| Written | 2017-03 | Thomas 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. |
| Identity |
| Alias (NCBI) | CCAAT/enhancer binding protein (C/EBP) | CRP1 |
| HGNC (Hugo) | CEBPE |
| HGNC Alias symb | CRP1 |
| HGNC Previous name | "CCAAT/enhancer binding protein (C/EBP), epsilon | CCAAT/enhancer binding protein epsilon" |
| 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 GRCh38/hg38-Dec_2013) [Mapping CEBPE.png] |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| CEBPE (14q11.2) / FOCAD (9p21.3) | STPG1 (1p36.11) / CEBPE (14q11.2) |
| 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 : |
| Thomas Burmeister |
| CEBPE (CCAAT/enhancer binding protein epsilon) |
| Atlas Genet Cytogenet Oncol Haematol. 2017;21(12):438-440. |
| Free journal version : [ pdf ] [ DOI ] |
| Other Leukemias implicated (Data extracted from papers in the Atlas) [ 6 ] |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Feb 19 17:47:49 CET 2021 |
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