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CPEB4 (cytoplasmic polyadenylation element binding protein 4)

Written2013-08Joan Gibert, Héctor Anta, Pilar Navarro
Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain (JG, HA, PN); Molecular Medicine Program, Institute for Research in Biomedicine (IRBBarcelona), Barcelona, Spain (HA)

(Note : for Links provided by Atlas : click)


HGNC Alias symbKIAA1673
LocusID (NCBI) 80315
Atlas_Id 52626
Location 5q35.2  [Link to chromosome band 5q35]
Location_base_pair Starts at 173888349 and ends at 173961980 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping CPEB4.png]
Local_order UCSC Genome Browser.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CPEB4 (5q35.2)::STK32A (5q32)SSR3 (3q25.31)::CPEB4 (5q35.2)


  Diagram of the genomic organization of CPEB4.
Description CPEB4 gene covers 71.98 kb on human chromosome 5 (5q35.2), between 173315331 and 173387313 (according to hg19-Feb_2009, UCSC).
Transcription The mRNA of CPEB4 contains 10 exons and 9 introns. Multiple transcript variants encoding different isoforms (10 splice variants) have been found for this gene.


  Diagram of CPEB4 protein in scale (Isoform a). CPEB4 presents 2 different RNA Recognition Motifs (RRM1 - green and RRM2 - blue), which recognize U-rich sequences. Moreover, CPEB4 has two Zinc-finger-like motifs (ZnFs - brown). CPEBs share these conserved RNA-binding domain at the C-terminal of the protein.
Description CPEB4 is a RNA binding protein that belongs to the CPEB-family of proteins. In vertebrates, 4 members (CPEB1, CPEB2, CPEB3, CPEB4) have been identified, CPEBs2-4 are closely related whereas CPEB1 is the most distant member of the family (Wang et al., 2010). All members have a conserved carboxy-terminal region, composed of two RNA Recognition motifs (RRM) and two zinc-finger-like motifs (Hake et al., 1998), and a regulatory highly variable N-terminal domain.
10 different isoforms have been described for CPEB4:
- Isoform a: 729 amino acids, 80.2 kDa protein, RRM motifs: aa 472-563 and aa 580-662.
- Isoform b: Exon 3 skipped, 712 amino acids, 78.3 kDa protein.
- Isoform c: Exon 3 and 4 skipped, 704 amino acids, 77.3 kDa protein.
- Isoform d: Exons 3, 4 and 9 skipped, 639 amino acids, 69.8 kDa protein.
- Isoform e: Exons 3, 4, 5, 6, 7, 8, 9 and 10 skipped, 389 amino acids, 43.1 KDa protein.
- Isoform f: Exons 1 and 4 skipped, 339 amino acids, 38 kDa protein.
- Isoform g: Exons 1, 3 and 4 skipped, 322 amino acids, 36.2 kDa protein.
- Isoform h: Exons 1, 2, 3 and 4 skipped, 295 amino acids, 33 KDa protein.
- Isoform i: Exons 1 (partly) 3, 4, 5, 6, 7, 8, 9 and 10 skipped, 226 amino acids, 25.3 KDa protein.
- Isoform j: Exons 1 (partly) 4, 6, 7, 8, 9 and 10 skipped, 146 amino acids, 16.3 kDa protein.
Expression CPEBs are widely expressed in different mammalian tissues and tumours and sometimes with overlapping patterns. CPEB4 mRNA is highly expressed in embryonic stages (E14.5) brain, heart, kidney and lung. Moreover, a lower expression is also present in liver, spleen and ovary (Fernandez-Miranda et al., 2012). At protein level, an upregulation in Pancreatic Ductal Adenocarcinoma (PDA) and glioblastoma (Ortiz-Zapater et al., 2011) has also been described. At RNA level, CPEB4 misregulation is present in several types of cancer: prostate, breast, skin, lung, brain and digestive apparatus (D'Ambrogio et al., 2013) but this misregulation requires further characterization because CPEB4 mRNA is under a strong post-transcriptional regulation.
Localisation Cytoplasmic Polyadenylation Element Binding protein 4 (CPEB4) is mostly cytosolic, however it has been reported that it can be a nucleus-cytoplasm shuttling protein in neurons, in response to calcium-mediated signalling. In fact, CPEB4 becomes nuclear in response to focal ischemia and when cultured neurons are deprived of oxygen and glucose (Kan et al., 2010).
Function CPEBs are RNA binding proteins that recognize cis-acting elements named Cytoplasmic Polyadenylation Element (CPE), that are located in the 3'UTR of some mRNAs. They were originally described in Xenopus laevis oocytes, where they control translation of maternal mRNAs during meiosis by regulation of the length of the polyA tail (Hake and Richter, 1994). However, these proteins can be also found in other non-germ cells suggesting other functions for CPEBs (Costa-Mattioli et al., 2009; Mendez and Richter, 2001; Richter, 2007). CPEB4 recognizes the same CPE as CPEB1, although with less affinity (Novoa et al., 2010; Igea et al., 2010). In oocytes, CPEB4 is required for meiotic progression between MI and MII and regulates CSF arrest (Igea et al., 2010). In somatic cells, CPEB4, together with CPEB, regulates mitotic poly(A) tail elongation and is required for cell proliferation (Novoa et al., 2010). Moreover, CPEB4 also plays a role in cancer where overexpression of CPEB4 correlates with increased malignancy, tumour growth and vascularization in pancreatic cancer and glioblastoma (Ortiz-Zapater et al., 2011), suggesting that overexpression of CPEB4 can be a general mechanism in cancer development and that CPEB4 could behave as an oncogene.
Homology CPEB4 orthologs are also present in other species, such as Mus musculus (Cpeb4), Xenopus laevis (cpeb4), Danio rerio (cpeb4), Drosophila melanogaster (Orb2) and Caenorhabditis elegans (cpb1-2).


Note Relevant point mutations have been described for other members of the CPEB family, such as the point mutation T>C in exon 3 of the CPEB3 mRNA (rs11186856), which has been associated with a reduced translation efficiency and impaired episodic memory (Vogler et al., 2009). However, even though there are some point mutations described for CPEB4, up to date none of them have been proved to have a functional relevance.

Implicated in

Entity Pancreatic cancer
Note CPEB4 is overexpressed in human Pancreatic Ductal Adenocarcinoma (PDAC) where it supports tumour growth, vascularization and invasion (Ortiz-Zapater et al., 2011). In addition, knockdown of CPEB4 both in vitro and in vivo causes significant reduction of the malignancy of pancreatic tumor cells, suggesting the use of CPEB4 inhibitors as a PDA therapy.
Disease The most common type of human pancreatic cancer (95%) is pancreatic ductal adenocarcinoma that is the fifth most common cause of cancer-related deaths worldwide, second only to colon cancer among malignancies of the digestive tract (Siegel et al., 2013). Despite notable efforts to develop novel therapeutic targets, PDA is still highly resistant to therapy, with a median survival of 4-6 months and a 5-year survival rate lower than 5% (Hidalgo, 2010).
Prognosis CPEB4 expression was specifically upregulated in human pancreatic cancer, correlating with tumor stages. CPEB4 expression is absent in normal pancreas, low in low-grade precursor tumor lesions (PanIN - Pancreatic Intraepithelial Neoplasia), medium in high-grade PanINs and high in well-differentiated PDAC. These data suggest that CPEB4 expression can be a prognostic factor in pancreatic carcinogenesis.
Oncogenesis CPEB4 has been reported as a master gene involved in the reprogramming of cancer gene expression. The pro-oncogenic functions of CPEB4 originate in the translational activation of mRNAs that are silenced in normal tissue. RNA immunoprecipitation (RIP) analysis, identify more than 800 transcripts significantly enriched in a number of cancer-related cellular functions such as cell signalling molecules (Ras-related, Smad3, PI3 K, CamKII, G-protein coupled-receptor), chromatin-remodelling proteins (i.e. histone deacetylases, MYST histone acetyltransferase), cyclins, apoptosis-related molecules (CASP8, BCL2 binding component 3), stress/inflammation factors (interleukin 32, HIG1, interferon receptor 2, heat shock 70) and genes associated with cell migration/metastasis (MMP-7, tissue plasminogen activator, β-catenin, Twist) (Ortiz-Zapater et al., 2011).
Entity Glioblastoma
Note CPEB4 is overexpressed in human glioblastoma, increasing its capacity to proliferate and invade. CPEB4 downregulation in vivo correlates with less tumour size, proliferation and vascularization (Ortiz-Zapater et al., 2011).
Disease Glioblastoma (formerly GlioBlastoma Multiforme, GBM) represents both the most common and most malignant primary brain tumour variant. Its widely infiltrative growth precludes definitive surgical resection, and its invariably aggressive biological behaviour leads to dismal clinical outcome (Wen et al., 2007). GBM could arise from a WHO grade II or III astrocytoma (secondary GBM) or emerging in a fully malignant state (primary GBM) (Ohgaki et al., 2005).
Prognosis CPEB4 is absent in human normal astrocytes but was very abundant in high-grade glioblastoma, suggesting a prognostic value for CPEB4 expression in this tumor.
Entity Ischemic stroke
Note Ischemic stroke is a leading cause of death and dissability worldwide. It is produced from a vascular oclussion, which reduces the perfussion of the blood into specific areas of the brain. The subsequent restoration of the blood flow has been demonstrated to exacerbate the damage.
Prognosis CPEB4 has been described to shuttle to the nucleus of neurons in response to pathological levels of the neurotransmitter glutamate (a hallmark of the ischemic stroke) both in vitro and in vivo. Moreover, the nuclear accumulation of CPEB4 has been associated to an enhanced survival of hippocampal neurons under low levels of oxygen and glucose, pointing to a neuroprotective role of CPEB4 (Kan et al., 2010).

To be noted

Joan Gibert and Héctor Anta contributed equally to this work and share first authorship.


Translational control of long-lasting synaptic plasticity and memory.
Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N.
Neuron. 2009 Jan 15;61(1):10-26. doi: 10.1016/j.neuron.2008.10.055. (REVIEW)
PMID 19146809
Translational control of cell growth and malignancy by the CPEBs.
D'Ambrogio A, Nagaoka K, Richter JD.
Nat Rev Cancer. 2013 Apr;13(4):283-90. doi: 10.1038/nrc3485. Epub 2013 Feb 28.
PMID 23446545
The CPEB-family of proteins, translational control in senescence and cancer.
Fernandez-Miranda G, Mendez R.
Ageing Res Rev. 2012 Sep;11(4):460-72. doi: 10.1016/j.arr.2012.03.004. Epub 2012 Apr 21. (REVIEW)
PMID 22542725
Specificity of RNA binding by CPEB: requirement for RNA recognition motifs and a novel zinc finger.
Hake LE, Mendez R, Richter JD.
Mol Cell Biol. 1998 Feb;18(2):685-93.
PMID 9447964
CPEB is a specificity factor that mediates cytoplasmic polyadenylation during Xenopus oocyte maturation.
Hake LE, Richter JD.
Cell. 1994 Nov 18;79(4):617-27.
PMID 7954828
Pancreatic cancer.
Hidalgo M.
N Engl J Med. 2010 Apr 29;362(17):1605-17. doi: 10.1056/NEJMra0901557. (REVIEW)
PMID 20427809
Meiosis requires a translational positive loop where CPEB1 ensues its replacement by CPEB4.
Igea A, Mendez R.
EMBO J. 2010 Jul 7;29(13):2182-93. doi: 10.1038/emboj.2010.111. Epub 2010 Jun 8.
PMID 20531391
CPEB4 is a cell survival protein retained in the nucleus upon ischemia or endoplasmic reticulum calcium depletion.
Kan MC, Oruganty-Das A, Cooper-Morgan A, Jin G, Swanger SA, Bassell GJ, Florman H, van Leyen K, Richter JD.
Mol Cell Biol. 2010 Dec;30(24):5658-71. doi: 10.1128/MCB.00716-10. Epub 2010 Oct 11.
PMID 20937770
Translational control by CPEB: a means to the end.
Mendez R, Richter JD.
Nat Rev Mol Cell Biol. 2001 Jul;2(7):521-9. (REVIEW)
PMID 11433366
Mitotic cell-cycle progression is regulated by CPEB1 and CPEB4-dependent translational control.
Novoa I, Gallego J, Ferreira PG, Mendez R.
Nat Cell Biol. 2010 May;12(5):447-56. doi: 10.1038/ncb2046. Epub 2010 Apr 4.
PMID 20364142
Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas.
Ohgaki H, Kleihues P.
J Neuropathol Exp Neurol. 2005 Jun;64(6):479-89. (REVIEW)
PMID 15977639
Key contribution of CPEB4-mediated translational control to cancer progression.
Ortiz-Zapater E, Pineda D, Martinez-Bosch N, Fernandez-Miranda G, Iglesias M, Alameda F, Moreno M, Eliscovich C, Eyras E, Real FX, Mendez R, Navarro P.
Nat Med. 2011 Dec 4;18(1):83-90. doi: 10.1038/nm.2540.
PMID 22138752
CPEB: a life in translation.
Richter JD.
Trends Biochem Sci. 2007 Jun;32(6):279-85. Epub 2007 May 4. (REVIEW)
PMID 17481902
Cancer statistics, 2013.
Siegel R, Naishadham D, Jemal A.
CA Cancer J Clin. 2013 Jan;63(1):11-30. doi: 10.3322/caac.21166. Epub 2013 Jan 17.
PMID 23335087
CPEB3 is associated with human episodic memory.
Vogler C, Spalek K, Aerni A, Demougin P, Muller A, Huynh KD, Papassotiropoulos A, de Quervain DJ.
Front Behav Neurosci. 2009 May 4;3:4. doi: 10.3389/neuro.08.004.2009. eCollection 2009.
PMID 19503753
Comparative in silico analyses of cpeb1-4 with functional predictions.
Wang XP, Cooper NG.
Bioinform Biol Insights. 2010 Aug 30;4:61-83.
PMID 20838664
Malignant gliomas in adults.
Wen PY, Kesari S.
N Engl J Med. 2008 Jul 31;359(5):492-507. doi: 10.1056/NEJMra0708126. (REVIEW)
PMID 18669428


This paper should be referenced as such :
Gibert, J ; Anta, H ; Navarro, P
CPEB4 (cytoplasmic polyadenylation element binding protein 4)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(3):160-163.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)CPEB4   21747
Entrez_Gene (NCBI)CPEB4    cytoplasmic polyadenylation element binding protein 4
AliasesCPE-BP4; hCPEB-4
GeneCards (Weizmann)CPEB4
Ensembl hg19 (Hinxton)ENSG00000113742 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000113742 [Gene_View]  ENSG00000113742 [Sequence]  chr5:173888349-173961980 [Contig_View]  CPEB4 [Vega]
ICGC DataPortalENSG00000113742
TCGA cBioPortalCPEB4
Genatlas (Paris)CPEB4
SOURCE (Princeton)CPEB4
Genetics Home Reference (NIH)CPEB4
Genomic and cartography
GoldenPath hg38 (UCSC)CPEB4  -     chr5:173888349-173961980 +  5q35.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CPEB4  -     5q35.2   [Description]    (hg19-Feb_2009)
GoldenPathCPEB4 - 5q35.2 [CytoView hg19]  CPEB4 - 5q35.2 [CytoView hg38]
Genome Data Viewer NCBICPEB4 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AA968616 AB051460 AB586689 AI742270 AK310905
RefSeq transcript (Entrez)NM_001308189 NM_001308191 NM_001308192 NM_001308193 NM_030627
Consensus coding sequences : CCDS (NCBI)CPEB4
Gene ExpressionCPEB4 [ NCBI-GEO ]   CPEB4 [ EBI - ARRAY_EXPRESS ]   CPEB4 [ SEEK ]   CPEB4 [ MEM ]
Gene Expression Viewer (FireBrowse)CPEB4 [ Firebrowse - Broad ]
GenevisibleExpression of CPEB4 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)80315
GTEX Portal (Tissue expression)CPEB4
Human Protein AtlasENSG00000113742-CPEB4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ17RY0   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ17RY0  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ17RY0
Domaine pattern : Prosite (Expaxy)RRM (PS50102)   
Domains : Interpro (EBI)CEBP_ZZ    CEBP_ZZ_sf    CPEB    Nucleotide-bd_a/b_plait_sf    RBD_domain_sf    RRM_dom   
Domain families : Pfam (Sanger)CEBP_ZZ (PF16366)    RRM_7 (PF16367)   
Domain families : Pfam (NCBI)pfam16366    pfam16367   
Domain families : Smart (EMBL)RRM (SM00360)  
Conserved Domain (NCBI)CPEB4
PDB (RSDB)2MKI    2MKJ    5DIF   
PDB Europe2MKI    2MKJ    5DIF   
PDB (PDBSum)2MKI    2MKJ    5DIF   
PDB (IMB)2MKI    2MKJ    5DIF   
Structural Biology KnowledgeBase2MKI    2MKJ    5DIF   
SCOP (Structural Classification of Proteins)2MKI    2MKJ    5DIF   
CATH (Classification of proteins structures)2MKI    2MKJ    5DIF   
AlphaFold pdb e-kbQ17RY0   
Human Protein Atlas [tissue]ENSG00000113742-CPEB4 [tissue]
Protein Interaction databases
IntAct (EBI)Q17RY0
Ontologies - Pathways
Ontology : AmiGOtranslation repressor activity, mRNA regulatory element binding  response to ischemia  RNA binding  mRNA 3'-UTR binding  protein binding  nucleus  nucleus  nucleus  cytoplasm  cytoplasm  cytoplasm  endoplasmic reticulum  translation  translation factor activity, RNA binding  postsynaptic density  dendrite  growth cone  ionotropic glutamate receptor signaling pathway  cellular response to decreased oxygen levels  cellular response to glucose starvation  neuron projection  ribosome binding  dendritic spine  negative regulation of neuron apoptotic process  synapse  metal ion binding  perinuclear region of cytoplasm  cellular response to amino acid stimulus  messenger ribonucleoprotein complex  negative regulation of cytoplasmic translation  
Ontology : EGO-EBItranslation repressor activity, mRNA regulatory element binding  response to ischemia  RNA binding  mRNA 3'-UTR binding  protein binding  nucleus  nucleus  nucleus  cytoplasm  cytoplasm  cytoplasm  endoplasmic reticulum  translation  translation factor activity, RNA binding  postsynaptic density  dendrite  growth cone  ionotropic glutamate receptor signaling pathway  cellular response to decreased oxygen levels  cellular response to glucose starvation  neuron projection  ribosome binding  dendritic spine  negative regulation of neuron apoptotic process  synapse  metal ion binding  perinuclear region of cytoplasm  cellular response to amino acid stimulus  messenger ribonucleoprotein complex  negative regulation of cytoplasmic translation  
NDEx NetworkCPEB4
Atlas of Cancer Signalling NetworkCPEB4
Wikipedia pathwaysCPEB4
Orthology - Evolution
GeneTree (enSembl)ENSG00000113742
Phylogenetic Trees/Animal Genes : TreeFamCPEB4
Homologs : HomoloGeneCPEB4
Homology/Alignments : Family Browser (UCSC)CPEB4
Gene fusions - Rearrangements
Fusion : MitelmanCPEB4::STK32A [5q35.2/5q32]  
Fusion : QuiverCPEB4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCPEB4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CPEB4
Exome Variant ServerCPEB4
GNOMAD BrowserENSG00000113742
Varsome BrowserCPEB4
ACMGCPEB4 variants
Genomic Variants (DGV)CPEB4 [DGVbeta]
DECIPHERCPEB4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCPEB4 
ICGC Data PortalCPEB4 
TCGA Data PortalCPEB4 
Broad Tumor PortalCPEB4
OASIS PortalCPEB4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCPEB4  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DCPEB4
Mutations and Diseases : HGMDCPEB4
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)CPEB4
DoCM (Curated mutations)CPEB4
CIViC (Clinical Interpretations of Variants in Cancer)CPEB4
NCG (London)CPEB4
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry CPEB4
NextProtQ17RY0 [Medical]
Target ValidationCPEB4
Huge Navigator CPEB4 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDCPEB4
Pharm GKB GenePA134869176
Clinical trialCPEB4
DataMed IndexCPEB4
Other databaseeuGenes
Other databaseH-invDB
PubMed60 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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