Affinage

RBM4

RNA-binding protein 4 · UniProt Q9BWF3

Length
364 aa
Mass
40.3 kDa
Annotated
2026-04-28
76 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RBM4 is a multifunctional RNA-binding protein that orchestrates tissue-specific alternative splicing programs during muscle, neural, pancreatic, and hematopoietic differentiation, while also regulating mRNA translation and stability under stress and in cancer contexts. It binds CU-rich intronic and exonic elements via its RRM domains to promote or repress exon inclusion, consistently antagonizing PTB/PTBP1 across a broad range of pre-mRNA targets including alpha-tropomyosin, tau, Numb, Dab1, PKM, Hsf1, TFEB, and MCL-1, thereby directing developmental isoform switches in myogenesis, neurogenesis, and pancreatic beta-cell differentiation (PMID:16260624, PMID:27821480, PMID:27009199, PMID:29581187, PMID:23129807, PMID:39214303). Under cellular stress, p38 MAPK phosphorylates RBM4 at serine-309, triggering cytoplasmic translocation to stress granules where it suppresses cap-dependent translation and activates IRES-mediated translation through eIF4A recruitment; RBM4 also directly binds G-quadruplex structures within VEGFA IRES to promote its translation (PMID:17284590, PMID:35054929). RBM4 functions as a tumor suppressor by antagonizing SRSF1-mTORC1 signaling and promoting pro-apoptotic Bcl-xS and MCL-1S isoforms, while nuclear AURKA subverts this program by switching RBM4 splicing to a short isoform via an m6A-YTHDC1-hnRNP K mechanism; additionally, RBM4 suppresses endogenous retroviral transcripts by binding CGG elements in HERV LTRs and regulates mRNA stability of targets such as VEGFR2 and STAT1 through interaction with YTHDF2 (PMID:25203323, PMID:35361747, PMID:33020268, PMID:32248017, PMID:36601864).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2005 High

    The first mechanistic question—how does RBM4 regulate tissue-specific splicing—was answered by showing it binds intronic CU-rich elements to activate muscle-specific exon inclusion while directly competing with PTB, establishing the antagonistic RBM4–PTB paradigm.

    Evidence Minigene splicing assays, RNA binding competition, and OE/KD of RBM4 on alpha-tropomyosin pre-mRNA in muscle cells

    PMID:16260624

    Open questions at the time
    • Structural basis of CU-element recognition unresolved
    • Genome-wide target repertoire unknown at this stage
    • Whether RBM4–PTB antagonism generalizes beyond alpha-TM was untested
  2. 2006 High

    RBM4's splicing activity was extended to neurodegeneration-relevant targets (tau exon 10) and its subnuclear localization to speckles/nucleoli was mapped, with WT1(+KTS) identified as a modulator of RBM4 splicing activity.

    Evidence Tau minigene with RRM mutagenesis, immunofluorescence co-localization with speckle markers, co-IP of WT1–RBM4 complex

    PMID:16777844 PMID:16907643 PMID:16934801

    Open questions at the time
    • In vivo relevance of WT1–RBM4 interaction not tested
    • C-terminal domain's role in speckle targeting not mapped at residue level
  3. 2007 High

    A major open question—how does stress redirect RBM4 from splicing to translation regulation—was resolved by discovering that p38 MAPK phosphorylates S309, driving cytoplasmic accumulation, stress granule localization, suppression of cap-dependent translation, and activation of IRES-mediated translation via eIF4A recruitment.

    Evidence Phospho-mapping, p38 inhibitors/activators, phospho-mutant S309A, stress granule IF, cap/IRES translation reporters, eIF4A co-IP

    PMID:17284590

    Open questions at the time
    • Direct structural basis of eIF4A–RBM4 interaction unknown
    • Scope of IRES mRNAs regulated by RBM4 undefined
  4. 2011 High

    The RBM4–PTB antagonism was shown to operate as a hierarchical cascade in myogenesis: RBM4 actively downregulates PTB/nPTB through exon-skipping-coupled NMD, establishing RBM4 as an upstream master regulator of the muscle splicing program.

    Evidence RT-PCR isoform analysis, NMD inhibition restoring PTB/nPTB transcripts, comparison of shared target genes

    PMID:21518792

    Open questions at the time
    • Upstream signals triggering RBM4 upregulation during myogenesis not identified
    • Whether RBM4-mediated PTB downregulation occurs in other tissue contexts untested
  5. 2012 High

    RBM4's physiological importance was demonstrated in vivo: Rbm4 heterozygous knockout mice showed hyperglycemia and reduced insulin due to mis-splicing of Isl1 and Pax4, proving RBM4 is essential for pancreatic endocrine differentiation.

    Evidence Rbm4 KO mice, insulin measurement, isoform analysis of Isl1/Pax4, AR42J cell transdifferentiation upon RBM4 OE

    PMID:23129807

    Open questions at the time
    • Whether RBM4 acts cell-autonomously in beta cells versus other pancreatic cells not resolved
    • Full splicing target repertoire in pancreas unknown
  6. 2013 Medium

    A new post-translational regulatory layer was uncovered: miR-146a, induced by TLR4, promotes unphosphorylated RBM4 cytoplasmic retention and its assembly with Ago2 into a translation-repressor complex targeting TNFα and IL-6 mRNAs, linking RBM4 to innate immune regulation.

    Evidence Co-IP of RBM4–Ago2, antagomir knockdown, phospho-specific antibodies, cytokine translation assays

    PMID:23897118

    Open questions at the time
    • Direct RNA-binding site of RBM4 on TNFα/IL-6 mRNAs not mapped
    • Mechanism by which miR-146a blocks p38-mediated phosphorylation unclear
    • Not independently replicated
  7. 2014 High

    RBM4 was established as a tumor suppressor in cancer through two convergent mechanisms: it promotes pro-apoptotic Bcl-xS and MCL-1S isoforms by binding CU-rich elements and antagonizes SRSF1-mTORC1 signaling to suppress proliferation and migration.

    Evidence Multiple cancer cell lines, Bcl-xL rescue of RBM4-mediated apoptosis, RIP showing direct MCL-1 pre-mRNA binding, tumor xenografts

    PMID:25140042 PMID:25203323

    Open questions at the time
    • In vivo tumor suppressor role not validated in genetic mouse models
    • SRPK1-mediated cytoplasmic mislocalization as a cancer mechanism needs broader validation
  8. 2016 High

    RBM4's role in neuronal differentiation was mechanistically defined: it promotes Numb exon 3 inclusion and PKM2-to-PKM1 metabolic switching, both antagonizing PTB, to drive neurite outgrowth and mitochondrial respiration during neurogenesis.

    Evidence P19 cell and embryonic brain KD/KO, in utero electroporation, Numb and PKM minigene assays, Seahorse metabolic profiling, isoform rescue

    PMID:27009199 PMID:27821480

    Open questions at the time
    • Whether metabolic switching and Numb splicing are coordinately regulated or independent programs unknown
    • Adult neurogenesis role untested
  9. 2018 High

    RBM4 was shown to regulate cortical neuronal migration through Dab1 splicing in the reelin pathway, with RIP-seq providing the first transcriptome-wide view of direct RBM4 RNA targets in brain.

    Evidence Rbm4a KO mouse brain, RIP-seq, in utero electroporation, Dab1 isoform rescue of migration defects

    PMID:29581187

    Open questions at the time
    • Full RIP-seq target catalog not functionally validated
    • Relationship between Dab1 splicing and Numb/PKM splicing programs during neurogenesis unclear
  10. 2020 High

    Two new functional dimensions were established: RBM4 directly binds ERV transcripts at CGG elements to suppress HERV-K expression (PAR-CLIP), and separately interacts with YTHDF2 to destabilize m6A-modified STAT1 mRNA, suppressing M1 macrophage polarization.

    Evidence PAR-CLIP for ERV binding, LTR reporter assays, co-IP/MS for YTHDF2, Seahorse glycolysis assays

    PMID:32248017 PMID:33020268

    Open questions at the time
    • Functional consequence of ERV derepression upon RBM4 loss in disease not explored
    • Whether RBM4–YTHDF2 interaction is direct or RNA-mediated not determined
  11. 2022 High

    A cancer-specific evasion mechanism was elucidated: nuclear AURKA, in a kinase-independent manner, switches RBM4 pre-mRNA splicing from full-length to a short isoform by replacing the m6A–YTHDC1–SRSF3 complex with m6A–YTHDC1–hnRNP K, abolishing RBM4's tumor-suppressive splicing activity.

    Evidence Co-IP, RNA-seq isoform analysis, kinase-dead AURKA mutants, mTORC1 readouts, inhibitors of AURKA nuclear import

    PMID:35361747

    Open questions at the time
    • Whether RBM4-S has gain-of-function oncogenic activity beyond loss of RBM4-FL function not tested
    • Prevalence of AURKA-driven RBM4 isoform switching across cancer types unknown
  12. 2023 High

    RBM4's in vivo neural role was consolidated: Rbm4 double-knockout mice exhibit cerebellar foliation defects, reduced BDNF/TrkB expression, and motor learning impairment, with RBM4 promoting Hsf1 intron excision at CU-rich motifs to sustain BDNF signaling; TrkB agonist supplementation rescues the phenotype.

    Evidence Rbm4 dKO mice, BDNF/TrkB expression, 7,8-DHF rescue of cerebellar defects and motor learning, Hsf1 intron retention RT-PCR, minigene assays

    PMID:37670183 PMID:39738787

    Open questions at the time
    • Whether human neurodevelopmental disorders are linked to RBM4 mutations is unknown
    • Relative contributions of individual splicing targets to cerebellar phenotype not dissected
  13. 2023 Medium

    Additional regulatory layers emerged: p53 directly activates RBM4 transcription (ChIP), RBM4 destabilizes VEGFR2 mRNA to inhibit angiogenesis, and RBM4 depletion destabilizes pri-miR-1244, de-repressing SERPINE1 and inducing senescence; separately, RBM4 disrupts the LKB1/STRAD/MO25 complex by recruiting TRIM26 to ubiquitinate LKB1.

    Evidence ChIP for p53–RBM4 promoter binding, RIP for RBM4–VEGFR2 mRNA, pri-miRNA stability assays, co-IP and ubiquitination assays for LKB1–TRIM26

    PMID:36601864 PMID:36639375 PMID:37080995

    Open questions at the time
    • LKB1 degradation mechanism described in single cancer type (ESCC)
    • Whether RBM4-mediated pri-miRNA regulation is a general mechanism is unknown
    • p53–RBM4 transcriptional axis not validated in vivo
  14. 2024 Medium

    RBM4's own expression was shown to be regulated by m6A: YTHDF1 reads m6A on RBM4 mRNA to enhance its translation during cardiomyocyte hypertrophy, while FTO demethylase stabilizes RBM4 mRNA in odontoblasts; functionally, RBM4 promotes TFEB-L splicing to activate autophagy in AML differentiation.

    Evidence MeRIP and mRNA stability assays, YTHDF1 co-IP/KD, RBM4 OE/KD in cardiomyocytes and AML cells, TFEB minigene with CU element, Fto KO rescue

    PMID:37698901 PMID:39118568 PMID:39214303

    Open questions at the time
    • Whether m6A-mediated regulation of RBM4 is tissue-universal or context-specific is untested
    • TFEB-L splicing mechanism needs in vivo validation in AML models

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of RBM4's dual recognition of CU-rich and CGG elements, the complete inventory of direct splicing targets across tissues, and whether RBM4 loss-of-function mutations cause human developmental or neurological disease.
  • No crystal or cryo-EM structure of RBM4 bound to RNA
  • No genome-wide splicing map (e.g., eCLIP + RNA-seq) across multiple human tissues
  • No Mendelian disease association established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 9 GO:0003723 RNA binding 6 GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-8953854 Metabolism of RNA 9 R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 1
Partners
AGO2EIF4A1PTBP1SRSF1TRIM26WT1YTHDC1YTHDF2

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 RBM4 directly influences muscle cell-specific alternative splicing of alpha-tropomyosin (alpha-TM) by binding to intronic pyrimidine-rich/CU-rich elements, activating skeletal muscle-specific exon selection; RBM4 antagonizes PTB-mediated exon exclusion by competing with PTB for binding to a CU-rich element. Differential display of RBM4-associated mRNPs in vivo, minigene splicing assays, ectopic overexpression/knockdown, RNA binding competition assays Molecular and cellular biology High 16260624
2006 RBM4 stimulates tau exon 10 inclusion by interacting with a putative intronic splicing enhancer in intron 10; RNA-binding domain mutations of RBM4 abolish this activity, demonstrating requirement of RNA binding for splicing regulation. Expression cloning strategy with tau minigene, RBM4 overexpression and knockdown, mutagenesis of RNA-binding domain, minigene reporter assays The Journal of biological chemistry High 16777844
2006 RBM4 (Lark) localizes to nuclear speckles and nucleoli; the C-terminus is required for targeting to speckles. Upon transcription inhibition, RBM4 redistributes to perinucleolar clusters, distinct from other splicing factors, suggesting a novel subnuclear targeting pathway. Immunofluorescence imaging of full-length and C-terminally truncated/mutated RBM4, co-localization with known speckle markers, transcription inhibition experiments DNA and cell biology Medium 16907643
2006 WT1(+KTS) isoform interacts with RBM4, co-localizes in nuclear speckles and co-sediments with supraspliceosomes; WT1(+KTS) overexpression abrogates RBM4-mediated alternative splicing regulation, whereas WT1(-KTS) does not. Co-immunoprecipitation, glycerol gradient sedimentation, immunofluorescence co-localization, minigene splicing reporter assays with WT1 isoform overexpression Experimental cell research Medium 16934801
2007 Cell stress (arsenite) induces phosphorylation of RBM4 at serine 309 via the MKK3/6-p38 signaling pathway, driving RBM4 cytoplasmic accumulation and targeting to stress granules. Phosphorylated RBM4 suppresses cap-dependent translation and activates IRES-mediated translation by promoting association of eIF4A with IRES-containing mRNAs. A non-phosphorylatable S309 mutant fails to activate IRES translation and is unresponsive to arsenite stress. Phosphorylation mapping, p38 pathway inhibitors/activators, cytoplasmic fractionation, stress granule immunofluorescence, cap-dependent and IRES translation reporter assays, eIF4A co-immunoprecipitation, RNA loading assays, phospho-mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 17284590
2011 RBM4 down-regulates PTB and nPTB expression during muscle differentiation by activating exon skipping coupled to nonsense-mediated mRNA decay. RBM4 and PTB target a common set of transcripts for muscle-specific alternative splicing, with RBM4 invariably promoting muscle-specific isoforms and PTB acting oppositely, establishing a hierarchical splicing cascade in myogenesis. RT-PCR isoform analysis, RBM4 overexpression, minigene assays, NMD inhibition experiments, comparison of RBM4 and PTB splicing targets The Journal of cell biology High 21518792
2012 RBM4 promotes pancreatic cell differentiation and insulin expression in vivo; Rbm4 heterozygous knockout mice exhibit hyperglycemia and reduced insulin. RBM4 alters isoform balance of transcription factors Isl1 and Pax4 via alternative splicing, and overexpression of RBM4 is sufficient to convert acinar AR42J cells into insulin-producing cells. RBM4 also mediates glucose-induced insulin receptor isoform switches. Rbm4 gene knockout mice, RT-PCR isoform analysis of pancreatic transcripts, overexpression in AR42J cells, glucose stimulation assays, insulin measurement Molecular and cellular biology High 23129807
2013 TLR4-induced miR-146a promotes cytoplasmic accumulation of RBM4 and its interaction with Ago2, assembling a translation-repressor complex that disrupts TNFα and IL-6 cytokine mRNA translation. miR-146a prevents p38 MAPK-mediated phosphorylation of RBM4 at serine-309, leading to RBM4 cytoplasmic retention and Ago2 interaction; miR-146a knockdown or phosphatase inhibition restores p38-mediated S309 phosphorylation and nuclear RBM4 relocalization, disrupting the RBM4-Ago2 complex. Co-immunoprecipitation of RBM4 with Ago2, subcellular fractionation, antagomir knockdown of miR-146a, okadaic acid treatment, phospho-specific antibodies, cytokine translation assays Immunology and cell biology Medium 23897118
2014 RBM4 suppresses cancer cell proliferation and migration by regulating cancer-related alternative splicing, including Bcl-x splicing to induce apoptosis. Co-expression of Bcl-xL partially reverses RBM4-mediated tumor suppression. RBM4 antagonizes the oncogenic splicing factor SRSF1 to inhibit mTOR activation. RBM4 overexpression/knockdown in multiple cancer cell lines, splicing reporter assays, Bcl-xL rescue experiments, mTOR pathway analysis, tumor xenograft models Cancer cell High 25203323
2014 Elevated SRPK1 causes cytoplasmic accumulation of RBM4 in breast cancer cells. RBM4 overexpression promotes exon skipping of MCL-1 exon 2 by simultaneously binding CU-rich elements within MCL-1 exon 2 and the downstream intron, facilitating MCL-1S isoform production and reducing apoptotic resistance. RBM4 also promotes IR-B isoform of insulin receptor. RT-PCR isoform analysis, RBM4 and SRPK1 overexpression/knockdown, RNA immunoprecipitation demonstrating RBM4 binding to MCL-1 pre-mRNA CU elements, subcellular fractionation, apoptosis assays RNA (New York, N.Y.) High 25140042
2016 RBM4 promotes neuronal differentiation and neurite outgrowth by modulating alternative splicing of Numb pre-mRNA, specifically promoting exon 3 inclusion and exon 9 exclusion. RBM4-induced Numb isoforms (exon 3+/exon 9-) rescue neurite outgrowth defects in RBM4-depleted neurons. RBM4 depletion reduces proneural gene Mash1 expression, which is reversed by the RBM4-induced Numb isoform. RBM4 knockdown in P19 cells and embryonic brain, minigene splicing reporter assays, in utero electroporation, neurite outgrowth assays, Mash1 expression analysis, isoform rescue experiments Molecular biology of the cell High 27009199
2016 During neuronal differentiation, RBM4 directly regulates PKM alternative splicing to switch from PKM2 to PKM1, antagonizing PTB function. This isoform switch increases mitochondrial respiration capacity. RBM4 also induces a PTB isoform with attenuated splicing activity. PKM1 overexpression alone is sufficient to promote neuronal gene expression and differentiation of mesenchymal stem cells. PKM minigene assays, RBM4 KO mouse brain analysis, human MSC differentiation model, Seahorse metabolic assays, RBM4 and PKM1 overexpression Molecular and cellular biology High 27821480
2017 RBM4 constitutes an upstream regulator of SRSF3 splicing, and SRSF3 in turn regulates MAP4K4 exon 16 utilization in a sequence-dependent manner. Alternatively spliced MAP4K4 variants differentially phosphorylate JNK1, modulating E-cadherin, N-cadherin, and vimentin expression and CRC cell migration/invasion. This RBM4-SRSF3-MAP4K4 cascade modulates CRC metastatic signatures. Transcriptome analysis of CRC tissues, RT-PCR isoform profiling, overexpression/knockdown, JNK1 phosphorylation assays, migration/invasion assays Biochimica et biophysica acta. Molecular cell research Medium 29138007
2018 RBM4 regulates cortical neuronal radial migration by modulating alternative splicing of Disabled-1 (Dab1), a reelin signaling adaptor. RBM4 promotes inclusion of Dab1 exons 7/8, while its antagonist PTBP1 acts oppositely. Full-length Dab1 (containing exons 7/8), but not exon 7/8-truncated Dab1, rescues neuronal migration defects in RBM4-depleted neurons. Rbm4a KO mouse brain, in utero electroporation knockdown, RNA immunoprecipitation-sequencing (RIP-seq), minigene assays, isoform rescue of neuronal migration defects Molecular and cellular biology High 29581187
2019 SRSF1 and RBM4 act antagonistically on HIF-1α exon 14 splicing in a CU element-dependent manner: SRSF1 facilitates exon 14 skipping (HIF-1αS), while RBM4 enhances exon 14 inclusion (HIF-1αL). The HIF-1αS isoform more prominently activates VEGFR2 and SRSF1 gene promoters, enhancing metastatic signatures. Splicing reporter assays, RBM4 and SRSF1 overexpression, CU element mutation analysis, promoter activity assays, migration assays Biochimica et biophysica acta. Molecular cell research Medium 31491447
2020 RBM4 suppresses M1 macrophage polarization by inhibiting STAT1-mediated glycolysis. RBM4 increases STAT1 mRNA degradation by interacting with YTHDF2, which recognizes m6A-modified STAT1 mRNA, thereby reducing STAT1 expression and downstream glycolytic gene transcription. RNA-sequencing, protein immunoprecipitation with mass spectrometry (co-IP/MS), extracellular acidification rate (Seahorse) assays, RBM4 overexpression/knockdown, YTHDF2 co-IP International immunopharmacology Medium 32248017
2020 RBM4 binds directly to ERV transcripts (HERV-K and -H families) at CGG consensus elements, as demonstrated by PAR-CLIP. Loss of RBM4 elevates ERV transcript levels and HERV-K envelope protein expression. RBM4 regulation of HERV-K maps to a conserved CGG-containing element in the LTRs of HERV-K-10, -K-11, and -K-20. Photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation (PAR-CLIP), RBM4 knockdown with ERV transcript quantification, reporter assays with LTR elements Proceedings of the National Academy of Sciences of the United States of America High 33020268
2022 Nuclear AURKA promotes oncogenic splicing of RBM4 from the full-length isoform (RBM4-FL) to a short isoform (RBM4-S) in a kinase-independent manner by disrupting the m6A-YTHDC1-SRSF3 complex that produces RBM4-FL, and instead recruiting hnRNP K to YTHDC1 to promote m6A-YTHDC1-hnRNP K-dependent exon skipping. RBM4-S abolishes RBM4-FL-mediated inhibition of SRSF1-mTORC1 signaling. Co-immunoprecipitation, RNA-seq isoform analysis, YTHDC1 interaction mapping, AURKA nuclear translocation experiments, kinase-dead AURKA mutants, mTORC1 pathway assays, small molecule inhibitors of AURKA nuclear translocation Signal transduction and targeted therapy High 35361747
2022 RBM4 promotes VEGFA mRNA translation by binding to the G-quadruplex (G4) structure within the IRES-A element of VEGFA 5'-UTR, as shown by EMSA direct binding. Disruption of the G4 structure by base mutation reduces IRES activity; RBM4 knockdown reduces and overexpression increases IRES-mediated VEGFA translation. Dicistronic reporter assay with VEGFA IRES-A, G4 stabilizer (PDS) treatment, EMSA with purified RBM4 and G4 RNA, RBM4 knockdown and overexpression International journal of molecular sciences Medium 35054929
2023 RBM4 competitively binds LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex, then recruits the E3 ligase TRIM26 to LKB1, promoting LKB1 ubiquitination and degradation in the nucleus. This suppresses LKB1-AMPK-mTOR signaling, allowing bypass of senescence and sustaining glutamine-dependent cell proliferation in ESCC. Co-immunoprecipitation, ubiquitination assays, protein complex disruption experiments, AMPK pathway assays, senescence assays, knockdown/overexpression Signal transduction and targeted therapy Medium 37080995
2023 RBM4 depletion reduces miR-1244 levels by promoting degradation of primary miR-1244 transcripts (pri-miR1244), thereby de-repressing SERPINE1 (a senescence promoter) and inducing cellular senescence. miR-1244 mimics or SERPINE1 inhibitor attenuate RBM4 depletion-induced senescence. RBM4 knockdown in cancer cell lines, miR-1244 level measurement, pri-miRNA stability assays, SERPINE1 3'-UTR luciferase assays, miR-1244 mimic rescue, SERPINE1 inhibitor rescue, senescence assays Cell death & disease Medium 36639375
2023 p53 binds the RBM4 promoter and promotes its transcription; RBM4 in turn binds and shortens the half-life of VEGFR2 mRNA, promoting its degradation. AMG232, which blocks MDM2-p53 interaction, upregulates p53 and consequently RBM4, which reduces VEGFR2 expression to inhibit glioma angiogenesis. Chromatin immunoprecipitation (p53 binding to RBM4 promoter), mRNA stability assays for VEGFR2, p53/RBM4 knockdown, RIP for RBM4-VEGFR2 mRNA interaction, tube formation and angiogenesis assays in vivo Journal of cell science Medium 36601864
2023 RBM4 promotes RBM4-mediated intron excision of Hsf1, and loss of RBM4 causes intron 6 retention in Hsf1 mRNA, downregulating HSF1 protein and its downstream target BDNF. NMDAR signaling promotes RBM4 nuclear expression, thereby enhancing HSF1 and BDNF expression. RBM4 and PTBP1 act antagonistically on Hsf1 intron excision at a CU-rich motif. Rbm4 knockout mouse brain analysis, intron retention RT-PCR, RBM4 overexpression rescue of cerebellar foliation and motor learning, HSF1 ectopic expression rescue, NMDAR signaling experiments, minigene assays, PTBP1 antagonism Communications biology High 39738787
2023 Constitutive RBM4 double knockout reduces BDNF expression in developing brain; RBM4 promotes expression of full-length TrkB and BDNF. Prenatal TrkB agonist (7,8-dihydroxyflavone) supplementation rescues granule cell differentiation, Purkinje cell dendritic arborization, cerebellar foliation defects, and motor learning in Rbm4 dKO mice. Rbm4 double knockout mouse model, BDNF and TrkB expression analysis, TrkB agonist in vivo rescue, cerebellar foliation histology, motor learning behavioral assays Communications biology High 37670183
2024 RBM4 recognizes CU-rich sequences in intron 8 of TFEB pre-mRNA, promoting the TFEB-L spliceosome, which activates autophagy and promotes differentiation of AML cells. Combination of TFEB-L with rapamycin further promotes AML cell differentiation. RT-PCR splicing analysis, RBM4 overexpression in THP-1 and K562 cells, minigene with CU-rich element, autophagy assays, differentiation assays, primary AML cells The Journal of biological chemistry Medium 39214303
2024 Under cardiomyocyte hypertrophic stimulation (Ang II), RBM4 protein is upregulated via m6A methylation of its mRNA followed by YTHDF1-mediated enhanced translation. RBM4 localizes in the nucleus and downregulates PTBP1 expression to protect against cardiomyocyte hypertrophy; RBM4 knockdown aggravates and overexpression represses hypertrophy. Cardiomyocyte Ang II stimulation, RBM4 and PTBP1 expression analysis, m6A methylation assay of RBM4 mRNA, YTHDF1 co-IP and knockdown, RBM4 OE/KD, nuclear fractionation/immunofluorescence Acta biochimica et biophysica Sinica Medium 39118568
2009 CoAA and RBM4 transcripts undergo trans-splicing during stem/progenitor cell neural differentiation, generating intergenic splice variants (CoAZ, ncCoAZ). CoAA and RBM4 counter-regulate tau exon 10 inclusion, and their splicing activities are controlled by their respective splice variants. Stable expression of CoAA, RBM4, or their variants prevents the trans-splicing switch and disrupts embryoid body formation. RT-PCR detection of trans-spliced transcripts, overexpression of CoAA/RBM4/variants in stem cells, tau minigene splicing assays, embryoid body differentiation assay The Journal of biological chemistry Medium 19416963
2013 RBM4 homologs from multiple species can be phosphorylated by SR protein kinases (SRPKs), suggesting regulation by a conserved phosphorylation mechanism. The N-terminal RNA-binding domain of RBM4 has a dominant role in determining splicing outcome, while the C-terminal unstructured domain contributes to functional divergence between homologs. In vitro SRPK phosphorylation assay, chimeric RBM4 protein splicing assays, subnuclear localization analysis of RBM4 homologs PloS one Medium 23527094
2023 FTO demethylase stabilizes RBM4 mRNA by removing m6A modifications; FTO knockdown increases m6A levels on RBM4 mRNA, destabilizing it and reducing RBM4 protein. RBM4 in turn promotes RUNX2 exon 5 inclusion in odontoblast differentiation. Rbm4 overexpression in Fto-/- cells partly restores RUNX2 exon 5 inclusion and differentiation capacity. MeRIP (m6A methylated RNA immunoprecipitation), mRNA stability assays, semiquantitative RT-PCR for RUNX2 exon 5 inclusion, Fto knockout cells/mice, RBM4 overexpression rescue International endodontic journal Medium 37698901

Source papers

Stage 0 corpus · 76 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression. Cancer cell 185 25203323
2007 LARK activates posttranscriptional expression of an essential mammalian clock protein, PERIOD1. Proceedings of the National Academy of Sciences of the United States of America 87 17264215
2007 Cell stress modulates the function of splicing regulatory protein RBM4 in translation control. Proceedings of the National Academy of Sciences of the United States of America 87 17284590
2020 RBM4 regulates M1 macrophages polarization through targeting STAT1-mediated glycolysis. International immunopharmacology 75 32248017
2014 Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events. RNA (New York, N.Y.) 70 25140042
1996 Regulation of a specific circadian clock output pathway by lark, a putative RNA-binding protein with repressor activity. Journal of neurobiology 70 9120432
2011 RBM4 down-regulates PTB and antagonizes its activity in muscle cell-specific alternative splicing. The Journal of cell biology 65 21518792
2005 Exon selection in alpha-tropomyosin mRNA is regulated by the antagonistic action of RBM4 and PTB. Molecular and cellular biology 64 16260624
2022 Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4. Signal transduction and targeted therapy 60 35361747
2017 RBM4-SRSF3-MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell. Biochimica et biophysica acta. Molecular cell research 50 29138007
2006 RBM4 interacts with an intronic element and stimulates tau exon 10 inclusion. The Journal of biological chemistry 50 16777844
2017 RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M. Molecular and cellular biology 43 27821480
2013 MicroRNA-146a and RBM4 form a negative feed-forward loop that disrupts cytokine mRNA translation following TLR4 responses in human THP-1 monocytes. Immunology and cell biology 43 23897118
2019 Identification of LARK as a novel and conserved G-quadruplex binding protein in invertebrates and vertebrates. Nucleic acids research 42 31165881
2012 RBM4 promotes pancreas cell differentiation and insulin expression. Molecular and cellular biology 42 23129807
2006 WT1 interacts with the splicing protein RBM4 and regulates its ability to modulate alternative splicing in vivo. Experimental cell research 41 16934801
2023 RBM4 dictates ESCC cell fate switch from cellular senescence to glutamine-addiction survival through inhibiting LKB1-AMPK-axis. Signal transduction and targeted therapy 39 37080995
2008 RBM4: a multifunctional RNA-binding protein. The international journal of biochemistry & cell biology 39 18723113
2000 Circadian regulation of the lark RNA-binding protein within identifiable neurosecretory cells. Journal of neurobiology 36 10992253
2019 SRSF1 and RBM4 differentially modulate the oncogenic effect of HIF-1α in lung cancer cells through alternative splicing mechanism. Biochimica et biophysica acta. Molecular cell research 32 31491447
2009 Functional pre- mRNA trans-splicing of coactivator CoAA and corepressor RBM4 during stem/progenitor cell differentiation. The Journal of biological chemistry 32 19416963
2016 RBM4 promotes neuronal differentiation and neurite outgrowth by modulating Numb isoform expression. Molecular biology of the cell 30 27009199
2016 RBM4-Nova1-SRSF6 splicing cascade modulates the development of brown adipocytes. Biochimica et biophysica acta 27 27535496
2014 Translational regulation of the DOUBLETIME/CKIδ/ε kinase by LARK contributes to circadian period modulation. PLoS genetics 27 25211129
2008 The Drosophila FMRP and LARK RNA-binding proteins function together to regulate eye development and circadian behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 18842880
2001 Genetic analysis of functional domains within the Drosophila LARK RNA-binding protein. Genetics 24 11560900
2020 USP3 promotes proliferation of non-small cell lung cancer through regulating RBM4. European review for medical and pharmacological sciences 21 32271432
2018 RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development. Molecular and cellular biology 21 29581187
2007 Genetic and phenotypic variation among geographically isolated populations of the globally threatened Dupont's lark Chersophilus duponti. Molecular phylogenetics and evolution 21 17719801
2003 Cell-specific expression of the lark RNA-binding protein in Drosophila results in morphological and circadian behavioral phenotypes. Journal of neurogenetics 21 14668198
2016 RBM4a-regulated splicing cascade modulates the differentiation and metabolic activities of brown adipocytes. Scientific reports 20 26857472
2006 Lark is the splicing factor RBM4 and exhibits unique subnuclear localization properties. DNA and cell biology 20 16907643
2018 RBM4a-SRSF3-MAP4K4 Splicing Cascade Constitutes a Molecular Mechanism for Regulating Brown Adipogenesis. International journal of molecular sciences 19 30200638
2016 Transcriptome-wide targets of alternative splicing by RBM4 and possible role in cancer. Genomics 19 26898347
2015 RBM4-MEF2C network constitutes a feed-forward circuit that facilitates the differentiation of brown adipocytes. RNA biology 19 25826570
2012 Cellular requirements for LARK in the Drosophila circadian system. Journal of biological rhythms 18 22653887
2017 The impact of the RBM4-initiated splicing cascade on modulating the carcinogenic signature of colorectal cancer cells. Scientific reports 17 28276498
2019 RNA-Binding Motif 4 (RBM4) Suppresses Tumor Growth and Metastasis in Human Gastric Cancer. Medical science monitor : international medical journal of experimental and clinical research 14 31145716
2018 RBM4a modulates the impact of PRDM16 on development of brown adipocytes through an alternative splicing mechanism. Biochimica et biophysica acta. Molecular cell research 14 30327195
2009 Altered LARK expression perturbs development and physiology of the Drosophila PDF clock neurons. Molecular and cellular neurosciences 14 19303442
2022 G-Quadruplex Regulation of VEGFA mRNA Translation by RBM4. International journal of molecular sciences 13 35054929
2020 Posttranscriptional regulation of human endogenous retroviruses by RNA-binding motif protein 4, RBM4. Proceedings of the National Academy of Sciences of the United States of America 13 33020268
2012 Multiple roles of RBM4 in muscle cell differentiation. Frontiers in bioscience (Scholar edition) 13 22202052
2019 RBM4 modulates the proliferation and expression of inflammatory factors via the alternative splicing of regulatory factors in HeLa cells. Molecular genetics and genomics : MGG 12 31489484
2023 RBM4 regulates cellular senescence via miR1244/SERPINE1 axis. Cell death & disease 11 36639375
2004 The Drosophila RNA-binding protein Lark is required for the organization of the actin cytoskeleton and Hu-li tai shao localization during oogenesis. Genesis (New York, N.Y. : 2000) 10 15452872
2014 RBM4-regulated alternative splicing suppresses tumorigenesis. Cancer discovery 9 25367940
2021 miR-504 Promoted Gastric Cancer Cell Proliferation and Inhibited Cell Apoptosis by Targeting RBM4. Journal of immunology research 8 34195294
2020 Enteric infection induces Lark-mediated intron retention at the 5' end of Drosophila genes. Genome biology 8 31948480
2013 Phylogenetic and molecular characterization of the splicing factor RBM4. PloS one 8 23527094
2017 Clock gene is associated with individual variation in the activation of reproductive endocrine and behavior of Asian short toed lark. Scientific reports 7 29101400
2023 AMG232 inhibits angiogenesis in glioma through the p53-RBM4-VEGFR2 pathway. Journal of cell science 6 36601864
2020 Multiple species delimitation approaches applied to the avian lark genus Alaudala. Molecular phylogenetics and evolution 6 33250446
2020 The LARK protein is involved in antiviral and antibacterial responses in shrimp by regulating humoral immunity. Developmental and comparative immunology 5 32784011
2008 The LARK/RBM4a protein is highly expressed in cerebellum as compared to cerebrum. Neuroscience letters 5 18708123
2008 The Drosophila RNA-binding protein Lark is required for localization of Dmoesin to the oocyte cortex during oogenesis. Development genes and evolution 5 18958492
2006 Expression analysis of two types of transcripts from circadian output gene lark in Bombyx mori. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 5 17287137
2005 Identification and expression pattern of Bmlark, a homolog of the Drosophila gene lark in Bombyx mori. DNA sequence : the journal of DNA sequencing and mapping 5 16147879
2023 Hypergravity enhances RBM4 expression in human bone marrow-derived mesenchymal stem cells and accelerates their differentiation into neurons. Regenerative therapy 4 36712961
2023 The N6-methyladenosine demethylase FTO is required for odontoblast differentiation in vitro and dentine formation in mice by promoting RUNX2 exon 5 inclusion through RBM4. International endodontic journal 4 37698901
2022 RBM4 inhibits the growth of clear cell renal cell carcinoma by enhancing the stability of p53 mRNA. Molecular carcinogenesis 4 36585906
2024 Selected Lark Mitochondrial Genomes Provide Insights into the Evolution of Second Control Region with Tandem Repeats in Alaudidae (Aves, Passeriformes). Life (Basel, Switzerland) 3 39063634
2024 Overexpression of RBM4 promotes acute myeloid leukemia cell differentiation by regulating alternative splicing of TFEB. The Journal of biological chemistry 3 39214303
2023 Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency. Communications biology 3 37670183
2020 De Novo Assembly of a High-Quality Reference Genome for the Horned Lark (Eremophila alpestris). G3 (Bethesda, Md.) 3 31857331
2019 Molecular and morphological analysis of a Caryospora-like isolate (Apicomplexa: Eimeriidae) from the magpie-lark (Grallina cyanoleuca) (Latham, 1801) in Western Australia. Parasitology research 3 31754855
2024 PURPL Promotes M2 Macrophage Polarization in Lung Cancer by Regulating RBM4/xCT Signaling. Critical reviews in eukaryotic gene expression 2 38842204
2024 RBM4-mediated intron excision of Hsf1 induces BDNF for cerebellar foliation. Communications biology 2 39738787
2017 Complete mitochondrial genome of the Mongolian lark, Melanocorypha mongolica (Aves: Passeriformes). Mitochondrial DNA. Part B, Resources 2 33473794
2024 Endogenous RBM4 prevents Ang II-induced cardiomyocyte hypertrophy via downregulating the expression of PTBP1. Acta biochimica et biophysica Sinica 1 39118568
2015 Characterization of major histocompatibility complex class I loci of the lark sparrow (Chondestes grammacus) and insights into avian MHC evolution. Genetica 1 26071093
2026 m5C-Modified tRF3b-CysGCA-23 Suppresses Bladder Cancer Malignancy by Repressing H3K18 Lactylation via Stabilizing RBM4. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41757512
2025 Hsa_circ_0075451 promotes NSCLC proliferation, metastasis, and glycolysis through interaction with the RNA-binding protein RBM4. Discover oncology 0 41003853
2023 Immunity and Growth Plasticity of Asian Short-Toed Lark Nestlings in Response to Changes in Food Conditions: Can It Buffer the Challenge of Climate Change-Induced Trophic Mismatch? Animals : an open access journal from MDPI 0 36899717
2021 The complete mitochondrial genome of Asian short-toed Lark Alaudala cheleensis (Aves: Passeriformes: Alaudidae). Mitochondrial DNA. Part B, Resources 0 33628912
2021 Complete Mitochondrial Genome Sequence of the Magpie-Lark (Grallina cyanoleuca). Microbiology resource announcements 0 34137635