CPEB4 (cytoplasmic polyadenylation element binding protein 4)

2013-08-01   Joan 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)

Identity

HGNC
LOCATION
5q35.2
LOCUSID
ALIAS
CPE-BP4,hCPEB-4
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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 (DAmbrogio 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 3UTR 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).

Mutations

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 name
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 name
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 name
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).

Article Bibliography

Pubmed IDLast YearTitleAuthors
191468092009Translational control of long-lasting synaptic plasticity and memory.Costa-Mattioli M et al
234465452013Translational control of cell growth and malignancy by the CPEBs.D'Ambrogio A et al
225427252012The CPEB-family of proteins, translational control in senescence and cancer.Fernández-Miranda G et al
94479641998Specificity of RNA binding by CPEB: requirement for RNA recognition motifs and a novel zinc finger.Hake LE et al
79548281994CPEB is a specificity factor that mediates cytoplasmic polyadenylation during Xenopus oocyte maturation.Hake LE et al
204278092010Pancreatic cancer.Hidalgo M et al
205313912010Meiosis requires a translational positive loop where CPEB1 ensues its replacement by CPEB4.Igea A et al
209377702010CPEB4 is a cell survival protein retained in the nucleus upon ischemia or endoplasmic reticulum calcium depletion.Kan MC et al
114333662001Translational control by CPEB: a means to the end.Mendez R et al
203641422010Mitotic cell-cycle progression is regulated by CPEB1 and CPEB4-dependent translational control.Novoa I et al
159776392005Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas.Ohgaki H et al
221387522011Key contribution of CPEB4-mediated translational control to cancer progression.Ortiz-Zapater E et al
174819022007CPEB: a life in translation.Richter JD et al
233350872013Cancer statistics, 2013.Siegel R et al
195037532009CPEB3 is associated with human episodic memory.Vogler C et al
208386642010Comparative in silico analyses of cpeb1-4 with functional predictions.Wang XP et al
186694282008Malignant gliomas in adults.Wen PY et al

Other Information

Locus ID:

NCBI: 80315
MIM: 610607
HGNC: 21747
Ensembl: ENSG00000113742

Variants:

dbSNP: 80315
ClinVar: 80315
TCGA: ENSG00000113742
COSMIC: CPEB4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000113742ENST00000265085Q17RY0
ENSG00000113742ENST00000334035Q17RY0
ENSG00000113742ENST00000517880Q17RY0
ENSG00000113742ENST00000519152H0YBG1
ENSG00000113742ENST00000519467A0A590UJI5
ENSG00000113742ENST00000519835E5RJM0
ENSG00000113742ENST00000520867B7ZLQ8
ENSG00000113742ENST00000522336E5RFP2
ENSG00000113742ENST00000656232A0A590UJN2
ENSG00000113742ENST00000657000A0A590UJI5
ENSG00000113742ENST00000659882A0A590UK96

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45

Pathways

PathwaySourceExternal ID
Dorso-ventral axis formationKEGGko04320
Progesterone-mediated oocyte maturationKEGGko04914
Dorso-ventral axis formationKEGGhsa04320
Progesterone-mediated oocyte maturationKEGGhsa04914
Oocyte meiosisKEGGko04114
Oocyte meiosisKEGGhsa04114

References

Pubmed IDYearTitleCitations
383052902024Down-Regulation of CPEB4 Alleviates Preeclampsia through the Inhibition of Ferroptosis by PFKFB3.0
383052902024Down-Regulation of CPEB4 Alleviates Preeclampsia through the Inhibition of Ferroptosis by PFKFB3.0
369199842023Antitumor T-cell function requires CPEB4-mediated adaptation to chronic endoplasmic reticulum stress.4
369199842023Antitumor T-cell function requires CPEB4-mediated adaptation to chronic endoplasmic reticulum stress.4
354428822022Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation.12
354428822022Macrophage inflammation resolution requires CPEB4-directed offsetting of mRNA degradation.12
332376622021Investigation of the expression levels of CPEB4, APC, TRIP13, EIF2S3, EIF4A1, IFNg, PIK3CA and CTNNB1 genes in different stage colorectal tumors.7
347748112021Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis.6
332376622021Investigation of the expression levels of CPEB4, APC, TRIP13, EIF2S3, EIF4A1, IFNg, PIK3CA and CTNNB1 genes in different stage colorectal tumors.7
347748112021Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis.6
319044782020LncRNA RP11-361F15.2 promotes osteosarcoma tumorigenesis by inhibiting M2-Like polarization of tumor-associated macrophages of CPEB4.46
321138752020CPEB1 or CPEB4 knockdown suppresses the TAK1 and Smad signalings in THP-1 macrophage-like cells and dermal fibroblasts.8
321694292020CPEB4 Increases Expression of PFKFB3 to Induce Glycolysis and Activate Mouse and Human Hepatic Stellate Cells, Promoting Liver Fibrosis.35
325569172020LncRNA EWSAT1 upregulates CPEB4 via miR-330-5p to promote cervical cancer development.8
325941592020Polyadenylation of mRNA as a novel regulatory mechanism of gene expression in temporal lobe epilepsy.3

Citation

Joan Gibert ; Héctor Anta ; Pilar Navarro

CPEB4 (cytoplasmic polyadenylation element binding protein 4)

Atlas Genet Cytogenet Oncol Haematol. 2013-08-01

Online version: http://atlasgeneticsoncology.org/gene/52626/img/favicon/gene-fusions-explorer/