Affinage

CPEB4

Cytoplasmic polyadenylation element-binding protein 4 · UniProt Q17RY0

Length
729 aa
Mass
80.2 kDa
Annotated
2026-06-09
72 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CPEB4 is a sequence-specific RNA-binding protein that controls mRNA translation and stability by binding cytoplasmic polyadenylation elements (CPEs) in target 3'-UTRs and modulating cytoplasmic poly(A) tail length, with binding specificity distinct from CPEB1 and mediated by its tandem RRM domains (PMID:17024188, PMID:25081215). Depending on context it either activates translation by directing cytoplasmic polyadenylation—of targets such as tPA, VEGF, MITF/RAB7A, PFKFB3, c-Fos, IL-22, and SCN5A (PMID:22138752, PMID:26627607, PMID:27857118, PMID:32169429, PMID:29166615, PMID:35243213, PMID:41846068)—or represses translation, including through interaction with the eIF3 initiation complex during terminal erythropoiesis (PMID:25220394). CPEB4 functions sequentially and non-redundantly with CPEB1 across the meiotic and mitotic cell cycles: CPEB1 polyadenylates CPEB4 mRNA to activate it, after which CPEB4 takes over to drive M-phase and anaphase/cytokinesis transitions via spindle-associated CPE mRNAs (PMID:20364142, PMID:20531391, PMID:33323527). Its activity is gated by ERK2/Cdk1 hyperphosphorylation, which maintains the active monomeric state, whereas the unphosphorylated intrinsically disordered N-terminal domain undergoes liquid-liquid phase separation into inactive condensates (PMID:27802129); in neurons, a 24-bp microexon encodes histidine-cluster heterotypic interactions that keep these condensates reversible and prevent the irreversible aggregation seen when the microexon is lost in autism spectrum disorder and schizophrenia brains (PMID:39633052, PMID:30111840, PMID:36958377). CPEB4 shuttles between nucleus and cytoplasm under calcium- and CaMKII-dependent control linked to ER calcium and the IP3 receptor (PMID:20937770). Through these mechanisms CPEB4 coordinates stress-adaptive translational reprogramming in liver ER-stress/UPR and circadian control (PMID:28092655, PMID:37543852), inflammation resolution by opposing TTP-mediated mRNA decay (PMID:35442882), and disease-relevant programs in cancer, fibrosis, and cardiac sodium-channel homeostasis (PMID:22138752, PMID:32169429, PMID:41846068).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2006 High

    Established that CPEB4 is a distinct RNA-binding protein with sequence specificity different from CPEB1, answering whether the CPEB paralogs are functionally redundant.

    Evidence SELEX, RNA structure probing and footprinting comparing CPEB1, CPEB3, and CPEB4 binding

    PMID:17024188

    Open questions at the time
    • Did not define in vivo target mRNAs
    • Structural basis of specificity not resolved
  2. 2010 High

    Showed CPEB4 acts sequentially after CPEB1 in both meiosis and mitosis, resolving how successive cell-cycle transitions are coupled to phase-specific poly(A) changes.

    Evidence siRNA/KO with poly(A) tail and cell-cycle assays in mitotic cells, and Xenopus oocyte meiotic progression with kinase-inhibitor and reporter assays

    PMID:20364142 PMID:20531391

    Open questions at the time
    • Kinases distinguishing CPEB1 vs CPEB4 timing not fully defined here
    • Full target mRNA set per phase not enumerated
  3. 2010 High

    Identified calcium/CaMKII- and ER-calcium-dependent nucleocytoplasmic shuttling and a role in cell survival, answering how CPEB4 localization is signal-regulated.

    Evidence Subcellular fractionation, live imaging, CaMKII and IP3R manipulation, in vivo focal ischemia and oxygen-glucose deprivation

    PMID:20937770

    Open questions at the time
    • Nuclear function of CPEB4 not defined
    • Export machinery beyond NES not identified
  4. 2014 High

    Defined the structural basis of CPE recognition, showing both tandem RRMs are required and how they engage RNA.

    Evidence NMR, ITC, EMSA, and ion mobility-mass spectrometry of RRM1-RRM2

    PMID:25081215

    Open questions at the time
    • Did not address the N-terminal IDR contribution
    • Affinity differences among physiological targets not mapped
  5. 2014 High

    Revealed a repressive mode via eIF3 and an autoregulatory negative feedback loop essential for terminal erythropoiesis, broadening CPEB4 beyond polyadenylation-driven activation.

    Evidence Co-IP of eIF3, ribosome profiling, siRNA, and primary erythroid differentiation downstream of Gata1/Tal1

    PMID:25220394

    Open questions at the time
    • Switch between repressive and activating modes not mechanistically defined
    • eIF3 subunit contact points unresolved
  6. 2016 High

    Demonstrated that ERK2/Cdk1 phosphorylation controls a phase-separation switch governing CPEB4 activity and coordinates it with CPEB1 inactivation.

    Evidence In vitro kinase assays, phosphomutants, droplet microscopy, cell-cycle synchronization, biophysical assays

    PMID:27802129

    Open questions at the time
    • In vivo condensate dynamics during division not directly imaged
    • Phosphatase reversing this state not identified
  7. 2011 High

    Linked CPEB4-driven cytoplasmic polyadenylation to oncogenic translational reprogramming in solid tumors, showing pathological reactivation of silenced mRNAs.

    Evidence RNA-IP, poly(A) assays, siRNA, luciferase reporters, and xenografts in pancreatic cancer and glioblastoma

    PMID:22138752

    Open questions at the time
    • Full oncogenic target network incomplete
    • Upstream signal activating CPEB4 in tumors not defined
  8. 2016 High

    Extended CPEB4 cell-cycle and target control to melanoma drivers MITF/RAB7A, showing lineage-specific target repertoires.

    Evidence RIP-seq, poly(A) length tests, siRNA, cell-cycle analysis, clinical biopsy validation

    PMID:27857118

    Open questions at the time
    • Determinants of lineage-specific target selection unknown
  9. 2015 High

    Showed CPEB1 nuclear processing of VEGF and CPEB4 mRNAs licenses CPEB4 to drive pathological angiogenesis, integrating nuclear and cytoplasmic regulation.

    Evidence siRNA, poly(A) assays, 3' RACE, tube formation, CPEB-deficient mice

    PMID:26627607

    Open questions at the time
    • Mechanism of CPEB1-directed alternative processing not fully detailed
  10. 2017 High

    Established CPEB4 as a UPR- and circadian-gated effector maintaining hepatic ER/mitochondrial homeostasis, defining a translational stress-adaptation circuit.

    Evidence Circadian analysis, uORF reporters, CPEB4 KO mice, ER-stress and high-fat-diet liver models

    PMID:28092655

    Open questions at the time
    • Second-wave UPR target mRNAs not enumerated
    • uORF-sensing factor not identified
  11. 2017 High

    Identified c-Fos as a CPEB4 target in olfactory bulb granule cells, linking CPEB4 translational control to neuronal survival.

    Evidence CPEB4 KO mice, immunofluorescence, poly(A) assays, electrophysiology, behavior

    PMID:29166615

    Open questions at the time
    • Signal coupling olfactory experience to CPEB4 activity not detailed
  12. 2018 High

    Connected a neuron-specific CPEB4 microexon to autism by showing its loss reduces poly(A) length and protein output of ASD risk genes, providing a unifying regulatory hub.

    Evidence RNA-IP, poly(A)-tail sequencing, RT-PCR, microexon-imbalance mouse model with human brain validation

    PMID:30111840

    Open questions at the time
    • Mechanism by which microexon loss alters activity left to later structural work
    • Splicing regulator controlling microexon inclusion not identified here
  13. 2024 High

    Provided the molecular explanation for the microexon, showing it encodes histidine-cluster heterotypic interactions that keep neuronal condensates reversible and prevent dominant-negative aggregation.

    Evidence Phase separation and depolarization-dependent dissolution assays, structural analysis of microexon-histidine interactions, ASD brain and mouse models

    PMID:39633052

    Open questions at the time
    • In vivo condensate dynamics in human neurons not directly observed
  14. 2020 High

    Showed CPEB4 drives PFKFB3-dependent glycolysis to activate hepatic stellate cells, defining a metabolic-translational axis in fibrosis.

    Evidence RNA-IP, poly(A) assays, siRNA, CPEB4 KO mice, bile-duct ligation

    PMID:32169429

    Open questions at the time
    • Whether the same axis operates in non-hepatic fibrosis untested
  15. 2022 High

    Established that CPEB4 stabilizes anti-inflammatory CPE/ARE mRNAs by opposing TTP deadenylation under MAPK control, defining its role in inflammation resolution.

    Evidence siRNA, poly(A) assays, LPS stimulation, MAPK inhibition, in vivo sepsis model

    PMID:35442882

    Open questions at the time
    • Direct competition vs TTP at shared 3'-UTRs not biochemically reconstituted
  16. 2021 High

    Identified CPEB4 as a translational regulator of cardiac growth, repressing Zeb1/Zbtb20 to restrain pathological hypertrophy.

    Evidence RNA interactome capture, RNA-IP, siRNA, in vitro and in vivo hypertrophy models

    PMID:33979607

    Open questions at the time
    • Repressive vs activating mode at these targets not mechanistically separated
  17. 2021 High

    Showed CPEB4 promotes diet-induced obesity by activating translation of inflammatory/metabolic mRNAs (Cebpb, Stat5a, Ccl2, Tlr4) in adipocytes.

    Evidence RIP-seq, CPEB4 KO mice, high-fat diet, siRNA

    PMID:34774811

    Open questions at the time
    • Signal activating CPEB4 in obese adipocytes not defined
  18. 2025 High

    Demonstrated CPEB4 stabilizes SCN5A mRNA to sustain Nav1.5 sodium current, with restoration rescuing post-infarction conduction defects.

    Evidence Cpeb4-deficient mice, ECG, patch clamp, sodium-current measurement, infarction-restoration model

    PMID:41846068

    Open questions at the time
    • Whether stabilization is purely poly(A)-mediated not fully isolated
    • Other cardiac ion-channel targets not surveyed
  19. 2024 Medium

    Revealed a nuclear splicing-regulatory role, with CPEB4 interacting with SRSF5/SRSF6 in nuclear bodies via its RNA-binding (RRM7) capacity to regulate Id2 splicing.

    Evidence Co-IP, immunofluorescence, domain-deletion mutants, RNA-seq, leptomycin B export inhibition during osteoclast differentiation

    PMID:38284484

    Open questions at the time
    • Single-lab; direct CPEB4 binding to spliced pre-mRNA not shown
    • Generality beyond osteoclasts untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CPEB4 switches between translational activation and repression on a given target, and how its phosphorylation/phase-separation state, nuclear splicing role, and shuttling are integrated in vivo, remains unresolved.
  • No unified model of activator-vs-repressor mode selection
  • Nuclear functions (splicing, shuttling purpose) mechanistically incomplete
  • Phosphatase and condensate-resolution machinery in non-neuronal cells unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0140098 catalytic activity, acting on RNA 5 GO:0045182 translation regulator activity 4 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005730 nucleolus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1640170 Cell Cycle 4 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
CPEB1CPSFEIF3GLD2SRSF5SRSF6TRIM25

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 CPEB3 and CPEB4 interact with different RNA sequences than CPEB1, as determined by SELEX, RNA structure probing, and RNA footprinting, establishing them as distinct classes of RNA-binding proteins with different binding specificities. SELEX, RNA structure probing, RNA footprinting The EMBO journal High 17024188
2010 CPEB4 mediates cytoplasmic polyadenylation-dependent translational control specifically required for M-phase entry in mitotically dividing cells. CPEB1 and CPEB4 act sequentially: CPEB1 regulates G2/M mRNAs and CPEB4 regulates M-phase mRNAs through phase-specific poly(A) tail length changes. Loss-of-function (siRNA/KO), poly(A) tail length assays, cell cycle analysis Nature cell biology High 20364142
2010 CPEB1 activates translation of CPEB4 mRNA during meiosis by cytoplasmic polyadenylation, generating a positive feedback loop. CPEB4 then replaces CPEB1 after its degradation at meiosis I and drives the metaphase I to metaphase II transition. CPEB1 and CPEB4 are differentially regulated by phase-specific kinases. Xenopus oocyte meiotic progression assays, poly(A) tail assays, kinase inhibitor experiments, translation reporter assays The EMBO journal High 20531391
2010 CPEB4 is a nucleus-cytoplasm shuttling protein that accumulates in the nucleus in response to calcium-mediated signaling and CaMKII activity. CPEB2, -3, and -4 (but not CPEB1) contain conserved nuclear export signals. Nuclear accumulation of CPEB4 is controlled by ER calcium depletion through the IP3 receptor. CPEB4 is required for cell survival and becomes nuclear in response to focal ischemia in vivo and oxygen-glucose deprivation in vitro. Subcellular fractionation, immunofluorescence, live imaging, CaMKII inhibition, IP3 receptor manipulation, focal ischemia model, oxygen-glucose deprivation Molecular and cellular biology High 20937770
2011 CPEB4 promotes translational activation of mRNAs silenced in normal tissue, including tissue plasminogen activator (tPA) mRNA, through cytoplasmic polyadenylation. This supports tumor growth, vascularization, and invasion in pancreatic ductal adenocarcinoma and glioblastoma. RNA immunoprecipitation, poly(A) tail assays, siRNA knockdown, xenograft tumor models, luciferase reporter assays Nature medicine High 22138752
2014 Cpeb4 is induced by erythroid transcription factors Gata1 and Tal1, and interacts with translation initiation factor eIF3 to repress translation of a large set of mRNAs including its own mRNA, forming a negative feedback loop essential for terminal erythropoiesis. Co-immunoprecipitation (eIF3 interaction), ribosome profiling, siRNA knockdown, primary erythroid cell differentiation assay Developmental cell High 25220394
2014 The tandem RRM domains of CPEB4 are both required for optimal CPE-containing RNA binding. RRM1 alone and tandem RRM1-RRM2 can dimerize as a minor population without affecting RNA binding. NMR shows the two RRM domains are oriented toward each other, with RNA binding occurring on the β-sheet surface of RRM1 and C-terminus of RRM2. NMR spectroscopy, isothermal titration calorimetry (ITC), electrophoretic mobility shift assay (EMSA), ion mobility-mass spectrometry Nucleic acids research High 25081215
2014 CPEB4 localizes to stress granules under arsenite-induced stress. Vinexin, a SH3-domain adaptor protein, is a CPEB4-interacting protein and novel stress granule component. Arsenite-activated JNK signaling enhances the CPEB4-Vinexin interaction, facilitating Vinexin translocation from focal adhesions to stress granules and promoting stress granule assembly and cell survival. Co-immunoprecipitation, immunofluorescence, JNK inhibition, siRNA knockdown, cell viability assays PloS one Medium 25237887
2015 CPEB1 promotes alternative nuclear processing of VEGF and CPEB4 mRNAs deleting translational repressor elements. The resulting CPEB4 overexpression then mediates cytoplasmic polyadenylation of VEGF mRNA to increase its translation, driving pathological angiogenesis. CPEB1 and CPEB4 function sequentially and non-redundantly in this pathway. siRNA knockdown, poly(A) tail assays, 3' RACE, luciferase reporter assays, Matrigel tube formation assay, CPEB-deficient mice, immunoblot Gastroenterology High 26627607
2016 CPEB4 activity is regulated by ERK2- and Cdk1-mediated hyperphosphorylation in M-phase, which maintains CPEB4 in its monomeric active state. Unphosphorylated CPEB4 phase-separates into inactive liquid-like droplets through its intrinsically disordered N-terminal domain. Cdk1 coordinates CPEB4 activation with CPEB1 inactivation to regulate cell cycle progression. In vitro kinase assays, phosphomutant analysis, fluorescence microscopy of liquid droplets, cell cycle synchronization, FRET/biophysical assays eLife High 27802129
2016 CPEB4 has lineage-specific functions in melanoma: it is required to prevent mitotic aberrations and to progress through G1/S cell cycle checkpoints, and binds to and regulates poly(A) tail length of melanoma-specific target mRNAs including the melanoma drivers MITF and RAB7A. RNA immunoprecipitation followed by sequencing, poly(A) length tests, siRNA knockdown, cell cycle analysis Nature communications High 27857118
2016 The low-complexity N-terminal domain (LCD) of CPEB4, when expressed alone, forms nucleolar aggregates and causes impaired neurodevelopment including reduced motor axon branching and abnormal neuromuscular junction formation. This is associated with altered ribosomal RNA biogenesis, ribosomal protein gene expression, and elevated stress response genes including actin-bundling protein DRR1, which impedes neurite outgrowth. Transgenic mouse model expressing only CPEB4-LCD, immunofluorescence, rRNA biogenesis assays, gene expression analysis Scientific reports Medium 27381259
2017 CPEB4 protein synthesis is regulated by the unfolded protein response (UPR) through upstream open reading frames (uORFs) within the 5'UTR of Cpeb4 mRNA, so that CPEB4 protein is made only following ER stress. Cpeb4 mRNA transcription is controlled by the circadian clock. CPEB4 in turn activates a second wave of UPR translation required to maintain ER and mitochondrial homeostasis, and its deficiency results in non-alcoholic fatty liver disease. Circadian clock analysis, uORF reporter assays, CPEB4 knockout mice, ER stress induction, high-fat diet model, hepatic function assays Nature cell biology High 28092655
2017 CPEB4 activates translation of c-Fos mRNA in olfactory bulb granule cells during the early postnatal period in response to olfactory experience; this is required for c-FOS-dependent neurotrophic signaling and granule cell survival. CPEB4-knockout mice show c-FOS insufficiency, reduced neurotrophic signaling, impaired granule cell survival, and olfactory bulb hypoplasia. CPEB4-knockout mice, immunofluorescence, poly(A) tail assays, electrophysiology, behavioral assays Cell reports High 29166615
2018 CPEB4 binds transcripts of most high-confidence ASD risk genes. A neuron-specific 24 bp microexon (exon 4) of CPEB4 is decreased in inclusion in brains of idiopathic ASD patients, resulting in reduced poly(A)-tail length and reduced protein expression of ASD risk gene products. Equivalent microexon imbalance in mice reproduces ASD-like neuroanatomical, electrophysiological, and behavioral phenotypes. RNA immunoprecipitation, poly(A) tail sequencing, RT-PCR, mouse model with microexon imbalance, electrophysiology, behavioral testing Nature High 30111840
2020 CPEB4 binds to cytoplasmic polyadenylation elements (CPEs) within the 3'-UTR of PFKFB3 mRNA to induce its cytoplasmic polyadenylation and translational upregulation (not transcriptional). This drives glycolysis and activates hepatic stellate cells, promoting liver fibrosis. CPEB4-knockout mice show decreased PFKFB3 and reduced fibrosis. RNA immunoprecipitation, poly(A) tail assays, siRNA knockdown, CPEB4-KO mice, bile duct ligation fibrosis model Gastroenterology High 32169429
2020 Cpeb4 translocates from the cytoplasm to nuclear bodies in response to RANKL stimulation during osteoclast differentiation, dependent on PI3K-Akt and calcium-NFAT signaling pathways. shRNA-mediated Cpeb4 depletion impairs TRAP-positive osteoclast formation and expression of key differentiation markers (Acp5, Ctsk, Nfatc1, Dcstamp), establishing Cpeb4 as a positive regulator of osteoclastogenesis. Immunofluorescence, shRNA knockdown, PI3K/NFAT inhibition, Western blot Biochemical and biophysical research communications Medium 32517870
2021 Cpeb4 is identified as a dynamic RNA-binding protein in cardiomyocytes that regulates cardiac growth (hypertrophy) in vitro and in vivo. Cpeb4 binds and represses expression of Zeb1 and Zbtb20 mRNAs; Cpeb4 depletion increases their expression. Cpeb4 loss inhibits pathological cardiomyocyte growth. RNA interactome capture, RNA immunoprecipitation, in vitro and in vivo cardiac hypertrophy models, siRNA knockdown Cell reports High 33979607
2021 CPEB4 and CPEB1 localize to the mitotic spindle and associate with spindle-localized CPE-containing mRNAs and translating ribosomes. CPEB1 and CPEB4 function sequentially: CPEB1 drives metaphase and CPEB4 drives anaphase/cytokinesis by controlling the expression/localization of spindle-associated transcripts. Immunofluorescence of spindle localization, RNA immunoprecipitation, ribosome association assays, siRNA knockdown, cell cycle analysis RNA (New York, N.Y.) Medium 33323527
2021 CPEB4 acts as a translational regulator of CSAG2 (TRAG-3) mRNA by binding its 3'-UTR and inducing cytoplasmic polyadenylation to increase CSAG2 protein expression, which mediates paclitaxel resistance in ovarian cancer cells. RNA immunoprecipitation, poly(A) tail assay, siRNA knockdown, cell viability assay Frontiers in pharmacology Medium 33519462
2021 CircRNA cDOPEY2 acts as a protein scaffold to enhance interaction between CPEB4 and E3 ligase TRIM25, facilitating ubiquitination and proteasomal degradation of CPEB4. Elevated CPEB4 in cisplatin-resistant cells drives Mcl-1 translation via binding to its mRNA 3'-UTR; cDOPEY2-mediated CPEB4 degradation reduces Mcl-1 and restores cisplatin sensitivity. Mass spectrometry, co-immunoprecipitation, ubiquitination assay, RNA immunoprecipitation, Western blot Journal of experimental & clinical cancer research : CR Medium 34781999
2021 CPEB4 overexpression in obese adipocytes activates translation of Cebpb, Stat5a, Ccl2, and Tlr4 mRNAs, as demonstrated by RNA-immunoprecipitation and high-throughput sequencing. CPEB4 knockout in mice protects against diet-induced obesity and adipose tissue expansion and inflammation. RNA immunoprecipitation followed by high-throughput sequencing, CPEB4-KO mice, high-fat diet model, siRNA knockdown Molecular metabolism High 34774811
2022 CPEB4 stabilizes anti-inflammatory mRNAs containing both CPEs and AREs in their 3'-UTRs in macrophages, opposing TTP-directed mRNA deadenylation. Coordination between CPEB4 and TTP is sequentially regulated through MAPK signaling. CPEB4 depletion impairs inflammation resolution in an LPS-induced sepsis model. siRNA knockdown, poly(A) tail assays, LPS stimulation, MAPK pathway inhibition, in vivo sepsis model eLife High 35442882
2022 CPEB4 is required for translation of interleukin-22 mRNA and other cytokine mRNAs in intestinal immune cells upon tissue injury. CPEB4 is required for development of gut-associated lymphoid tissues and maintenance of intestinal immune homeostasis. CPEB4 conditional knockout, RNA immunoprecipitation, poly(A) tail assays, intestinal inflammation models iScience Medium 35243213
2023 In CD8 T lymphocytes, CPEB4 constitutes a new branch of the UPR activated during T-cell activation and effector function; ER stress triggers CPEB4 expression, and CPEB4 mediates chronic stress adaptation (decoupled from terminal UPR) to maintain cellular fitness, effector molecule production, and cytotoxic activity. CPEB4 disruption in T cells exacerbates tumor growth. T cell activation assays, ER stress induction, CPEB4 knockdown/KO, cytotoxicity assays, tumor growth models The EMBO journal Medium 36919984
2023 Decreased CPEB4 microexon (exon 4) inclusion is found in schizophrenia brains (in antipsychotic-free individuals), correlated with decreased protein levels of CPEB4-target SCZ-associated genes. Mice mildly overexpressing exon 4-lacking CPEB4 (CPEB4Δ4) show decreased protein levels of CPEB4-target SCZ genes and SCZ-linked behaviors. RT-PCR, Western blot on postmortem brain tissue, CPEB4Δ4 transgenic mice, behavioral testing, MAGMA-enrichment analysis Biological psychiatry Medium 36958377
2023 CPEB4 regulates mitochondrial proteome and activity through mitochondrial translational control in muscle stem cells. CPEB4 loss induces cellular senescence; restoring CPEB4 rescues impaired mitochondrial metabolism and prevents senescence in murine muscle stem cells and human cell lines. Proteomics of aged muscle stem cells, CPEB4 KO/restoration, mitochondrial function assays, senescence markers Developmental cell Medium 37321216
2023 CLOCK binds to recognition sites in the CPEB4 promoter region during status epilepticus to increase Cpeb4 mRNA levels. CPEB4 in turn regulates poly(A) tail length of Clock mRNA, creating a positive transcriptional-translational feedback loop. CPEB4-deficient mice show altered CLOCK expression and altered circadian function. Chromatin immunoprecipitation (ChIP), poly(A) tail analysis, CPEB4-KO mice, kainic acid epilepsy model, CLOCK overexpression in cells Epilepsia Medium 37543852
2024 The neuronal CPEB4 microexon encodes a sequence whose heterotypic interactions with a cluster of histidine residues prevent irreversible CPEB4 aggregation by competing with homotypic interactions between histidine clusters. Neuronal CPEB4 forms condensates that dissolve after depolarization (transition from translational repression to activation). Microexon-lacking CPEB4 (as in ASD) forms irreversible aggregates with dominant-negative effects on ASD risk gene expression. Phase separation assays, condensate dissolution upon depolarization, NMR/structural analysis of microexon-histidine interactions, ASD patient brain analysis, mouse model Nature High 39633052
2024 Cpeb4 co-localizes and interacts with splicing factors SRSF5 and SRSF6 in nuclear bodies, where its RNA-binding ability (specifically RRM7 domain) is required for nuclear body localization and regulation of normal splicing of the Id2 gene during osteoclast differentiation. Cpeb4 depletion alters Id2 splicing pattern and elevates expression of cell cycle-related genes. Co-immunoprecipitation, immunofluorescence, domain deletion mutant analysis, RNA-sequencing, leptomycin B nuclear export inhibition Journal of cellular physiology Medium 38284484
2024 CPEB4 deficiency suppresses hepcidin expression, leading to elevated ferroportin levels, decreased intracellular iron accumulation, and reduced lipid peroxidation, thereby decreasing sensitivity to ferroptosis in liver cancer cells. CPEB4 translationally regulates hepcidin, and CPEB4 KO mice show increased tumor burden in diet-induced liver cancer models. CPEB4 KO and knockdown mice and cell lines, xenograft models, ferroptosis induction assays, iron/lipid peroxidation measurements JHEP reports : innovation in hepatology Medium 39980747
2025 CPEB4 promotes cytoplasmic polyadenylation and stabilizes SCN5A mRNA, thereby supporting Nav1.5 protein expression and sodium current in cardiomyocytes. Cpeb4 deficiency in mice causes QRS widening, reduced Nav1.5 protein, and decreased sodium current. Restoring Cpeb4 after infarction preserved SCN5A/Nav1.5 and sodium current. Cpeb4-deficient mice, cardiac electrophysiology (ECG, patch clamp), sodium current measurements, in vivo infarction model with Cpeb4 restoration JACC. Basic to translational science High 41846068
2025 In shock-sensitive rats suppressing methamphetamine self-administration, CPEB4 mRNA levels are increased along with elevated protein levels of its interacting partners CPSF and GLD2. GLD2-regulated GLUN2A mRNA and protein are also increased, suggesting a CPEB4/GLD2 polyadenylation complex regulates NMDA receptor subunit expression in the dorsal striatum. Differential gene expression analysis, Western blot for CPSF and GLD2 protein levels, mRNA/protein quantification in dorsal striatum International journal of molecular sciences Low 40141377
2010 miR-92 and miR-26 bind conserved target sites in the 3'-UTRs of CPEB2, CPEB3, and CPEB4 at paralog positions, coordinately downregulating all three paralogs by reducing their mRNA levels. Mutagenesis of miRNA-binding sites in reporter constructs confirmed direct targeting. Luciferase reporter assays, miRNA binding site mutagenesis, miRNA overexpression and depletion, endogenous mRNA level measurement Nucleic acids research Medium 20660482

Source papers

Stage 0 corpus · 72 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 CPEB3 and CPEB4 in neurons: analysis of RNA-binding specificity and translational control of AMPA receptor GluR2 mRNA. The EMBO journal 193 17024188
2010 Mitotic cell-cycle progression is regulated by CPEB1 and CPEB4-dependent translational control. Nature cell biology 133 20364142
2020 CPEB4 Increases Expression of PFKFB3 to Induce Glycolysis and Activate Mouse and Human Hepatic Stellate Cells, Promoting Liver Fibrosis. Gastroenterology 130 32169429
2011 Key contribution of CPEB4-mediated translational control to cancer progression. Nature medicine 128 22138752
2018 Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing. Nature 127 30111840
2010 Meiosis requires a translational positive loop where CPEB1 ensues its replacement by CPEB4. The EMBO journal 93 20531391
2017 MicroRNA-29c-5p suppresses gallbladder carcinoma progression by directly targeting CPEB4 and inhibiting the MAPK pathway. Cell death and differentiation 79 28060377
2015 Sequential Functions of CPEB1 and CPEB4 Regulate Pathologic Expression of Vascular Endothelial Growth Factor and Angiogenesis in Chronic Liver Disease. Gastroenterology 76 26627607
2020 LncRNA RP11-361F15.2 promotes osteosarcoma tumorigenesis by inhibiting M2-Like polarization of tumor-associated macrophages of CPEB4. Cancer letters 68 31904478
2017 Circadian- and UPR-dependent control of CPEB4 mediates a translational response to counteract hepatic steatosis under ER stress. Nature cell biology 64 28092655
2016 CPEB4 is regulated during cell cycle by ERK2/Cdk1-mediated phosphorylation and its assembly into liquid-like droplets. eLife 53 27802129
2021 CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation. Journal of experimental & clinical cancer research : CR 52 34781999
2016 Lineage-specific roles of the cytoplasmic polyadenylation factor CPEB4 in the regulation of melanoma drivers. Nature communications 49 27857118
2019 Silencing lncRNA FOXD2-AS1 inhibits proliferation, migration, invasion and drug resistance of drug-resistant glioma cells and promotes their apoptosis via microRNA-98-5p/CPEB4 axis. Aging 45 31770107
2010 CPEB4 is a cell survival protein retained in the nucleus upon ischemia or endoplasmic reticulum calcium depletion. Molecular and cellular biology 43 20937770
2014 Cpeb4-mediated translational regulatory circuitry controls terminal erythroid differentiation. Developmental cell 42 25220394
2020 MSC-AS1 knockdown inhibits cell growth and temozolomide resistance by regulating miR-373-3p/CPEB4 axis in glioma through PI3K/Akt pathway. Molecular and cellular biochemistry 35 33106913
2015 MicroRNA-203-mediated posttranscriptional deregulation of CPEB4 contributes to colorectal cancer progression. Biochemical and biophysical research communications 33 26361147
2024 Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD. Nature 32 39633052
2017 CPEB4 promotes cell migration and invasion via upregulating Vimentin expression in breast cancer. Biochemical and biophysical research communications 29 28536077
2021 Identification of dynamic RNA-binding proteins uncovers a Cpeb4-controlled regulatory cascade during pathological cell growth of cardiomyocytes. Cell reports 28 33979607
2010 CPEB2, CPEB3 and CPEB4 are coordinately regulated by miRNAs recognizing conserved binding sites in paralog positions of their 3'-UTRs. Nucleic acids research 28 20660482
2021 Circular RNA Circ_0003221 Promotes Cervical Cancer Progression by Regulating miR-758-3p/CPEB4 Axis. Cancer management and research 27 34262342
2013 CPEB4 knockout mice exhibit normal hippocampus-related synaptic plasticity and memory. PloS one 27 24386439
2023 Restoration of CPEB4 prevents muscle stem cell senescence during aging. Developmental cell 26 37321216
2021 mRNA spindle localization and mitotic translational regulation by CPEB1 and CPEB4. RNA (New York, N.Y.) 25 33323527
2022 Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation. eLife 22 35442882
2020 CPEB1 or CPEB4 knockdown suppresses the TAK1 and Smad signalings in THP-1 macrophage-like cells and dermal fibroblasts. Archives of biochemistry and biophysics 22 32113875
2013 CPEB4 is a candidate biomarker for defining metastatic cancers and directing personalized therapies. Medical hypotheses 22 24045092
2018 CPEB4 promotes growth and metastasis of gastric cancer cells via ZEB1-mediated epithelial- mesenchymal transition. OncoTargets and therapy 21 30288051
2021 Evolution of CPEB4 Dynamics Across its Liquid-Liquid Phase Separation Transition. The journal of physical chemistry. B 19 34787433
2023 Pathogenic Mis-splicing of CPEB4 in Schizophrenia. Biological psychiatry 18 36958377
2018 Knockdown of CPEB4 expression suppresses cell migration and invasion via Akt pathway in non-small cell lung cancer. Cell biology international 18 29286212
2022 CircESRP1 enhances metastasis and epithelial-mesenchymal transition in endometrial cancer via the miR-874-3p/CPEB4 axis. Journal of translational medicine 17 35317822
2016 Impaired neurodevelopment by the low complexity domain of CPEB4 reveals a convergent pathway with neurodegeneration. Scientific reports 17 27381259
2014 Arsenite-activated JNK signaling enhances CPEB4-Vinexin interaction to facilitate stress granule assembly and cell survival. PloS one 17 25237887
2023 Antitumor T-cell function requires CPEB4-mediated adaptation to chronic endoplasmic reticulum stress. The EMBO journal 14 36919984
2021 Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis. Molecular metabolism 14 34774811
2020 LncRNA EWSAT1 upregulates CPEB4 via miR-330-5p to promote cervical cancer development. Molecular and cellular biochemistry 14 32556917
2021 CPEB4-Promoted Paclitaxel Resistance in Ovarian Cancer In Vitro Relies on Translational Regulation of CSAG2. Frontiers in pharmacology 13 33519462
2017 Olfactory-Experience- and Developmental-Stage-Dependent Control of CPEB4 Regulates c-Fos mRNA Translation for Granule Cell Survival. Cell reports 12 29166615
2022 Immune translational control by CPEB4 regulates intestinal inflammation resolution and colorectal cancer development. iScience 11 35243213
2016 Biphasic and Stage-Associated Expression of CPEB4 in Hepatocellular Carcinoma. PloS one 11 27158894
2014 RNA recognition and self-association of CPEB4 is mediated by its tandem RRM domains. Nucleic acids research 11 25081215
2020 The RNA-binding protein Cpeb4 is a novel positive regulator of osteoclast differentiation. Biochemical and biophysical research communications 10 32517870
2020 CircTTBK2 Contributes to the Progression of Glioma Through Regulating miR-145-5p/CPEB4 Axis. Cancer management and research 10 32982415
2024 Core-shell model of the clusters of CPEB4 isoforms preceding liquid-liquid phase separation. Biophysical journal 7 38943248
2021 CPEB4 Inhibit Cell Proliferation via Upregulating p21 mRNA Stability in Renal Cell Carcinoma. Frontiers in cell and developmental biology 7 34976999
2014 Dendritic cells transduced with CPEB4 induced antitumor immune response. Experimental and molecular pathology 7 24927871
2022 mmu-microRNA-92a-3p attenuates pulmonary fibrosis by modulating Cpeb4-mediated Smad2/3 signaling pathway. Functional & integrative genomics 6 35909199
2022 MiR-216b targets CPEB4 to suppress colorectal cancer progression through inhibiting IL-10-mediated M2 polarization of tumor-associated macrophages. American journal of translational research 6 36505286
2024 CPEB4 modulates liver cancer progression by translationally regulating hepcidin expression and sensitivity to ferroptosis. JHEP reports : innovation in hepatology 5 39980747
2023 CPEB4-CLOCK crosstalk during temporal lobe epilepsy. Epilepsia 5 37543852
2017 CPEB4 links the clock and the UPR to protect the liver. Nature cell biology 5 28139654
2024 The RNA-binding protein Cpeb4 regulates splicing of the Id2 gene in osteoclast differentiation. Journal of cellular physiology 4 38284484
2024 Cpeb4-mediated Dclk2 promotes neuronal pyroptosis induced by chronic cerebral ischemia through phosphorylation of Ehf. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 4 38513137
2023 Knockdown of CPEB1 and CPEB4 Inhibits Scar Formation via Modulation of TAK1 and SMAD Signaling. Annals of dermatology 4 37550230
2019 CPEB4-Dependent Neonate-Born Granule Cells Are Required for Olfactory Discrimination. Frontiers in behavioral neuroscience 4 30728769
2023 Hsa_circ_0000069 Accelerates Cervical Cancer Progression by Sponging miR-1270 to Facilitate CPEB4 Expression. Biochemical genetics 3 37667097
2024 Down-Regulation of CPEB4 Alleviates Preeclampsia through the Inhibition of Ferroptosis by PFKFB3. Critical reviews in eukaryotic gene expression 2 38305290
2023 miRNA-130a-3p/CPEB4 Axis Modulates Glioblastoma Growth and Progression. Technology in cancer research & treatment 2 38130149
2018 [The research progress of CPEB4 in tumor]. Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery 2 29986574
2026 Stress-Induced Down-Regulation of CPEB4 Disrupts Sodium Channel Regulation and Myocardial Excitability. JACC. Basic to translational science 1 41846068
2025 Punishment-Induced Suppression of Methamphetamine Self-Administration Is Accompanied by the Activation of the CPEB4/GLD2 Polyadenylation Complex of the Translational Machinery. International journal of molecular sciences 1 40141377
2023 CYP24A1, AHR, CPEB4, TRIP13, and PIK3CA genes expression in colorectal cancer patients: novel diagnostic biomarkers. European review for medical and pharmacological sciences 1 37750623
2026 Modeling the functional impact of CPEB3 and CPEB4 dysregulation in autism: A theoretical-computational framework. Molecular and cellular neurosciences 0 41581680
2026 SNAP23 regulates CPEB4 in the autophagy of hepatocellular carcinoma. Scientific reports 0 42086740
2026 CPEB4 deficiency promotes vasculogenic mimicry and resistance to anti-angiogenic therapy in hepatocellular carcinoma. Gut 0 42209191
2025 Single-cell sequencing analysis and multiple machine learning methods identified immune-associated SERPINB1 and CPEB4 as novel biomarkers for COVID-19-induced ARDS. Die Naturwissenschaften 0 40892227
2024 Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants. Frontiers in endocrinology 0 38628584
2020 [Effect of CPEB4 on Migration and Cycle of Chronic Myeloid Leukemia Cell]. Zhongguo shi yan xue ye xue za zhi 0 32798388
2019 [Effect of CPEB4 on Proliferation and Apoptosis of Chronic Myeloid Leukemia Cells]. Zhongguo shi yan xue ye xue za zhi 0 31839038

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