resistant to cellular senescence.\",\n      \"method\": \"Compound knockout/heterozygous mouse model, lifespan monitoring, MEF senescence assays, cytokine expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with compound mutants, MEF functional assays, multiple phenotypic readouts\",\n      \"pmids\": [\"29520104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ser-195 phosphorylation of Rbm38 by GSK3β increases p63α expression by disrupting the association of Rbm38 with the Ago2-miR203 complex; unphosphorylated WT Rbm38 associates with Ago2 and facilitates miR203-mediated p63 mRNA degradation; S195D phosphomimetic Rbm38 shows reduced Ago2 association and fails to promote p63 mRNA degradation.\",\n      \"method\": \"Phosphomimetic/phospho-null mutant knock-in MEFs, Co-IP of Rbm38 with Ago2, miR203-dependent mRNA degradation assays, GSK3β activation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphomimetic knock-in MEF system, Rbm38-Ago2 Co-IP, functional miRNA degradation assays, multiple orthogonal methods\",\n      \"pmids\": [\"30567739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBM38 promotes B19V pre-mRNA splicing at the D2 donor site by binding the intronic splicing enhancer 2 (ISE2) element containing the consensus 5'-UGUGUG-3' motif; this promotes 11-kDa viral protein expression that in turn facilitates viral DNA replication and virion release.\",\n      \"method\": \"In vitro RNA binding assay confirming RBM38-ISE2 interaction, siRNA knockdown of RBM38 in erythroid cells with measurement of spliced mRNA and viral replication\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro RNA binding plus functional knockdown showing splicing and replication consequences, single lab\",\n      \"pmids\": [\"29437973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rbm38 silencing improves migratory capacity and proliferation of endothelial cells; local silencing of Rbm38 in vivo improved re-endothelialization of denuded carotid arteries; miR-98 and let-7f regulate Rbm38 (identified by luciferase reporter assay) and their overexpression mimics Rbm38 silencing effects.\",\n      \"method\": \"siRNA knockdown in HUVECs, in vivo carotid artery injury model with local Rbm38 silencing, luciferase reporter assays for miRNA regulation of Rbm38\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo vascular model plus in vitro functional assays, single lab\",\n      \"pmids\": [\"30843048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the RRM domain of human RBM38 in complex with single-stranded RNA revealed that RBM38 recognizes G(U/C/A)GUG sequence in a sequence- and structure-specific manner; two phenylalanine residues stack with RNA bases and are crucial for binding; hydrogen bonds between RNA bases and RBM38 main-chain/side-chain atoms determine sequence specificity.\",\n      \"method\": \"X-ray crystallography of RRM domain–RNA complex, mutagenesis of key residues, RNA binding assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation, defines sequence-specific recognition mechanism\",\n      \"pmids\": [\"31860021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Alternative splicing of Cdh23 exon 68 is positively regulated by RBM38 (and RBM24) and negatively regulated by PTBP1; RBM38 identified in a cell-based screen as an enhancer of Cdh23 exon 68 inclusion.\",\n      \"method\": \"Cell-based splicing screen, minigene splicing assays, siRNA knockdown of splicing factors\",\n      \"journal\": \"Neural plasticity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based screen with functional minigene follow-up, single lab\",\n      \"pmids\": [\"32774357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rbm38 reduces the transcription elongation defect of the SMEK2 gene caused by splicing deficiency; this requires the N- and C-terminal regions as well as the RNA recognition motif of Rbm38.\",\n      \"method\": \"Transcription elongation assays under splicing-deficient conditions, domain deletion analysis of Rbm38\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain dissection with functional transcription elongation assay, single lab\",\n      \"pmids\": [\"33233740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM38 acts as a dual regulator of survivin mRNA: it suppresses let-7b from binding and degrading survivin mRNA (increasing survivin), while also facilitating Ago2-miR-203a-mediated survivin mRNA degradation (decreasing survivin); Ser-195 in RBM38 interacts with Glu-73/-76 in AGO2, and Pep8 blocks the RBM38-AGO2 interaction, inhibiting miR-203a-mediated degradation.\",\n      \"method\": \"RNA immunoprecipitation, Co-IP of RBM38 with AGO2, miRNA competition assays, Pep8 peptide disruption, tumor spheroid viability assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with AGO2, domain-level interaction mapping, functional miRNA assays, peptide disruption, multiple orthogonal methods\",\n      \"pmids\": [\"33472892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fine-tuning of p53 expression by RBM38-eIF4E interaction: KI of RBM38-S195D or -Y192C enhances eIF4E binding to p53 mRNA and increases p53; KI of RBM38-S195K/R/L weakens eIF4E binding and decreases p53; KI of eIF4E-D202K reduces RBM38 interaction and enhances p53; Rbm38-S193D KI mice show enhanced p53-dependent cellular senescence, shortened lifespan, and spontaneous tumors.\",\n      \"method\": \"Multiple knock-in cell lines (RBM38 and eIF4E point mutants), cap-binding assays, Rbm38-S193D KI mouse model, senescence assays, lifespan monitoring\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KI mouse model plus multiple KI cell lines, cap-binding assays, in vivo lifespan data, multiple orthogonal approaches\",\n      \"pmids\": [\"33664057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNPC1 (RBM38) stabilizes MST1/2 mRNA by directly binding to it, activating the Hippo pathway; inhibition of MST1/2 rescues RNPC1-mediated attenuation of endometrial cancer sphere stemness.\",\n      \"method\": \"RNA immunoprecipitation, overexpression with stemness assays, MST1/2 inhibitor epistasis\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP without EMSA or domain mutagenesis, functional epistasis, single lab\",\n      \"pmids\": [\"32088727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM38 stabilizes AURKB (aurora kinase B) mRNA by directly binding to the AURKB 3' UTR; RNPC1 overexpression increases AURKB mRNA and protein, promotes proliferation, migration and invasion, and causes mitotic defects and chromosomal instability in gastric cancer.\",\n      \"method\": \"RNA immunoprecipitation, EMSA, dual-luciferase reporter assay, mRNA stability assay, overexpression/knockdown, in vivo xenograft\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding shown by RIP/EMSA/reporter, functional assays, single lab\",\n      \"pmids\": [\"34302858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM38 competes with miR-92a-3p for binding to PTEN 3' UTR, stabilizing PTEN transcript and inhibiting colorectal cancer progression; PTEN overexpression attenuates the effects of RBM38 depletion on CRC.\",\n      \"method\": \"RNA immunoprecipitation, luciferase reporter assay, competition binding assay, overexpression/knockdown, in vivo xenograft\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive binding shown by RIP and reporter assay, functional epistasis, single lab\",\n      \"pmids\": [\"34453780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SPRR2A/2D expression is regulated by an RBM38-p73 axis; RBM38 knockout reduces SPRR2A/2D expression; compound Rbm38/Trp73 double-null mice exhibit weak SPRR2A/2D expression in multiple tissues and susceptibility to systemic chronic inflammation, leading to shortened lifespan.\",\n      \"method\": \"Compound knockout mouse model, gene expression analysis, lifespan and tumor monitoring\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo compound genetic model with functional phenotype, single lab\",\n      \"pmids\": [\"34204113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM38 directly binds to the lower bulge of the HBV epsilon (ε) stem loop via RNA recognition submotifs (RNPs) and interacts with HBV Pol in an RNA-independent manner; RBM38 forms heterogeneous oligomers with RBM24 to mediate Pol-ε binding; RBM38 also binds HBV core via its C-terminal region (ARD domain), facilitating Pol-ε–core combination and triggering pgRNA packaging for reverse transcription.\",\n      \"method\": \"Co-immunoprecipitation (RBM38 with ε, Pol, RBM24, HBV core), RNA binding assays, domain mapping (RNPs for RNA binding, C-terminal ARD for core interaction), pgRNA packaging assays\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP domain mapping, RNA binding assays, functional pgRNA packaging, single lab\",\n      \"pmids\": [\"35041910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM17 interacts with RBM38 and promotes K48-linked ubiquitination and proteasomal degradation of RBM38; TRIM17-mediated cisplatin resistance in NSCLC is markedly reversed by RBM38 restoration; RBM38 enhances cisplatin-induced ROS production.\",\n      \"method\": \"Co-IP of TRIM17 with RBM38, ubiquitination assay (K48-linked), overexpression/knockdown, in vitro and in vivo cisplatin resistance assays\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay, functional rescue, in vivo xenograft, single lab\",\n      \"pmids\": [\"37219768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CBX7 interacts with TARDBP (TDP-43) and positively regulates RBM38 expression in a TARDBP-dependent manner; overexpression of RBM38 inhibits proliferation of CBX7-depleted neonatal cardiomyocytes, placing RBM38 downstream of the CBX7-TARDBP axis in controlling cardiomyocyte cell cycle exit.\",\n      \"method\": \"Co-immunoprecipitation (CBX7-TARDBP), mass spectrometry, adenoviral overexpression of CBX7/RBM38, conditional Cbx7 knockout mice, cardiomyocyte proliferation marker immunostaining\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mass spectrometry plus genetic epistasis with KO mice and overexpression rescue, single lab\",\n      \"pmids\": [\"37158107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Small molecule compound 094 interacts with eIF4E via the same pocket as Pep8, dissociates RBM38 from eIF4E, and enhances TP53 mRNA translation in RBM38- and eIF4E-dependent manners; fluorobenzene and ethyl benzamide moieties are necessary for compound 094-eIF4E interaction; compound 094 suppresses tumor spheroid growth in RBM38- and TP53-dependent manners.\",\n      \"method\": \"Structure-activity relationship studies, eIF4E binding assays, p53 translation assays (polysome profiling/reporter), tumor spheroid assays, combination assays with doxorubicin/4EGI-1\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SAR studies, direct binding assays, translation assays, in vitro tumor models, multiple orthogonal methods\",\n      \"pmids\": [\"36940176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM38 binds and stabilizes lncRNA GAS5 in sorafenib-resistant HCC cells; RBM38 reverses sorafenib resistance in HCC both in vitro and in vivo in a GAS5-dependent manner.\",\n      \"method\": \"RNA immunoprecipitation, overexpression/knockdown, drug resistance assays, in vivo xenograft, GAS5 knockdown epistasis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP without detailed binding characterization, functional epistasis, single lab\",\n      \"pmids\": [\"37296859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDK4 phosphorylates RBM38 at Ser195; CDK4/6 inhibitors suppress mutant p53 mRNA translation through RBM38 by reducing Ser195 phosphorylation, which shifts RBM38 interaction from eIF4G (translation promotion) to eIF4E (translation repression) on p53 mRNA.\",\n      \"method\": \"CDK4/6 inhibitor treatment with RBM38 phosphorylation analysis, translation assays with p53 mRNA, RBM38 overexpression/knockdown, cell survival assays in RB-proficient and -deficient TNBC cells\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-substrate relationship with translation assays and functional cell survival, single lab\",\n      \"pmids\": [\"41154395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rbm38 regulates terminal erythropoiesis and heme biosynthesis by modulating alternative splicing, mRNA decay, and translation of Ferrochelatase (Fech); Rbm38-deficient mice develop microcytic hypochromic anemia, erythropoietic protoporphyria-like disease with PPIX accumulation; enforced Fech expression largely restores erythroid differentiation in Rbm38-null transplants.\",\n      \"method\": \"Conditional and whole-body knockout mouse models, transcriptome/splicing analysis, Fech rescue experiments (reconstitution transplant), erythroid differentiation assays, heme biosynthesis measurements\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mice, in vivo epistasis rescue with Fech, multiple regulatory mechanisms (splicing/stability/translation) identified, functional heme biosynthesis measurements\",\n      \"pmids\": [\"40961234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In zebrafish, Rbm38 destabilizes pdx1 mRNA by binding to its 3' UTR and regulates alternative splicing of isl1a, smad2, and nkx2.2a; loss of Rbm38 leads to abnormal pancreatic enlargement.\",\n      \"method\": \"Zebrafish rbm38 loss-of-function, mRNA stability assays for pdx1 3' UTR binding, alternative splicing analysis for isl1a/smad2/nkx2.2a, pancreatic morphology assessment\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish KO model, direct RNA binding for pdx1, splicing analysis, single lab\",\n      \"pmids\": [\"40796306\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM38 (RNPC1) is an RNA-binding protein that uses its RRM domain (preferentially recognizing GU/U-rich and AU-rich elements in target 3' and 5' UTRs) to regulate mRNA stability, alternative splicing, and translation of numerous targets including p21, p53, MDM2, p63, p73, HuR, PTEN, HIF1α, and Ferrochelatase; it represses p53 mRNA translation by physically blocking eIF4E from the p53 mRNA cap, a mechanism regulated by phosphorylation at Ser195 (by GSK3 or CDK4, reversed by PPM1D), which switches RBM38 from an eIF4E-interacting repressor to an eIF4G-recruiting activator of translation; RBM38 also controls miRNA accessibility to target mRNAs through association with Ago2, and its own expression is controlled transcriptionally by p53 family members and E2F1, post-translationally by ubiquitin ligases TRIM17 and RNF26, and upstream by TARDBP/CBX7 signaling in cardiomyocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM38 (RNPC1) is an RRM-domain RNA-binding protein that governs post-transcriptional gene expression—mRNA stability, alternative splicing, translation, and miRNA accessibility—within a regulatory hub centered on the p53 family and cell-cycle/senescence control [#0, #3, #10]. Its RRM recognizes G(U/C/A)GUG and AU/U-rich elements through two stacking phenylalanine residues and sequence-specific hydrogen bonds, as resolved by crystallography [#28]. Through these elements RBM38 stabilizes a set of growth-suppressive transcripts (p21, p73, PTEN, HuR, MIC-1) while destabilizing others (p63, MDM2, c-Myc), thereby coupling p53-family output to differentiation, growth arrest, and senescence [#0, #2, #5, #6, #7, #15]. A central node is translational repression of p53: RBM38 uses its N-terminus to bind p53 mRNA 5'/3' UTRs and its C-terminus to bind eIF4E, blocking cap recognition; this repression is converted to activation when Ser195 phosphorylation (by GSK3 or CDK4, reversed by PPM1D) switches RBM38 from an eIF4E-interacting repressor to an eIF4G-recruiting promoter of eIF4F assembly [#3, #11, #13, #42]. The same Ser195 switch governs RBM38's association with Ago2, tuning miRNA-mediated decay of targets such as p63 and survivin [#25, #31]. The p53-RBM38 loop and the RBM38-p63 loop operate in vivo, where Rbm38 loss accelerates aging, causes hematopoietic defects and tumors, and modulates p53/p63-dependent senescence [#12, #24]. Beyond the p53 axis, RBM38 controls alternative splicing during erythroid differentiation, regulating Protein 4.1R and Ferrochelatase to support heme biosynthesis—its loss producing microcytic anemia and an erythropoietic protoporphyria-like phenotype [#10, #43]. The eIF4E-binding interface is druggable: a derived peptide (Pep8) and small molecule 094 dissociate RBM38 from eIF4E to relieve p53 translational repression and suppress tumor growth [#22, #40].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established RBM38 as a direct, isoform-specific regulator of mRNA stability, linking it to p21 and cell-cycle arrest.\",\n      \"evidence\": \"RNA binding assays plus knockdown/overexpression mRNA stability and cell-cycle analysis of RNPC1a vs RNPC1b\",\n      \"pmids\": [\"17050675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing isoform a from b activity not defined\", \"binding-site element on p21 3' UTR not mapped at residue level\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed RBM38 acts cooperatively with HuR and can both stabilize (p21) and destabilize (p63) transcripts through its RRM, broadening its target logic.\",\n      \"evidence\": \"Reciprocal Co-IP/domain mapping with HuR, RNA-IP, EMSA, and RRM-mutant stability assays in keratinocyte differentiation\",\n      \"pmids\": [\"20064878\", \"20457941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines whether RBM38 stabilizes versus destabilizes a given target is unresolved\", \"no structural basis for HuR cooperativity\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined RBM38's translational-repression mechanism—blocking eIF4E from the p53 mRNA cap—and its miRNA-gating role, embedding it in a p53 autoregulatory circuit.\",\n      \"evidence\": \"Domain-mapped Co-IP with eIF4E, polysome profiling, MEF senescence assays, and a genetic screen for RBP control of miRNA activity\",\n      \"pmids\": [\"21764855\", \"22027593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of RBM38-eIF4E-mRNA complex unknown\", \"rules governing which miRNA target sites RBM38 occludes not generalized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Expanded the target network (MDM2, HuR, p73, MIC-1) and identified E2F1 as a transcriptional input, positioning RBM38 in multiple feedback loops controlling growth suppression and senescence.\",\n      \"evidence\": \"RNA-IP/EMSA stability assays with RRM mutants, KO corroboration, siRNA epistasis in MEFs, and E2F1 promoter ChIP\",\n      \"pmids\": [\"22710720\", \"22371495\", \"22508983\", \"23836903\", \"22798430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among competing targets in a single cell unclear\", \"E2F1 regulation is Medium-confidence and single-lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how RBM38's regulatory mode is switched and defined a splicing-activator role, with SELEX-Seq fixing a GU-rich binding motif.\",\n      \"evidence\": \"In vitro GSK3 kinase assay, phosphomimetic S195D mutants, Co-IP with eIF4E/eIF4G, and minigene/tethering splicing assays with SELEX-Seq\",\n      \"pmids\": [\"24142875\", \"24250749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser195 phosphorylation physically remodels the eIF4E vs eIF4G interface not structurally defined\", \"splicing target repertoire incomplete\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided in vivo genetic proof of the p53-Rbm38 autoregulatory loop through aging, tumor, and radiation-sensitivity phenotypes.\",\n      \"evidence\": \"Rbm38-null mice, IR challenge, and compound epistasis with p53-heterozygous mice\",\n      \"pmids\": [\"25512531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions of individual targets to phenotypes not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified PPM1D as the phosphatase reversing the Ser195 switch and extended translational control to HIF1α, defining bidirectional regulatory axes.\",\n      \"evidence\": \"In vitro dephosphorylation assay, Co-IP, RNA-IP, cap-binding assays, and reporter assays for PPM1D and HIF1α UTRs\",\n      \"pmids\": [\"25823026\", \"25622105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HIF1α regulation single-lab and Medium-confidence\", \"kinetics of phosphorylation/dephosphorylation cycling in vivo unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Embedded RBM38 in multiple cancer feedback loops (c-Myc, Snail/ZO-1, ER/PR, PTEN, ceRNA network) controlling proliferation and metastasis.\",\n      \"evidence\": \"ChIP, RNA-IP, EMSA, reporter assays, and migration/invasion assays across breast and other cancer models\",\n      \"pmids\": [\"28399911\", \"28683467\", \"29052531\", \"25881544\", \"27634883\", \"29733656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several of these (ER, PR, ceRNA) are Low-confidence single-RIP studies without domain mutagenesis\", \"in vivo relevance of many target loops untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated druggability of the eIF4E interface and provided in vivo confirmation of Rbm38-PTEN and Rbm38-p63 loops in tumor suppression, plus a viral splicing role.\",\n      \"evidence\": \"Structure-guided Pep8 peptide with xenografts, compound-mutant mouse models (mutant-p53 KI, TAp63+/-), Ago2 Co-IP in phosphomimetic MEFs, and B19V splicing assays\",\n      \"pmids\": [\"30591552\", \"29330147\", \"29520104\", \"30567739\", \"29437973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window of eIF4E-disrupting agents unknown\", \"generality of the Ser195-Ago2 switch beyond p63 not yet broad\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Delivered the structural basis of sequence-specific RNA recognition and expanded the splicing/transcription-coupling repertoire.\",\n      \"evidence\": \"X-ray crystallography of the RRM-ssRNA complex with mutagenesis, plus cell-based splicing screens (Cdh23) and transcription-elongation assays (SMEK2)\",\n      \"pmids\": [\"31860021\", \"32774357\", \"33233740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length RBM38 or its complexes with eIF4E/Ago2 not solved\", \"how single RRM achieves diverse target outcomes unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined the Ser195 fine-tuning of p53 in vivo and clarified RBM38's dual, opposing control of miRNA-mediated decay via direct AGO2 contacts.\",\n      \"evidence\": \"Multiple RBM38/eIF4E knock-in cell lines and Rbm38-S193D KI mice with cap-binding/senescence/lifespan data, plus reciprocal AGO2 Co-IP and Pep8 disruption on survivin\",\n      \"pmids\": [\"33664057\", \"33472892\", \"34302858\", \"34453780\", \"32088727\", \"34204113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RBM38 chooses between protective and decay-promoting miRNA modes on one transcript is unclear\", \"several downstream cancer targets remain Low/Medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified upstream regulators of RBM38 protein and expression (TRIM17 ubiquitination, CBX7-TARDBP axis) and a small-molecule eIF4E disruptor, linking RBM38 to drug resistance and cardiomyocyte cell-cycle exit.\",\n      \"evidence\": \"TRIM17 Co-IP/K48-ubiquitination assays, CBX7-TARDBP Co-IP/MS with conditional KO mice, and SAR-driven compound 094 binding/translation assays\",\n      \"pmids\": [\"37219768\", \"37158107\", \"36940176\", \"37296859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNF26 ubiquitin-ligase regulation not represented by a discovery in this timeline\", \"mechanism coupling CBX7-TARDBP to RBM38 transcription incompletely defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a dedicated developmental/physiological role in erythropoiesis and heme biosynthesis through multi-modal regulation of Ferrochelatase, and identified CDK4 as a second Ser195 kinase.\",\n      \"evidence\": \"Conditional/whole-body Rbm38 KO mice with Fech rescue transplants and heme measurements, and CDK4/6-inhibitor translation assays in TNBC\",\n      \"pmids\": [\"40961234\", \"41154395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination of splicing, decay, and translation of Fech by a single RBP not mechanistically integrated\", \"CDK4 phosphorylation data are Medium-confidence single-lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single RRM with one defined RNA motif selects between stabilizing, destabilizing, splicing-activating, translation-repressing, and miRNA-gating outcomes on different targets remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of RBM38 in its eIF4E/eIF4G/Ago2 complexes\", \"no global rule predicting target outcome from binding-site context\", \"interplay of competing trans-acting partners (HuR, Ago2, eIF4E/4G) on a shared transcript not quantitatively defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 28, 37]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [10, 29, 43, 44]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [3, 11, 14, 32]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 25, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 10, 43]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 8, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 11, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 10, 43, 44]}\n    ],\n    \"complexes\": [\n      \"eIF4F (eIF4E/eIF4G on p53 mRNA cap)\",\n      \"RBM38-Ago2 miRNA complex\"\n    ],\n    \"partners\": [\n      \"EIF4E\",\n      \"EIF4G\",\n      \"ELAVL1\",\n      \"AGO2\",\n      \"PPM1D\",\n      \"GSK3B\",\n      \"TRIM17\",\n      \"RBM24\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}