Affinage

CELF2

CUGBP Elav-like family member 2 · UniProt O95319

Length
508 aa
Mass
54.3 kDa
Annotated
2026-04-28
92 papers in source corpus 37 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CELF2 is a multifunctional RNA-binding protein that coordinates post-transcriptional gene regulation through alternative splicing, mRNA stability control, translational repression, and alternative polyadenylation across diverse cell types including T cells, neurons, and macrophages. Its three RRM domains recognize UG-rich and AU-rich RNA elements, and it regulates alternative splicing in a position-dependent manner—binding upstream of an exon promotes skipping while binding downstream promotes inclusion—mechanistically by blocking branchpoint formation or competing with U2AF65 and PTB (PMID:27096301, PMID:19680430, PMID:11931771, PMID:20631008). In the cytoplasm, CELF2 binds 3′UTR AU-rich elements to stabilize target mRNAs (COX-2, Mcl-1, AR, autophagy factors) while simultaneously inhibiting their translation, competing with the translational activator HuR (PMID:12535526, PMID:18292181, PMID:17383427). Signal-dependent nucleocytoplasmic shuttling—controlled by an NLS in RRM3, CRM1-dependent export, and AKT signaling—serves as a functional switch: cytoplasmic CELF2 represses translation to maintain neural progenitor self-renewal, while nuclear translocation releases targets and activates splicing programs during T-cell activation and neuronal differentiation, and de novo variants disrupting this shuttling cause cortical malformations (PMID:34107259, PMID:15226369, PMID:25870297).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1999 Medium

    Establishing CELF2 as a CUG-repeat-binding RNA-binding protein with high cardiac expression and potential autoregulatory capacity answered the initial question of whether CELF family members beyond CUG-BP1 existed with tissue-specific expression.

    Evidence RNA binding assays and tissue distribution analysis of ETR-3/CELF2

    PMID:9887331

    Open questions at the time
    • No functional consequence of CUG-repeat binding demonstrated
    • Autoregulation inferred from binding but not tested functionally
  2. 2001 High

    Discovery that CELF2 is a component of the apoB mRNA editing holoenzyme and dose-dependently inhibits C-to-U editing revealed an unexpected role in RNA editing beyond splicing regulation.

    Evidence Co-fractionation, co-immunoprecipitation with ACF/apobec-1, and reconstituted editing assay

    PMID:11577082

    Open questions at the time
    • Whether CELF2 regulates editing of other transcripts beyond apoB is unknown
    • Structural basis of editing inhibition not determined
  3. 2002 High

    Demonstrating that CELF2 directly activates exon inclusion via intronic UG-rich muscle-specific elements in competition with PTB established the paradigm that CELF2 and PTB antagonistically regulate tissue-specific splicing.

    Evidence In vitro splicing reconstitution with cTNT minigene plus dominant-negative mutants

    PMID:11931771

    Open questions at the time
    • In vivo relevance in cardiac tissue not yet shown
    • Direct physical competition between CELF2 and PTB on the same RNA not resolved
  4. 2003 High

    The discovery that CELF2 simultaneously stabilizes COX-2 mRNA yet inhibits its translation established the dual mRNA stability/translational repression paradigm central to CELF2 cytoplasmic function.

    Evidence UV cross-linking, luciferase-COX-2 3′UTR reporter, antisense knockdown, in vivo radiation model

    PMID:12535526

    Open questions at the time
    • Mechanism of translational inhibition not elucidated
    • Whether this dual activity applies to other targets was untested
  5. 2004 High

    Mapping the NLS to RRM3, CRM1-dependent nuclear export to the divergent domain, and cytoplasmic retention signals to RRM1/2 resolved how CELF2 achieves regulated nucleocytoplasmic distribution and linked domain architecture to splicing function.

    Evidence GFP fusion localization, systematic deletion analysis, leptomycin B treatment, cotransfection splicing assay

    PMID:14973222 PMID:15226369

    Open questions at the time
    • Signal-dependent regulation of shuttling not identified
    • Which upstream kinases or pathways control localization was unknown
  6. 2005 High

    SELEX identification of UG-rich motifs as the CELF2 RNA binding consensus, validated by mutagenesis of CFTR and MTMR1 reporters, provided the sequence rules enabling transcriptome-wide target prediction.

    Evidence SELEX, minigene splicing reporters, site-directed mutagenesis

    PMID:15657417

    Open questions at the time
    • Context-dependent binding preferences (structural RNA features) not addressed
    • Affinity measurements for different motif variants not determined
  7. 2007 High

    Demonstrating that CELF2 and HuR compete for COX-2 ARE binding with opposite translational outcomes, and that radiation shifts occupancy from HuR to CELF2, established a signal-responsive competitive binding model for translational control.

    Evidence Nitrocellulose filter binding, GST pulldown, yeast two-hybrid, heterokaryon shuttling assay, luciferase reporter

    PMID:17383427

    Open questions at the time
    • Whether CELF2-HuR competition operates on other shared mRNA targets was untested
    • The signal transduction pathway mediating the switch was not identified
  8. 2008 High

    Extension of the dual stabilize-but-repress-translation mechanism to Mcl-1 mRNA, with consequent apoptosis during G2-M, generalized the paradigm beyond COX-2 and linked it to cell fate decisions.

    Evidence RNA immunoprecipitation, Mcl-1 3′UTR reporter, flow cytometry in stable CELF2-expressing cells

    PMID:18258790 PMID:18292181

    Open questions at the time
    • Mechanism of translational repression still unresolved
    • Whether CELF2 recruits specific deadenylation or ribosome-stalling factors unknown
  9. 2009 High

    Chemical footprinting revealed that CELF2 binds GU-rich motifs at the perimeter of branchpoint sequences to block spliceosome assembly, providing the first direct mechanistic explanation for CELF2-mediated exon silencing and demonstrating autoregulation of its own exon 6.

    Evidence Chemical modification RNA footprinting, in vitro splicing with NMDA R1 NI exon and CELF2 exon 6

    PMID:19680430

    Open questions at the time
    • Whether branchpoint blocking applies to all CELF2-silenced exons or only a subset is unknown
    • Structural basis of branchpoint occlusion not resolved
  10. 2010 High

    Domain-swap experiments showing that the divergent domain unique to CELF2 (not shared with CUG-BP1) is required for CFTR exon 9 skipping via competition with U2AF65 established paralog-specific functional determinants within the CELF family.

    Evidence Minigene splicing assays, ETR-3/CUG-BP1 domain swapping, U2AF65 competition

    PMID:20631008

    Open questions at the time
    • Structural basis of divergent domain function not determined
    • Whether the divergent domain mediates all paralog-specific effects is untested
  11. 2012 High

    Identification that CELF2 stabilizes AR mRNA and that miR-196a-mediated CELF2 silencing ameliorates SBMA phenotypes in mice placed CELF2 in a disease-relevant mRNA stability pathway and demonstrated therapeutic potential of targeting CELF2 indirectly.

    Evidence AAV-mediated miR-196a delivery in SBMA mice, CELF2 gain/loss-of-function, AR mRNA stability assay

    PMID:22660636

    Open questions at the time
    • Whether CELF2-AR mRNA interaction is direct (specific binding site) was not mapped
    • Contribution of CELF2 to AR mRNA stability in normal physiology unknown
  12. 2012 High

    NMR characterization of a CELF2 splice isoform (R3δ) lacking part of RRM3 revealed an unstructured, flexible third RRM with target-specific functional consequences (opposite effects on insulin receptor vs. ACTN1 splicing), demonstrating that alternative splicing of CELF2 itself tunes its regulatory output.

    Evidence NMR spectroscopy, molecular dynamics, minigene splicing assays for ACTN1 and insulin receptor

    PMID:22433174

    Open questions at the time
    • Which isoform predominates in specific tissues/developmental stages was not determined
    • Crystal structure of full-length CELF2 remains unavailable
  13. 2015 High

    Establishing that TCR signaling induces CELF2 via NF-κB-dependent transcription followed by 3′UTR shortening-mediated mRNA stabilization, with CELF2 controlling dozens of downstream splicing events during T-cell activation and thymic development, defined CELF2 as a signal-responsive master splicing regulator in the immune system.

    Evidence T-cell stimulation with NF-κB inhibitor, transcription/stability assays, CELF2 knockdown with splicing RNA-seq, human thymus samples

    PMID:25870297

    Open questions at the time
    • Direct NF-κB binding site in CELF2 promoter not mapped
    • Full T-cell splicing network architecture downstream of CELF2 not resolved
  14. 2015 High

    Discovery of a JNK→CELF2→MKK7 splicing→JNK positive feedback loop revealed that CELF2 amplifies T-cell activation signaling, with ~25% of TCR-mediated splicing events being JNK- and CELF2-dependent.

    Evidence JNK inhibitor, CELF2 knockdown, minigene reporters, c-Jun phosphorylation, RNA-seq

    PMID:26443849

    Open questions at the time
    • How the feedback loop is terminated to prevent runaway signaling is unknown
    • Whether similar feedback operates in non-immune contexts untested
  15. 2016 High

    Genome-wide CLIP-Seq in T cells established the position-dependent splicing rule—upstream binding promotes skipping, downstream binding promotes inclusion—as a general principle across tissues (heart, brain, T cells), providing a predictive framework for CELF2 splicing regulation.

    Evidence CLIP-Seq in human T cells with bioinformatic positional analysis validated against known targets

    PMID:27096301

    Open questions at the time
    • Exceptions to the positional rule not systematically catalogued
    • Whether position-dependence reflects distinct co-factor recruitment is unknown
  16. 2017 High

    Identification of CELF2 and hnRNP C as co-regulators binding a defined intronic element upstream of TRAF3 exon 8 demonstrated combinatorial splicing control, with CELF2 expression level as the rate-limiting factor controlling non-canonical NF-κB activation.

    Evidence siRNA screen, CLIP, cis-element mutagenesis with distance alteration, minigene reporters

    PMID:28031331

    Open questions at the time
    • Whether CELF2-hnRNP C co-regulation extends beyond TRAF3 is partially addressed but incomplete
    • Structural basis of cooperative binding not determined
  17. 2019 High

    Revealing that CELF2 controls alternative polyadenylation by competing with polyadenylation machinery enhancers for RNA binding expanded CELF2's regulatory repertoire beyond splicing and translation to 3′ end processing, with ~half of T-cell signaling-induced APA events being CELF2-dependent.

    Evidence CELF2 knockdown, 3′READS APA profiling, CLIP-Seq overlap analysis, competition assay

    PMID:31509743

    Open questions at the time
    • Which specific polyadenylation factors CELF2 competes with directly was not fully resolved
    • Functional consequences of individual APA events not characterized
  18. 2020 Medium

    Multiple studies expanded CELF2's mRNA stability targets (autophagy factors Beclin-1/ATG5/ATG12, FAM198B, CXCL5) and identified upstream regulation of CELF2 itself by m6A modification (ALKBH5/YTHDF2 axis), reciprocal regulation with hnRNP C, and promoter hypermethylation in cancer, building a picture of CELF2 as a broadly acting mRNA stability regulator under multilayered control.

    Evidence RNA stability assays, RIP, 3′UTR reporters, CELF2 overexpression/knockdown, m6A modification assays, polysome fractionation, promoter methylation analysis across multiple cancer cell systems

    PMID:31020708 PMID:31409895 PMID:32338744 PMID:33335801 PMID:35941702 PMID:40154776

    Open questions at the time
    • Most mRNA stability targets characterized in single labs without independent replication
    • Relative contributions of splicing vs. stability regulation in cancer phenotypes not disentangled
    • Direct binding sites on most stability targets not mapped at nucleotide resolution
  19. 2020 Medium

    Studies of CELF2 in miRNA biology and non-canonical protein interactions revealed that CELF2 regulates pre-miR-155 maturation downstream of IL-10 in macrophages and interacts with PREX2 to relieve PTEN inhibition, extending CELF2 function to innate immune regulation and signaling pathway modulation.

    Evidence RIP for pre-miR-155, CRISPR-Cas9 CELF2 knockdown in macrophages, co-IP of CELF2-PREX2, PTEN phosphatase activity assay in PTEN-null controls

    PMID:31241130 PMID:32324763

    Open questions at the time
    • Mechanism by which CELF2 binding affects pre-miR-155 processing not determined
    • CELF2-PREX2 interaction not independently confirmed
    • Whether CELF2 broadly regulates miRNA biogenesis or is specific to miR-155 is unknown
  20. 2021 High

    Linking CELF2 nucleocytoplasmic shuttling to neural progenitor fate decisions—cytoplasmic CELF2 represses translation to maintain self-renewal, nuclear translocation releases mRNAs for differentiation—and demonstrating that de novo variants disrupting shuttling cause cortical malformations established CELF2 as a critical regulator of brain development with direct disease relevance.

    Evidence De novo variant identification in patients, transgenic mouse NPC analysis, subcellular fractionation, translational reporter assays

    PMID:34107259

    Open questions at the time
    • Identity of the full set of mRNAs repressed by cytoplasmic CELF2 in NPCs not catalogued
    • Whether cortical malformation phenotype is primarily due to splicing or translation defects is unresolved
  21. 2024 High

    Discovery that CELF2 loss stabilizes FAT10 mRNA and activates AKT/mTORC1 signaling to accelerate AML in mice established CELF2 as a tumor suppressor in hematopoietic malignancy through a defined mRNA target-signaling axis.

    Evidence RIP-Seq in hematopoietic cells, Celf2 conditional KO mice, MLL-AF9 AML model, rapamycin/EPZ-5676 rescue

    PMID:38514854

    Open questions at the time
    • Whether CELF2 destabilizes or translationally represses FAT10 mRNA not fully distinguished
    • Contribution of other CELF2 targets to the AML phenotype not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of CELF2's dual stabilize-but-repress-translation mechanism; how condensate formation via the intrinsically disordered hinge region integrates with splicing regulation in vivo; the full scope of CELF2's role in suppressing immunostimulatory dsRNA; and the precise kinase cascades controlling signal-dependent nucleocytoplasmic shuttling across different cell types.
  • No high-resolution structure of full-length CELF2 or CELF2-RNA complex
  • Condensate-dependent splicing regulation shown only in preprint, awaits peer review
  • dsRNA suppression function shown only in preprint, awaits independent confirmation
  • Complete upstream signaling pathway for CELF2 shuttling not mapped in any single system

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 9 GO:0098772 molecular function regulator activity 5 GO:0140110 transcription regulator activity 3 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3
Pathway
R-HSA-8953854 Metabolism of RNA 10 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 1 R-HSA-9612973 Autophagy 1
Partners
ACFAPOBEC1HNRNP CHURPREX2PTBU2AF65
Complex memberships
apoB mRNA editing holoenzyme

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CUGBP2/CELF2 binds AU-rich sequences (AREs) in the COX-2 3'UTR, stabilizes COX-2 mRNA, but simultaneously inhibits its translation; antisense suppression of CUGBP2 rendered radioprotection via a COX-2-dependent prostaglandin pathway, demonstrating in vivo translation inhibition activity. Nitrocellulose filter binding, UV cross-linking, chimeric luciferase-COX-2 3'UTR reporter assay, antisense knockdown in cells, in vivo radiation model Molecular cell High 12535526
2001 CUGBP2/CELF2 is a component of the apoB mRNA editing holoenzyme; it co-fractionates and co-immunoprecipitates with ACF and apobec-1, binds an AU-rich sequence upstream of the edited cytidine in apoB RNA, and dose-dependently inhibits C-to-U RNA editing in a reconstituted system. Co-fractionation, immunodepletion/co-precipitation, reconstituted editing system, recombinant protein addition, antisense knockout The Journal of biological chemistry High 11577082
2002 ETR-3/CELF2 binds U/G motifs in conserved intronic muscle-specific elements (MSEs) flanking cardiac troponin T (cTNT) exon 5 and directly activates exon inclusion in vitro; this activation is antagonized by PTB, and dominant-negative mutants demonstrate that endogenous CELF and PTB activities compete for cell-type-specific splicing outcomes. In vitro splicing assay, dominant-negative mutants, co-transfection with cTNT minigene Molecular cell High 11931771
1999 ETR-3/CELF2 binds (CUG)8 repeats and is expressed at high levels in heart; both CUG-BP and ETR-3 bind CUG repeats within ETR-3 mRNA itself, suggesting autoregulation of ETR-3 processing. RNA binding assays, RT-PCR, cDNA library screening, tissue distribution analysis Human molecular genetics Medium 9887331
2004 ETR-3/CELF2 protein contains a strong nuclear localization signal (NLS) overlapping the C-terminal RRM3, nuclear export activity in the divergent domain sensitive to leptomycin B (CRM1-dependent), and additional cytoplasmic localization regions in RRM1/2; the C-terminus and divergent domain are required for splicing activity. GFP fusion localization, deletion analysis, pyruvate kinase chimera, leptomycin B treatment, cotransfection splicing assay Journal of cell science High 15226369
2005 ETR-3/CELF2 preferentially binds UG-rich sequences (UG repeats and UGUU motifs) as identified by SELEX; these motifs are sufficient to confer ETR-3 responsiveness to non-responsive splicing reporters in vivo, and ETR-3 regulates CFTR and MTMR1 alternative splicing via these binding sites. SELEX (5 rounds), minigene splicing reporters, site-directed mutagenesis of binding sites Molecular and cellular biology High 15657417
2004 For ETR-3/CELF2, either RRM1 or RRM2 can independently bind MSE RNA; non-overlapping N- and C-terminal regions both activate MSE-dependent exon inclusion, demonstrating functional redundancy; for CELF4, RRM2 plus 66 amino acids of the divergent domain is sufficient for splicing activation. Comparative deletion analysis, RNA binding assays, cotransfection splicing assays with cTNT minigene Nucleic acids research High 14973222
2006 CUGBP2/CELF2 and HuR bind COX-2 ARE with similar affinities and compete for binding; they heterodimerize in vitro (GST pulldown and yeast 2-hybrid), colocalize in the nucleus, shuttle between nucleus and cytoplasm, and CUGBP2 competitively inhibits HuR-mediated translation activation of COX-2 mRNA; after radiation, binding switches from HuR to CUGBP2. Nitrocellulose filter binding, UV cross-linking, GST pulldown, yeast 2-hybrid, immunocytochemistry, heterokaryon nucleocytoplasmic shuttling assay, chimeric luciferase reporter Gastroenterology High 17383427
2008 CUGBP2/CELF2 binds the Mcl-1 3'UTR (in vitro and in cells), stabilizes Mcl-1 mRNA but inhibits Mcl-1 mRNA translation, leading to reduced Mcl-1 protein and apoptosis during G2-M phase. RNA immunoprecipitation, chimeric luciferase-Mcl-1 3'UTR reporter, Western blot, flow cytometry, stable CELF2-expressing cell line American journal of physiology. Gastrointestinal and liver physiology High 18292181
2009 CUGBP2/CELF2 splicing regulator binds GU-rich motifs at the boundaries (perimeter) of branch sites of the NI exon of NMDA R1 receptor; this perimeter-binding arrangement mechanistically blocks branchpoint formation to silence the exon, and CUGBP2 also autoregulates its own splicing by binding functionally significant motifs surrounding branch sites upstream of CUGBP2 exon 6. Chemical modification RNA footprinting, in vitro splicing assay, identification of novel target exons with similar motif configuration PLoS genetics High 19680430
2010 ETR-3/CELF2 strongly stimulates CFTR exon 9 skipping by functionally antagonizing U2AF65 binding to the polymorphic U-stretch; the divergent domain of ETR-3 (not present in CUG-BP1) is critical for this skipping activity, demonstrated by deletion and domain-swapping experiments. Minigene splicing assays, deletion mutants, domain-swapping between ETR-3 and CUG-BP1, competition with U2AF65 Nucleic acids research High 20631008
2011 CELF2 directly activates LEF1 exon 6 inclusion by binding to two intronic sequences flanking the regulated exon; CELF2 knockdown reduces exon 6 inclusion, and blocking the exon 6 splice site reduces TCR-alpha mRNA expression, placing CELF2-regulated LEF1 splicing upstream of TCR-alpha expression. CELF2 knockdown, minigene reporters, CELF2 binding site mutation, TCR-alpha mRNA measurement Molecular and cellular biology High 21444716
2012 miR-196a silences CELF2, and CELF2 directly acts on AR mRNA to enhance its stability; reducing CELF2 via miR-196a delivery decreases AR mRNA stability and ameliorates SBMA phenotypes in a mouse model. AAV-mediated miR-196a delivery in SBMA mice, CELF2 knockdown/overexpression, AR mRNA stability assay Nature medicine High 22660636
2012 CUGBP2/CELF2 has isoform-specific functional consequences: alternative splicing produces a CUGBP2 R3δ isoform lacking part of RRM3; full-length and R3δ have similar effects on ACTN1 SM exon but opposite effects on insulin receptor exon 11 splicing; NMR and molecular dynamics reveal the R3δ third RRM is flexible and unstructured. Alternative splicing analysis, minigene splicing assays (ACTN1, insulin receptor), NMR spectroscopy, molecular dynamics simulation BMC biochemistry High 22433174
2015 CELF2 expression in T cells is induced by T-cell receptor signaling via NF-κB-dependent transcriptional induction within 6 h, followed by increased CELF2 mRNA stability linked to a change in 3'UTR length; signal-induced CELF2 expression controls dozens of downstream alternative splicing events during T-cell activation and thymic development. T-cell stimulation, NF-κB inhibitor, transcription inhibition, RNA stability assay, CELF2 knockdown with splicing RNA-seq, human thymus analysis Proceedings of the National Academy of Sciences of the United States of America High 25870297
2015 JNK signaling induces CELF2 expression during T-cell activation; CELF2 binds flanking intronic sequences to repress MKK7 exon 2 inclusion, generating an isoform with restored JNK-docking site that enhances JNK pathway activity (c-Jun phosphorylation, TNF-α upregulation), creating a positive feedback loop; ~25% of T-cell receptor-mediated alternative splicing events are JNK- and CELF2-dependent. JNK inhibitor, CELF2 knockdown, minigene reporters, CELF2 binding site analysis, c-Jun phosphorylation assay, RNA-seq Genes & development High 26443849
2016 CLIP-Seq in human T cells demonstrates that CELF2 binding position relative to an exon predicts its effect on splicing: binding upstream promotes exon skipping while binding downstream promotes inclusion; this position-dependence is generalizable across cellular contexts (heart, brain, T cells). CLIP-Seq, comparison with known functional splicing targets, bioinformatic positional analysis RNA biology High 27096301
2017 CELF2 and hnRNP C directly bind a cis-acting intronic element 340-440 nt upstream of TRAF3 exon 8 and together mediate activation-dependent exon skipping in T cells; CELF2 expression level is the decisive factor while hnRNP C is necessary but not sufficient; CELF2-mediated TRAF3 exon 8 skipping activates non-canonical NF-κB signaling. siRNA screen, cross-link immunoprecipitation (CLIP), mutational analysis of cis element, minigene with distance-alteration, correlation analysis across model systems Molecular and cellular biology High 28031331
2019 CELF2 controls alternative polyadenylation (APA) of its own mRNA and broadly in T cells by competing with core enhancers of the polyadenylation machinery for RNA binding; CELF2 binding overlaps with APA enhancers transcriptome-wide, and ~half of T-cell signaling-induced APA events are CELF2-dependent. CELF2 knockdown, 3'READS APA profiling, CELF2 CLIP-Seq overlap analysis, competition assay with polyadenylation factors Cell reports High 31509743
2019 CELF2 restoration in breast cancer cells with CELF2 promoter hypermethylation has growth-inhibitory effects and restores normal alternative splicing patterns of ULK1 and CARD10; epigenetic silencing via promoter hypermethylation is a mechanism of CELF2 loss in cancer. Promoter methylation analysis, CELF2 restoration by demethylation/transfection, RNA splicing analysis of downstream targets, cell growth assays Oncogene Medium 31409895
2020 CELF2 interacts with PREX2 protein and reduces PREX2-PTEN association, thereby upregulating PTEN phosphatase activity; CELF2 overexpression represses Akt phosphorylation and cell proliferation only in the presence of PTEN. Co-immunoprecipitation, PTEN phosphatase activity assay, CELF2/PREX2 interaction pulldown, Akt phosphorylation assay, PTEN-null cell controls, patient-derived xenograft (PDX) ex vivo Carcinogenesis Medium 31241130
2020 CELF2 regulates CD44 alternative splicing (CD44s to CD44v conversion) in pancreatic cancer, and this is regulated upstream by ALKBH5-mediated m6A modification leading to CELF2 mRNA degradation via YTHDF2; CELF2-mediated CD44 splicing affects endoplasmic reticulum-associated degradation (ERAD) pathway activity. m6A modification assay, ALKBH5/YTHDF2 knockdown, CELF2 splicing reporter, RNA-seq of CD44 splicing, ERAD pathway inhibitor rescue Cell & bioscience Medium 35941702
2020 CELF2 increases mRNA stability of Beclin-1, ATG5, and ATG12 (autophagy components) and promotes autophagic flux in colorectal cancer cells; CELF2 knockdown abrogates IR-induced autophagy both in vitro and in vivo. RNA stability assay, immunoblotting, immunofluorescence, autophagic vacuole and electron microscopy analysis, siRNA knockdown, xenograft model Molecular carcinogenesis Medium 31020708
2020 CELF2 increases stability of FAM198B mRNA by binding AU/U-rich elements in the FAM198B 3'UTR; CELF2-mediated FAM198B stabilization suppresses ovarian cancer progression via inhibiting MAPK/ERK signaling. RNA immunoprecipitation, 3'UTR reporter assay, mRNA stability assay, CELF2 knockdown/overexpression, FAM198B rescue experiment Molecular therapy. Nucleic acids Medium 33335801
2020 CELF2 regulates TREM2 exon 3 alternative splicing; only CELF2 (not CELF1) reduces full-length TREM2 protein by promoting exon 3 skipping; a CELF-responsive sequence was mapped to intron 3 of human TREM2 using chimeric human-mouse minigenes. CELF1/CELF2 overexpression, siRNA knockdown, chimeric human/mouse TREM2 minigenes, Western blot for full-length TREM2 Scientific reports Medium 33093587
2020 hnRNP C and CELF2 reciprocally regulate each other's expression: loss of hnRNP C reduces CELF2 transcription, while loss of CELF2 decreases hnRNP C translation efficiency; this cross-regulation fine-tunes downstream splicing patterns. siRNA knockdown of each RBP, transcription assay, polysome fractionation/translation efficiency measurement, downstream splicing RNA-seq Nucleic acids research Medium 32338744
2020 De novo CELF2 variants clustering in the C-terminal 20 amino acids (overlapping the nuclear localization signal) cause extranuclear mislocalization of CELF2 in transfected cells, demonstrating that the C-terminus is required for nuclear localization. Exome sequencing, expression of mutant CELF2 constructs in cells, immunofluorescence localization Human mutation Medium 33131106
2021 CELF2 undergoes nucleocytoplasmic shuttling that is functionally linked to neural stem cell fate: in self-renewing NPCs CELF2 resides in the cytoplasm where it represses mRNAs encoding cell-fate regulators; translocation to the nucleus releases these mRNAs for translation and triggers NPC differentiation; de novo missense variants disrupting this shuttling cause cortical malformations. De novo variant identification, transgenic mouse NPC analysis, subcellular fractionation, CELF2 localization imaging, translational reporter assays, patient cortical malformation phenotype Cell reports High 34107259
2020 In IL-10-treated macrophages, CELF2 association with pre-miR-155 increases; CRISPR-Cas9 knockdown of CELF2 impairs IL-10's ability to inhibit miR-155 expression and TNF-α expression, placing CELF2 in the IL-10 signaling pathway controlling pre-miR-155 maturation. RNA immunoprecipitation, CRISPR-Cas9 CELF2 knockdown, miR-155 and TNF-α expression assay, IL-10 treatment PloS one Medium 32324763
2024 CELF2 deficiency in hematopoietic cells stabilizes FAT10 mRNA (shown by RIP-Seq) and promotes FAT10 translation, increasing AKT phosphorylation and mTORC1 signaling; loss of Celf2 in mice accelerates AML development in MLL-AF9 models. RIP-Seq, gene expression profiling, mTORC1 signaling assay, Celf2 conditional KO mice, MLL-AF9 AML model, rapamycin/EPZ-5676 combination treatment Oncogene High 38514854
2024 CELF2 undergoes activity-dependent nucleocytoplasmic shuttling in excitatory neurons; cytoplasmic retention of CELF2 (caused by disease-associated variants) causes neuronal hyperexcitability and learning/memory deficits; cytoplasmic CELF2 regulates mRNAs critical for synaptic function; AKT signaling regulates CELF2 shuttling. iPSC-derived neurons from probands, transgenic mouse models, neuronal excitability recordings, drug screening identifying AKT as regulator, subcellular fractionation medRxivpreprint Medium 40666314
2024 CELF2 hinge domain contains an intrinsically disordered region (IDR) that mediates CELF2 condensate formation; condensation is required for tau exon 10 splicing regulation; CELF2 co-condenses with NOVA2 and SFPQ to cooperatively regulate tau exon 10 inclusion; a conserved negatively charged residue D388 in the IDR is critical for condensate formation, protein-protein interactions, and splicing function. TurboID proximity labeling, IDR deletion/swap (with FUS/TAF15 IDRs), D388 mutagenesis, tau exon 10 splicing assay, CELF2 KO mouse brain, live-cell imaging of condensates bioRxivpreprint Medium 39553957
2024 CELF2 binds AU-rich motifs in the CXCL5 3'UTR, reducing CXCL5 mRNA stability and thereby suppressing CXCL5/CXCR2/AKT signaling and bladder cancer cell proliferation and migration. RNA binding assay (RNA pulldown), mRNA stability assay, CELF2 overexpression/knockdown, AKT phosphorylation assay, cell functional assays, in vivo xenograft Life sciences Medium 40154776
2025 CELF2 suppresses immunostimulatory endogenous double-stranded RNA ligands in macrophages; CELF2 depletion leads to spontaneous IFN and ISG induction dependent on RIG-I-MAVS pathway; RNA from CELF2-depleted cells can transfer IFN-inducing activity to naïve cells. CELF2 knockdown in macrophages, IFN/ISG expression assay, RIG-I/MAVS pathway inhibition, RNA transfer experiment, RNase III treatment, dsRNA immunoprecipitation bioRxivpreprint Medium
2025 CELF2 regulates STAT3 alternative splicing by binding UG-rich elements in intron 22 of STAT3 pre-mRNA, modulating the balance between STAT3α and STAT3β isoforms. Minigene splicing assay, cis-element identification by deletion, CELF2 overexpression, RNA binding to intron 22 Biochemical and biophysical research communications Medium 39550869
2008 CUGBP2/CELF2 variant 1 (but not variants 2 or 3) is predominantly nuclear and inhibits translation of COX-2 mRNA; variants 2 and 3 (with additional N-terminal sequences from alternative promoters) are predominantly cytoplasmic and do not induce G2/M arrest or apoptosis, demonstrating isoform-specific subcellular localization and function. Identification of splice variants, subcellular localization by immunocytochemistry, COX-2 3'UTR luciferase reporter, cell cycle analysis, apoptosis assays American journal of physiology. Gastrointestinal and liver physiology Medium 18258790
2013 CUGBP2/CELF2 controls trafficking of COX-2 mRNA to cytoplasmic stress granules in cardiac H9c2 cells in response to pro-inflammatory stimuli; gene silencing experiments demonstrate this is a mechanism for maintaining homeostasis. Gene silencing, fluorescence microscopy, stress granule co-localization Cell biology international Low 23661609
2021 In spinal cord injury, GAS5 lncRNA recruits CELF2 to the coding region of VAV1 mRNA, increasing VAV1 mRNA stability and expression; GAS5 knockdown reduces CELF2-mediated VAV1 mRNA stabilization and alleviates oxidative stress and cell injury. RIP assay, mRNA stability assay, GAS5/CELF2 knockdown, OGD cell model, SCI rat model Scientific reports Low 33574559

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS genetics 202 21379329
2003 Coupled mRNA stabilization and translational silencing of cyclooxygenase-2 by a novel RNA binding protein, CUGBP2. Molecular cell 191 12535526
2002 Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing. Molecular cell 155 11931771
2012 Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2. Nature medicine 118 22660636
1999 Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. Human molecular genetics 97 9887331
2001 Novel role for RNA-binding protein CUGBP2 in mammalian RNA editing. CUGBP2 modulates C to U editing of apolipoprotein B mRNA by interacting with apobec-1 and ACF, the apobec-1 complementation factor. The Journal of biological chemistry 84 11577082
2005 Identification of putative new splicing targets for ETR-3 using sequences identified by systematic evolution of ligands by exponential enrichment. Molecular and cellular biology 81 15657417
2008 Translation inhibition during cell cycle arrest and apoptosis: Mcl-1 is a novel target for RNA binding protein CUGBP2. American journal of physiology. Gastrointestinal and liver physiology 64 18292181
2006 Functional antagonism between RNA binding proteins HuR and CUGBP2 determines the fate of COX-2 mRNA translation. Gastroenterology 63 17383427
2015 Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation. Genes & development 60 26443849
2011 RNA binding protein CUGBP2/CELF2 mediates curcumin-induced mitotic catastrophe of pancreatic cancer cells. PloS one 60 21347286
2018 miR-615-3p promotes proliferation and migration and inhibits apoptosis through its potential target CELF2 in gastric cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 57 29501762
2019 Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer. Oncogene 55 31409895
2015 Induced transcription and stability of CELF2 mRNA drives widespread alternative splicing during T-cell signaling. Proceedings of the National Academy of Sciences of the United States of America 54 25870297
2020 LncRNA CRNDE facilitates epigenetic suppression of CELF2 and LATS2 to promote proliferation, migration and chemoresistance in hepatocellular carcinoma. Cell death & disease 51 32826865
2004 Multiple domains control the subcellular localization and activity of ETR-3, a regulator of nuclear and cytoplasmic RNA processing events. Journal of cell science 51 15226369
2011 Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing. Biochimica et biophysica acta 50 21439371
2012 Reduced Expression of RNA Binding Protein CELF2, a Putative Tumor Suppressor Gene in Colon Cancer. Immuno-gastroenterology 44 23795348
2011 Signal- and development-dependent alternative splicing of LEF1 in T cells is controlled by CELF2. Molecular and cellular biology 44 21444716
2006 ETR-3 represses Tau exons 2/3 inclusion, a splicing event abnormally enhanced in myotonic dystrophy type I. Journal of neuroscience research 44 16862542
2020 CELF2 suppresses non-small cell lung carcinoma growth by inhibiting the PREX2-PTEN interaction. Carcinogenesis 43 31241130
2022 Exosomal miR-625-3p secreted by cancer-associated fibroblasts in colorectal cancer promotes EMT and chemotherapeutic resistance by blocking the CELF2/WWOX pathway. Pharmacological research 42 36336217
2016 Position-dependent activity of CELF2 in the regulation of splicing and implications for signal-responsive regulation in T cells. RNA biology 42 27096301
2020 The RNA-Binding Protein CELF2 Inhibits Ovarian Cancer Progression by Stabilizing FAM198B. Molecular therapy. Nucleic acids 41 33335801
2019 RNA Binding Protein CELF2 Regulates Signal-Induced Alternative Polyadenylation by Competing with Enhancers of the Polyadenylation Machinery. Cell reports 41 31509743
2001 Genomic organization and isoform-specific tissue expression of human NAPOR (CUGBP2) as a candidate gene for familial arrhythmogenic right ventricular dysplasia. Genomics 40 11414768
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2002 Expression and mutation analysis of BRUNOL3, a candidate gene for heart and thymus developmental defects associated with partial monosomy 10p. Journal of molecular medicine (Berlin, Germany) 37 12110949
2003 CUGBP2 plays a critical role in apoptosis of breast cancer cells in response to genotoxic injury. Annals of the New York Academy of Sciences 35 15033780
2015 Downregulation of miR-95-3p inhibits proliferation, and invasion promoting apoptosis of glioma cells by targeting CELF2. International journal of oncology 32 26165303
2008 CUGBP2 downregulation by prostaglandin E2 protects colon cancer cells from radiation-induced mitotic catastrophe. American journal of physiology. Gastrointestinal and liver physiology 30 18325984
2009 The CUGBP2 splicing factor regulates an ensemble of branchpoints from perimeter binding sites with implications for autoregulation. PLoS genetics 29 19680430
2022 N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer. Cell & bioscience 27 35941702
2020 CELF2 regulates the species-specific alternative splicing of TREM2. Scientific reports 27 33093587
2010 CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3. Nucleic acids research 27 20631008
2018 microRNA-451 protects neurons against ischemia/reperfusion injury-induced cell death by targeting CELF2. Neuropsychiatric disease and treatment 26 30425495
2004 Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage. Proceedings of the National Academy of Sciences of the United States of America 26 15358864
2021 Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates. Cell reports 25 34107259
2020 De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy. Human mutation 25 33131106
2008 Novel intestinal splice variants of RNA-binding protein CUGBP2: isoform-specific effects on mitotic catastrophe. American journal of physiology. Gastrointestinal and liver physiology 24 18258790
2021 Triclosan regulates alternative splicing events of nerve-related genes through RNA-binding protein CELF2 to induce zebrafish neurotoxicity. Journal of hazardous materials 22 33621777
2021 LncRNA-SNHG16 promotes proliferation and migration of acute myeloid leukemia cells via PTEN/PI3K/AKT axis through suppressing CELF2 protein. Journal of biosciences 21 33576342
2020 Reciprocal regulation of hnRNP C and CELF2 through translation and transcription tunes splicing activity in T cells. Nucleic acids research 20 32338744
2020 STYXL1 promotes malignant progression of hepatocellular carcinoma via downregulating CELF2 through the PI3K/Akt pathway. European review for medical and pharmacological sciences 17 32271415
2021 miR-363-3p induces EMT via the Wnt/β-catenin pathway in glioma cells by targeting CELF2. Journal of cellular and molecular medicine 16 34636136
2017 Activation-Dependent TRAF3 Exon 8 Alternative Splicing Is Controlled by CELF2 and hnRNP C Binding to an Upstream Intronic Element. Molecular and cellular biology 16 28031331
2015 Upregulation of cugbp2 increases response of pancreatic cancer cells to chemotherapy. Langenbeck's archives of surgery 16 26691217
2012 Alternative splicing produces structural and functional changes in CUGBP2. BMC biochemistry 16 22433174
2020 Long noncoding RNA GAS5 ameliorates chronic constriction injury induced neuropathic pain in rats by modulation of the miR-452-5p/CELF2 axis. Canadian journal of physiology and pharmacology 15 33264082
2021 LncRNA CCDC26 Interacts with CELF2 Protein to Enhance Myeloid Leukemia Cell Proliferation and Invasion via the circRNA_ANKIB1/miR-195-5p/PRR11 Axis. Cell transplantation 14 33439746
2019 Pleotropic role of RNA binding protein CELF2 in autophagy induction. Molecular carcinogenesis 14 31020708
2021 CircPTK2 inhibits the tumorigenesis and metastasis of gastric cancer by sponging miR-134-5p and activating CELF2/PTEN signaling. Pathology, research and practice 12 34562827
2021 LncRNA RHPN1-AS1 promotes the progression of nasopharyngeal carcinoma by targeting CELF2 expression. Experimental and molecular pathology 11 34358519
2024 miR-208a-3p regulated by circUQCRC2 suppresses ischemia/reperfusion-induced acute kidney injury by inhibiting CELF2-mediated tubular epithelial cell apoptosis, inflammation and ferroptosis. Shock (Augusta, Ga.) 10 38664873
2023 Hypoxia-induced lncRNA MRVI1-AS1 accelerates hepatocellular carcinoma progression by recruiting RNA-binding protein CELF2 to stabilize SKA1 mRNA. World journal of surgical oncology 10 36973749
2021 GAS5 knockdown alleviates spinal cord injury by reducing VAV1 expression via RNA binding protein CELF2. Scientific reports 10 33574559
2023 M2 macrophage-derived exosomal miR-1911-5p promotes cell migration and invasion in lung adenocarcinoma by down-regulating CELF2 -activated ZBTB4 expression. Anti-cancer drugs 9 36730375
2023 Role of CELF2 in ferroptosis: Potential targets for cancer therapy (Review). International journal of molecular medicine 9 37594127
2021 RNA-binding protein CELF2 inhibits breast cancer cell invasion and angiogenesis by downregulating NFATc1. Experimental and therapeutic medicine 9 34257711
2009 Transcriptional induction and translational inhibition of Arc and Cugbp2 in mice hippocampus after transient global ischemia under normothermic condition. Brain research 9 19559013
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2021 Suppression of miR-106a-5p expression inhibits tumorigenesis via increasing CELF-2 expression in spinal cord glioma. Oncology letters 8 34267819
2020 Interleukin-10 control of pre-miR155 maturation involves CELF2. PloS one 8 32324763
2023 CELF2 Sustains a Proliferating/OLIG2+ Glioblastoma Cell Phenotype via the Epigenetic Repression of SOX3. Cancers 6 37894405
2022 MiR-210-3p targets CELF2 to facilitate progression of lung squamous carcinoma through PI3K/AKT pathway. Medical oncology (Northwood, London, England) 6 35972577
2022 Natural Antisense Long Noncoding RNA HHIP-AS1 Suppresses Non-Small-Cell Lung Cancer Progression by Increasing HHIP Stability via Interaction with CELF2. Critical reviews in eukaryotic gene expression 6 36374812
2013 A novel function for CUGBP2 in controlling the pro-inflammatory stimulus in H9c2 cells: subcellular trafficking of messenger molecules. Cell biology international 6 23661609
2024 Loss of RNA-binding protein CELF2 promotes acute leukemia development via FAT10-mTORC1. Oncogene 5 38514854
2024 CELF2 Deficiency Demonstrates Autism-Like Behaviors and Interferes with Late Development of Cortical Neurons in Mice. Molecular neurobiology 5 38829512
2022 ELK1-Induced upregulation of long non-coding TNK2-AS1 promotes the progression of acute myeloid leukemia by EZH2-mediated epigenetic silencing of CELF2. Cell cycle (Georgetown, Tex.) 5 35941836
2020 The Role of VEGFA, COX2, HUR and CUGBP2 in Predicting the Response to Neoadjuvant Therapy in Rectal Cancer Patients. Medicina (Kaunas, Lithuania) 5 32331433
2025 The HNRNPC/CELF2 signaling pathway drives glycolytic reprogramming and mitochondrial dysfunction in drug-resistant acute myeloid leukemia. Cell & bioscience 3 40380235
2024 CELF2 promotes tau exon 10 inclusion via hinge domain-mediated nuclear condensation. bioRxiv : the preprint server for biology 3 39553957
2022 The Histone Demethylase HR Suppresses Breast Cancer Development through Enhanced CELF2 Tumor Suppressor Activity. Cancers 3 36230572
2016 ORF13 in the Type III secretion system gene cluster of Edwardsiella tarda binds to the mammalian factor Cugbp2. Diseases of aquatic organisms 3 27137075
2024 Loss of CELF2 promotes skin tumorigenesis and increases drug resistance. International journal of dermatology 2 38887832
2024 LINC00261 triggers DNA damage via the miR-23a-3p/CELF2 axis to mitigate the malignant characteristics of 131I-resistant papillary thyroid carcinoma cells. Biochemistry and biophysics reports 2 39552712
2025 Genetic variants disrupting activity-dependent CELF2 shuttling cause neuronal hyperexcitability, learning deficits, and seizures. medRxiv : the preprint server for health sciences 1 40666314
2025 Transition of CELF2 PAS usage promotes recovery of refractory JDM through alternative splicing regulation of CTSB. Molecular therapy. Nucleic acids 1 40686855
2025 The regulation of miR-155 strand selection by CELF2, FUBP1 and KSRP proteins. Scientific reports 1 40825800
2025 Investigation of lncRNA expression in newly diagnosed multiple myeloma reveals a LINC01432-CELF2 axis as an inhibitor of apoptosis. Oncogenesis 1 41052980
2024 Generation and characterization of a human iPSC line and gene-corrected isogenic line derived from a patient with a CELF2 gene mutation. Stem cell research 1 38364506
2024 RNA binding protein CUGBP2/ETR-3 regulates STAT3 alternative splicing. Biochemical and biophysical research communications 1 39550869
2022 Erratum: RNA-binding protein CELF2 inhibits breast cancer cell invasion and angiogenesis by downregulating NFATc1. Experimental and therapeutic medicine 1 35222722
2019 Structure of an Unfolding Intermediate of an RRM Domain of ETR-3 Reveals Its Native-like Fold. Biophysical journal 1 31866002
2026 LncRNA Dleu2 regulates fear extinction memory through Celf2-driven synaptic plasticity. Brain research bulletin 0 41628728
2026 CELF2 Promotes Tau Exon 10 Inclusion via Hinge Domain-Mediated Nuclear Condensation, Driving Cognitive Dysfunction in Tauopathy Models. Research square 0 41646425
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2025 Exploring the Molecular Mechanisms and Biological Effects of CELF2 in the Development of Gastric Cancer. Recent patents on anti-cancer drug discovery 0 40798961
2013 Purification, crystallization and preliminary crystallographic studies of C-terminal RNA recognition motif (RRM-3) of human ELAV-type RNA-binding protein 3 (ETR-3). Acta crystallographica. Section F, Structural biology and crystallization communications 0 24100559
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