Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

CEBPE (CCAAT/enhancer binding protein epsilon)

Written2017-03Thomas Burmeister
Charite, Med. Klinik fur Hamatologie, Onkologie und Tumorimmunologie, Hindenburgdamm 30, 12200 Berlin, Germany; thomas.burmeister@charite.de

Abstract Review on CEBPE, with data on DNA, on the protein encoded, and where the gene is implicated.

Keywords CEBPE; Transcription factor; Neutrophil specific granule deficiency; Acute lymphoblastic leukemia; Translocation.

(Note : for Links provided by Atlas : click)

Identity

Alias_namesCCAAT/enhancer binding protein (C/EBP)
Alias_symbol (synonym)CRP1
Other alias
HGNC (Hugo) CEBPE
LocusID (NCBI) 1053
Atlas_Id 42984
Location 14q11.2  [Link to chromosome band 14q11]
Location_base_pair Starts at 23117306 and ends at 23119611 bp from pter ( according to hg19-Feb_2009)  [Mapping CEBPE.png]
Fusion genes
(updated 2016)
CEBPE/IGH

DNA/RNA

 
  Figure 1: Human CEBPE gene and mRNA transcript: a. according to the GRCh38.p7 assembly annotation (2016/03/21); b. according to Yamanaka et al. (1997); c. transcripts based on the Yamanaka exon organization
Description CEBPE is located on chromosome 14q11.2 in a telomer-centromer orientation. Conflicting data have been published on the gene structure of CEBPE. According to the GRCh38.p7 assembly annotation (2016/03/21) the gene consists of two exons (1030 bp and 517 bp), which are partially coding and separated by a 759 bp intron (Figure 1a).
This is in conflict with some previously published papers. Yamanaka et al. (1997) described an alternative 3-exon-organization of the human CEBPE gene (Figure 1b). However, exon 1, as described by Yamanaka et al. contains a frameshift according to the GRCh38.p7 NCBI assembly.
Transcription Various transcripts have been reported, resulting in four protein isoforms (Lekstrom-Himes 2001, Yamanaka 1997; Figure 1c). All transcripts share a common 3' end.

Protein

Description CEBPE is a member of the CCAAT/enhancer-binding protein (C/EBP) family, which also includes CEBPA, CEBPB, CEBPG, CEBPD and CEBPZ (Ramji & Foka; 2002). A common structural feature of the C/EBP proteins is the presence of a highly conserved 55-65 amino acid sequence at the C-terminus which encodes a basic leucine zipper motif (bZIP domain) that functions as a dimerization domain. In the aminoterminal part all C/EBP proteins possess a DNA-binding domain with relative specificity for the CCAAT DNA motif. C/EBP proteins exert their physiological functions as either homo- or heterodimers. They can also interact with other bZIP- and non-bZIP transcription factors. Different protein domains have been characterized. The full-length CEBPE protein basically consists of an activation domain at the aminoterminal end, a repression domain in the center and the leucine zipper at the carboxyterminus (Williamson et al. 1998).
At least four different CEBPE protein isoforms of 32, 30, 27, and 14 kDa have been described, but their functional significance is unclear (Lekstrom-Hines et al. 2001, Figure 1c).
The CEBPE translation product can undergo a number of post-translational modifications. Phosphorylation of CEBPE on threonine 75, located in the transactivation domain, is associated with increased DNA binding capacity and transcriptional activation (Williamson et al., 2005). Sumoylation of lysine residues within the repression domain has been found to modulate CEBPE function (Kim et al., 2005). Acetylation of lysine-121 and lysine-198 was found to be critical for terminal neutrophil differentiation (Bartels et. al., 2015).
Expression CEBPE is predominantly expressed in cells of the hematopoietic system and to a much lesser extent in ovarian tissue (Yamanaka, et al., 1997). In normal hematopoietic cells CEBPE is preferentially expressed in myeloid-committed cells and the protein is virtually only detectable in metamyelocytes and myelocytes. The gene is also expressed in more immature myeloid cells but protein translation is repressed by miRNA-130a (Larsen et al., 2014). The expression of CEBPE protein induces growth arrest, morphological differentiation, secondary granule proteins and has proapoptotic effects (Nakajima et al. 2006).
Localisation Nuclear.
Function CEBPE is a transcription factor, important for monocyte and granulocyte development. The transcription factor binds as a homodimer or heterodimer (with CEBPD) to specific DNA regulatory regions. Shorter CEBPE protein isoforms are hypothetical attenuators of the transcriptional activity of the long isoform.
Homozygous CEBPE knock-out (-/-) mice appear healthy at birth but survive only 2-5 months after birth, while heterozygous CEBPE knock-out mice appear normal. CEBPE (-/-) mice showed a marked increase in immature myeloid progenitors, increased numbers of morphologically abnormal neutrophils, that were functionally defect and lacked an oxidative burst, and decreased numbers of eosinophils. Thus it was concluded that CEBPE is essential for a normal terminal differentiation of committed granulocyte progenitor cells (Yamanaka, et al., 1997).

Implicated in

  
Entity Neutrophil specific granule deficiency (SGD)
Note Some, but not all of the very few known patients with SGD harboured CEBPE mutations which led to loss of the dimerization domain; phenotypically, SGD patients show bilobed nuclei, impaired chemotaxis and bactericidal activity with susceptibility to severe bacterial infections (Gombart & Koeffler 2002).
  
  
Entity Acute lymphoblastic leukemia (ALL)
Note The CEBPE single nucleotide polymorphism rs2239633 has been implicated as a susceptibility factor for the development of B lineage ALL in children and adults. The relative risk (odds ratio) conferred is 1.1-1.6 (Papaemmanuil et al., 2009; Burmeister et al. 2014).
  
  
Entity t(14;14)(q11;q32) CEBPE/IGH and inv(14)(q11q32) CEBPE/IGH
Note CEBPE is found recurrently translocated to the immunoglobulin heavy chain locus ( IGH) on 14q32 in acute lymphoblastic leukemia patients with inv(14)(q11q32)/t(14;14)(q11;q32). The translocation leads to an overexpression of CEBPE under the control of the immunoglobulin heavy chain gene promoters. At least five cases have been described (Akasaka et al. 2007).
  

Bibliography

Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
Akasaka T, Balasas T, Russell LJ, Sugimoto KJ, Majid A, Walewska R, Karran EL, Brown DG, Cain K, Harder L, Gesk S, Martin-Subero JI, Atherton MG, Brüggemann M, Calasanz MJ, Davies T, Haas OA, Hagemeijer A, Kempski H, Lessard M, Lillington DM, Moore S, Nguyen-Khac F, Radford-Weiss I, Schoch C, Struski S, Talley P, Welham MJ, Worley H, Strefford JC, Harrison CJ, Siebert R, Dyer MJ
Blood 2007 Apr 15;109(8):3451-61
PMID 17170124
 
Acetylation of C/EBP is a prerequisite for terminal neutrophil differentiation
Bartels M, Govers AM, Fleskens V, Lourenço AR, Pals CE, Vervoort SJ, van Gent R, Brenkman AB, Bierings MB, Ackerman SJ, van Loosdregt J, Coffer PJ
Blood 2015 Mar 12;125(11):1782-92
PMID 25568349
 
Germline variants in IKZF1, ARID5B, and CEBPE as risk factors for adult-onset acute lymphoblastic leukemia: an analysis from the GMALL study group
Burmeister T, Bartels G, Gröger D, Trautmann H, Schwartz S, Lenz K, Tietze-Bürger C, Viardot A, Wäsch R, Horst HA, Reinhardt R, Gökbuget N, Hoelzer D, Kneba M, Brüggemann M
Haematologica 2014 Feb;99(2):e23-5
PMID 24497567
 
Neutrophil specific granule deficiency and mutations in the gene encoding transcription factor C/EBP(epsilon)
Gombart AF, Koeffler HP
Curr Opin Hematol 2002 Jan;9(1):36-42
PMID 11753076
 
Translocation (14;14)(q11;q32) with simultaneous involvement of the IGH and CEBPE genes in B-lineage acute lymphoblastic leukemia
Han Y, Xue Y, Zhang J, Wu Y, Pan J, Wang Y, Shen J, Dai H, Bai S
Cancer Genet Cytogenet 2008 Dec;187(2):125-9
PMID 19027493
 
Repression and coactivation of CCAAT/enhancer-binding protein epsilon by sumoylation and protein inhibitor of activated STATx proteins
Kim J, Sharma S, Li Y, Cobos E, Palvimo JJ, Williams SC
J Biol Chem 2005 Apr 1;280(13):12246-54
PMID 15661739
 
miRNA-130a regulates C/EBP- expression during granulopoiesis
Larsen MT, Häger M, Glenthøj A, Asmar F, Clemmensen SN, Mora-Jensen H, Borregaard N, Cowland JB
Blood 2014 Feb 13;123(7):1079-89
PMID 24398327
 
The role of C/EBP(epsilon) in the terminal stages of granulocyte differentiation
Lekstrom-Himes JA
Stem Cells 2001;19(2):125-33
 
N-terminal region of CCAAT/enhancer-binding protein epsilon is critical for cell cycle arrest, apoptosis, and functional maturation during myeloid differentiation
Nakajima H, Watanabe N, Shibata F, Kitamura T, Ikeda Y, Handa M
J Biol Chem 2006 May 19;281(20):14494-502
PMID 16531405
 
Loci on 7p12
Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, Kinsey SE, Lightfoot T, Roman E, Irving JA, Allan JM, Tomlinson IP, Taylor M, Greaves M, Houlston RS
2, 10q21 2 and 14q11
PMID 19684604
 
Verification of the susceptibility loci on 7p12
Prasad RB, Hosking FJ, Vijayakrishnan J, Papaemmanuil E, Koehler R, Greaves M, Sheridan E, Gast A, Kinsey SE, Lightfoot T, Roman E, Taylor M, Pritchard-Jones K, Stanulla M, Schrappe M, Bartram CR, Houlston RS, Kumar R, Hemminki K
2, 10q21 2, and 14q11
PMID 20042726
 
CCAAT/enhancer-binding proteins: structure, function and regulation
Ramji DP, Foka P
Biochem J 2002 Aug 1;365(Pt 3):561-75
PMID 12006103
 
CCAAT/enhancer binding protein epsilon: changes in function upon phosphorylation by p38 MAP kinase
Williamson EA, Williamson IK, Chumakov AM, Friedman AD, Koeffler HP
Blood 2005 May 15;105(10):3841-7
PMID 15677566
 
CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing
Yamanaka R, Kim GD, Radomska HS, Lekstrom-Himes J, Smith LT, Antonson P, Tenen DG, Xanthopoulos KG
Proc Natl Acad Sci U S A 1997 Jun 10;94(12):6462-7
PMID 9177240
 

Citation

This paper should be referenced as such :
Burmeister T
CEBPE (CCAAT/enhancer binding protein epsilon);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/CEBPEID42984ch14q11.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 4 ]
  t(8;14)(q11;q32) IGH/CEBPD
t(14;14)(q11;q32) CEBPE/IGH::inv(14)(q11q32) CEBPE/IGH
t(14;19)(q32;q13) IGH/CEBPA
t(14;20)(q32;q13) IGH/CEBPB


External links

Nomenclature
HGNC (Hugo)CEBPE   1836
LRG (Locus Reference Genomic)LRG_45
Cards
AtlasCEBPEID42984ch14q11
Entrez_Gene (NCBI)CEBPE  1053  CCAAT/enhancer binding protein epsilon
AliasesC/EBP-epsilon; CRP1
GeneCards (Weizmann)CEBPE
Ensembl hg19 (Hinxton)ENSG00000092067 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000092067 [Gene_View]  chr14:23117306-23119611 [Contig_View]  CEBPE [Vega]
ICGC DataPortalENSG00000092067
TCGA cBioPortalCEBPE
AceView (NCBI)CEBPE
Genatlas (Paris)CEBPE
WikiGenes1053
SOURCE (Princeton)CEBPE
Genetics Home Reference (NIH)CEBPE
Genomic and cartography
GoldenPath hg38 (UCSC)CEBPE  -     chr14:23117306-23119611 -  14q11.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CEBPE  -     14q11.2   [Description]    (hg19-Feb_2009)
EnsemblCEBPE - 14q11.2 [CytoView hg19]  CEBPE - 14q11.2 [CytoView hg38]
Mapping of homologs : NCBICEBPE [Mapview hg19]  CEBPE [Mapview hg38]
OMIM245480   600749   
Gene and transcription
Genbank (Entrez)BC035797 BG387972 BX346756 BY995857 EU446853
RefSeq transcript (Entrez)NM_001805
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CEBPE
Cluster EST : UnigeneHs.558308 [ NCBI ]
CGAP (NCI)Hs.558308
Alternative Splicing GalleryENSG00000092067
Gene ExpressionCEBPE [ NCBI-GEO ]   CEBPE [ EBI - ARRAY_EXPRESS ]   CEBPE [ SEEK ]   CEBPE [ MEM ]
Gene Expression Viewer (FireBrowse)CEBPE [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1053
GTEX Portal (Tissue expression)CEBPE
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ15744   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ15744  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ15744
Splice isoforms : SwissVarQ15744
PhosPhoSitePlusQ15744
Domaine pattern : Prosite (Expaxy)BZIP (PS50217)   
Domains : Interpro (EBI)bZIP    C/EBP_chordates   
Domain families : Pfam (Sanger)bZIP_2 (PF07716)   
Domain families : Pfam (NCBI)pfam07716   
Domain families : Smart (EMBL)BRLZ (SM00338)  
Conserved Domain (NCBI)CEBPE
DMDM Disease mutations1053
Blocks (Seattle)CEBPE
PDB (SRS)3T92   
PDB (PDBSum)3T92   
PDB (IMB)3T92   
PDB (RSDB)3T92   
Structural Biology KnowledgeBase3T92   
SCOP (Structural Classification of Proteins)3T92   
CATH (Classification of proteins structures)3T92   
SuperfamilyQ15744
Human Protein AtlasENSG00000092067
Peptide AtlasQ15744
HPRD02852
IPIIPI00217782   
Protein Interaction databases
DIP (DOE-UCLA)Q15744
IntAct (EBI)Q15744
FunCoupENSG00000092067
BioGRIDCEBPE
STRING (EMBL)CEBPE
ZODIACCEBPE
Ontologies - Pathways
QuickGOQ15744
Ontology : AmiGORNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  nucleoplasm  transcription from RNA polymerase II promoter  phagocytosis  defense response  macrophage differentiation  cytokine biosynthetic process  defense response to bacterium  protein homodimerization activity  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  cellular response to lipopolysaccharide  
Ontology : EGO-EBIRNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  nucleoplasm  transcription from RNA polymerase II promoter  phagocytosis  defense response  macrophage differentiation  cytokine biosynthetic process  defense response to bacterium  protein homodimerization activity  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  cellular response to lipopolysaccharide  
Pathways : KEGGTranscriptional misregulation in cancer   
NDEx NetworkCEBPE
Atlas of Cancer Signalling NetworkCEBPE
Wikipedia pathwaysCEBPE
Orthology - Evolution
OrthoDB1053
GeneTree (enSembl)ENSG00000092067
Phylogenetic Trees/Animal Genes : TreeFamCEBPE
HOVERGENQ15744
HOGENOMQ15744
Homologs : HomoloGeneCEBPE
Homology/Alignments : Family Browser (UCSC)CEBPE
Gene fusions - Rearrangements
Fusion : MitelmanIGH/CEBPE [14q32.33/14q11.2]  [inv(14)(q11q32)]  [t(14;14)(q11;q32)]  
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCEBPE [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CEBPE
dbVarCEBPE
ClinVarCEBPE
1000_GenomesCEBPE 
Exome Variant ServerCEBPE
ExAC (Exome Aggregation Consortium)CEBPE (select the gene name)
Genetic variants : HAPMAP1053
Genomic Variants (DGV)CEBPE [DGVbeta]
DECIPHERCEBPE [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCEBPE 
Mutations
ICGC Data PortalCEBPE 
TCGA Data PortalCEBPE 
Broad Tumor PortalCEBPE
OASIS PortalCEBPE [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCEBPE  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCEBPE
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
BioMutasearch CEBPE
DgiDB (Drug Gene Interaction Database)CEBPE
DoCM (Curated mutations)CEBPE (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CEBPE (select a term)
intoGenCEBPE
NCG5 (London)CEBPE
Cancer3DCEBPE(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM245480    600749   
Orphanet17826   
MedgenCEBPE
Genetic Testing Registry CEBPE
NextProtQ15744 [Medical]
TSGene1053
GENETestsCEBPE
Target ValidationCEBPE
Huge Navigator CEBPE [HugePedia]
snp3D : Map Gene to Disease1053
BioCentury BCIQCEBPE
ClinGenCEBPE
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1053
Chemical/Pharm GKB GenePA26379
Clinical trialCEBPE
Miscellaneous
canSAR (ICR)CEBPE (select the gene name)
Probes
Litterature
PubMed64 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCEBPE
EVEXCEBPE
GoPubMedCEBPE
iHOPCEBPE
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Aug 1 17:23:06 CEST 2017

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.