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CEBPA (CCAAT/enhancer binding protein (C/EBP), alpha)

Written2006-05Lan-Lan Smith
Cancer Research UK Medical Oncology Unit, Charterhouse Square, Barts, the London School of Medicine, Dentistry, London, UK
Updated2014-07Tian V Tian, Thomas Graf
Gene Regulation, Stem Cells, Cancer Programme, Centre for Genomic Regulation (CRG), Dr Aiguader 88, 08003 Barcelona, Spain (TVT, TG); Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain (TVT, TG); Institucio Catalana de Recerca i Estudis Avancats (ICREA), Pg Lluis Companys 23, 08010 Barcelona, Spain (TG)

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Other aliasC/EBPa
LocusID (NCBI) 1050
Atlas_Id 40050
Location 19q13.1  [Link to chromosome band 19q13]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
STPG1 (1p36.11) / CEBPA (19q13.11)


  Figure 1: Human C/EBPa mRNA.
Description Human C/EBPα is an intronless gene located on the minus strand of chromosome 19q.
Transcription The C/EBPa mRNA (RNA messenger) consists of a short 5' unstranslated region (5'-UTR), a unique protein coding sequence (CDS) and a long 3'-UTR (Hendricks-Taylor et al., 1992).


  Figure 2: C/EBPa protein domains and interactions.
Description Human C/EBPα mRNA gives rise to two protein products by using two different translation starting sites (Figure 1 and 2) (Calkhoven et al., 2000). Compared to full-length C/EBPA protein, P42, the shorter P30 isoform lacks N-terminal 117 amino acids (Lin et al., 1993).
As a transcription factor, C/EBPA protein consists of DNA-binding domain (DBD) in its carboxyl-terminal (C-terminal), which is conserved between C/ebp family members (Leutz et al., 2011). The highly conserved C-terminus includes the basic DNA binding leucine zipper domain (bZip). The bZip domain in turn consists of a basic region that represents the DNA binding domain (DBD), the fork domain and the leucine zipper domain (LZ). The bZip domain is indispensable for homodimerization and heterodimerization with other members of the C/EBP family. This region is also involved in the interaction with other transcription factors (e.g. E2F, PU.1, c-JUN, RUNX1 and ETS1) (McNagny et al., 1998; Yamaguchi et al., 1999; Ramji and Foka, 2002; Nerlov, 2004; Koschmieder et al., 2005; Leutz et al., 2011).
The N-terminus of C/EBPa consists of three transactivation domains (TA), which can interact with components of the transcriptional machinery (e.g. CBP/P300, TBP/TFIIB) (Nerlov and Ziff, 1995; Kovacs et al., 2003; Schwartz et al., 2003), cell cycle regulators (e.g. E2F, CDK2, CDK4) (Porse et al., 2001; Porse et al., 2006) and chromatin remodellers (e.g. SWI/SNF) (Pedersen et al., 2001).
Expression C/EBPa is mainly expressed in terminally differentiated cells, such as mature adipocytes and myelomonocytic cells. C/EBPa is also found expressed in skin, intestine, lung, adrenal gland, mammary gland, ovary, prostate, placenta (Oh and Smart, 1998; Birkenmeier et al., 1989).
Localisation C/EBPa protein is localized in nucleus.
Function C/EBPa homozygous null mice lack white adipose tissues (Wang et al., 1995), as well as mature granulocytes and granulocyte-macrophage precursors (Zhang et al., 1997; Heath et al., 2004). In addition, forced expression of C/EBPa can direct uncommitted progenitors to differentiate into adipocytes and granulocytes (Freytag et al., 1994; Radomska et al., 1998; Nerlov et al., 1998). Further studies suggest that C/EBPa plays important roles in lineage determination by activating lineage-specific genes (Nerlov, 2004; Graf and Enver, 2009).
In hematopoiesis, C/EBPa is one of the key factors driving myeloid cell differentiation from hematopoietic stem cells by interacting with other proteins, such as the ETS family transcription factor PU.1, the ATP dependent chromatin remodeling complex SWI/SNF, the DNA modifying enzyme TET2 (McNagny et al., 1998; Koschmieder et al., 2005; Leutz et al., 2011; Kallin et al., 2012). Ectopic expression of C/EBPa leads to cell cycle arrest via direct interaction with the key cell cycle regulators CDK2/4 and E2F (Porse et al., 2001; Porse et al., 2006). The N-terminal truncated form of C/EBPa, P30, has been shown to act as a dominant negative regulator of the full-length form, P42. Modulation of P30 expression level in mice can alter normal adipogenesis and granulopoiesis (Kirstetter et al., 2008).
Notably, ectopic expression of C/EBPa in B and T-lymphocyte precursors results in transdifferentiation into functional macrophages (Xie et al., 2004; Laiosa et al., 2006; Bussmann et al., 2009; Di Tullio et al., 2011; Kallin et al., 2012). Interestingly, C/EBPa mediated conversion of B lymphoma cells into macrophages impairs significantly its tumorigenicity, providing a novel strategy for lymphoma treatment (Rapino et al., 2013). Moreover, a recent study showed that transient C/EBPa expression is also capable of facilitating the conversion of B cells into induced pluripotent stem cells (iPS cells) (Di Stefano et al., 2014).
Moreover, C/EBPa has been shown involved in lung development and airway epithelial differentiation (Cassel et al., 2000a; Cassel et al., 2000b; Cassel et al., 2002). The conditional deletion of C/EBPa gene in respiratory epithelium results in respiratory arrest and death soon after birth. This phenotype is associated with proliferation of immature type II alveolar cells, which causes epithelial expansion and loss of air space (Martis et al., 2006; Basseres et al., 2006).
Homology C/EBPa belongs to the CCAAT/enhancer binging protein family and is highly conserved across vertebrate species. Sequence alignments show that C/EBP members share several conserved regions including the bZip and transactivation domains (Leutz et al., 2011).


Note Mutations of the C/EBPα gene have been detected in 7%-15% of Acute Myeloid Leukemia (AML) (Pabst et al., 2001b; Preudhomme et al., 2002; Barjesteh van Waalwijk van Doorn-Khosrovani et al., 2003; Snaddon et al., 2003; Frohling et al., 2004; Lin et al., 2005), around 4% of Myelodysplastic Syndrome (MDS) and Chronic Myeloid Leukemia (CML) (Shih et al., 2005). In addition, two familial cases of AML harboring C/EBPA mutations have been reported (Smith et al., 2004; Renneville et al., 2009).
Germinal Germ line mutations of C/EBPα have been described for two familial cases of AML. In one Inherited acute myeloid leukemia case, a heterozygous deletion of cytosine 212 has been reported (Smith et al., 2004). Recently, the second family contained a heterozygous insertion of cytosine at nucleotide 217 (Renneville et al., 2009). These mutations result in frameshifts, leading to a premature termination of full-length C/EBPa P42 isoform translation. Nonetheless, the alternative C/EBPa P30 isoform translation could be potentially privileged. P30 isoform has dominant-negative activity on the full-length P42 isoform.
Somatic It has been shown that 7%-15% of AML harbor somatic mutations of the C/EBPα gene (Pabst et al., 2001b; Preudhomme et al., 2002; Barjesteh van Waalwijk van Doorn-Khosrovani et al., 2003; Snaddon et al., 2003; Frohling et al., 2004; Lin et al., 2005). In addition, C/EBPα mutations have been detected in MDS and CML patient samples. These mutations can be basically divided into two categories: C-terminal in-frame ins/del mutations altering C/EBPA DNA-binding activities, and N-terminal out-of-frame ins/del mutations impairing translation of full-length P42 isoform and leading aberrant expression of P30 isoform, which has dominant-negative activity on P42 isoform. The majority of leukemias with biallelic C/EBPA mutations harbor one allele with C-terminal mutations and the other one with N-terminal mutations. Tumors with homozygous N'-terminal or C'-terminal mutations are relatively rare.

Implicated in

Entity Acute myeloid leukemia (AML)
Disease Mutations in C/EBPα have been identified in 7-15% of AML cases (Pabst et al., 2001b; Preudhomme et al., 2002; Barjesteh van Waalwijk van Doorn-Khosrovani et al., 2003; Snaddon et al., 2003; Frohling et al., 2004; Lin et al., 2005). A meta-analysis of a cohort of 1175 patients reported that C/EBPα mutations are preferentially identified in M1, M2 and M4 FAB subtypes and associated with normal karyotype (Leroy et al., 2005).
Prognosis It has been shown that AML patients harboring C/EBPα mutations have favorable prognosis (Preudhomme et al., 2002).
Abnormal Protein C-terminal in-frame ins/del mutations can alter C/EBPa DNA-binding activities, and N-terminal out-of-frame ins/del mutations impairing translation of full-length P42 isoform and leading to aberrant expression of P30 isoform, which has dominant-negative activity on P42 isoform (Leroy et al., 2005).
Oncogenesis Mouse models harboring biallelic (C-terminal and N-terminal) C/EBPα mutations suggested that the co-existence of these mutations can increase the proliferation of long-term hematopoietic stem cells (LT-HSC) and override normal HSC homeostasis, leading to expansion of premalignant HSC (Kirstetter et al., 2008; Bereshchenko et al., 2009). Moreover, the fusion oncoproteins AML1-ETO (t(8;21)), CBFb-HYH11 (inv(16)) and PML-RARa (t(15;17)) suppress C/EBPA mRNA expression and/or protein activity in AML (Pabst et al., 2001a; Truong et al., 2003; Cilloni et al., 2003).
Entity B cell precursor acute lymphoblastic leukemia (BCP-ALL)
Note t(14;19)(q32;q13)
Disease It has been reported that C/EBPa is involved in several cases of BCP-ALL, although the prevalence of C/EBPa involved translocation need to be determined using larger cohorts (Chapiro et al., 2006; Akasaka et al., 2007; Jeffries et al., 2014). In these BCP-ALL cases, C/EBPa is aberrantly expressed by juxtaposition to the immunoglobulin gene enhancer upon its rearrangement with the immunoglobulin heavy-chain locus.
Oncogenesis Aberrant expression of C/EBPa in BCP-ALL samples harboring t(14;19)(q32;q13) suggests that C/EBPa may have oncogenic function in this disease, which is in contrast to its onco-suppressor role in AML (Chapiro et al., 2006). Further biological studies need to be performed to clarify this hypothesis.
Entity Non-small-cell lung cancer
Disease The chromosomal region including C/EBPa was reported deleted in 50% stage II and IIIA lung adenocarcinomas (Girard et al., 2000). However, mutations of C/EBPa in lung cancer are rare. It has been as well reported that an upstream promoter region of the C/EBPa gene is hypermethylated in approximately 65% of primary lung tumors (Tada et al., 2006). These evidences suggest that C/EBPa is a tumor suppressor in non-small-cell lung cancer.
Oncogenesis Ectopic expression of C/EBPa in lung cancer cell lines results in significant growth arrest (Halmos et al., 2002; Costa et al., 2007). A transcriptional analysis identified that differentiation associated gene FoxA2 is a direct target gene of C/EBPa in lung cancer cell line (Halmos et al., 2004). Recently, using urethane-induced lung cancer model, it has been shown that C/EBPa expression is extinguished through p38alpha MAP kinase inactivation, leading to tumor progression (Sato et al., 2013), confirming a tumor suppressor role of C/EBPa in lung cancer.
Entity Skin squamous cell carcinoma
Disease Although C/EBPa expression has been found in human precancerous skin lesions (Actinic Keratoses) and normal epidermis, its expression is undetectable in invasive squamous cell carcinoma samples (Thompson et al., 2011), suggesting a possible role as a tumor-suppressor in skin cancer.
Oncogenesis In normal epidermis, C/EBPa expression is located in basal and suprabasal keratinocytes (Maytin and Habener, 1998; Thompson et al., 2011). Forced C/EBPa expression in a skin cancer cell line inhibits cell proliferation (Shim et al., 2005). Moreover, C/EBPa-null mice are highly susceptible to 7,12-dimethylbenz[a]anthracene- and UVB-induced skin tumor development (Loomis et al., 2007; Thompson et al., 2011). Notably, It has been shown that down-regulation of C/EBPa in skin cancer cells is associated with oncogenic Ras activation (Shim et al., 2005; Loomis et al., 2007).
Entity Prostate cancer
Disease It has been shown that C/EBPa expression is down-regulated in prostate cancer sample comparing to normal prostate tissue (Yin et al., 2006). Interestingly, one study showed that C/EBPa expression is sequestered in cytosol, which could impair its transcription factor activity (Zhang et al., 2008). Although further studies need to be performed with larger prostate cancer cohorts for confirmation, these observations suggest an emerging tumor suppressor role of C/EBPa in prostate cancer.
Oncogenesis C/EBPa is mainly expressed in basal layer in normal prostate. In most prostate adenocarcinoma samples, its expression level is low (Yin et al., 2006; Zhang et al., 2008). Forced expression of C/EBPa in prostate cancer cell lines can inhibit PSA (Prostate Specific Antigen) expression and regulate negatively androgen receptor (AR) signaling (Chattopadhyay et al., 2006; Yin et al., 2006; Zhang et al., 2010). In addition, in AR-negative prostate cancer cell lines, ectopically expressed C/EBPA protein can physically interact with Ku proteins (Ku70, Ku80) and Poly [ADP-ribose] polymerase 1 (PARP-1), conferring prostate cancer cells an increased sensitivity to DNA-damaging agents (Yin and Glass, 2006).
Entity Hepatocellular carcinoma
Disease The expression of C/EBPa is reduced in hepatocellular carcinoma samples and higher expression of C/EBPa in hepatocellular carcinoma reversibly correlated with the tumor size and clinical stage (Tomizawa et al., 2003).
Oncogenesis Forced C/EBPa expression in hepatoma cell lines impairs proliferation and tumorigenicity (Watkins et al., 1996). Liver specific C/EBPa knock-in mice are resistant, at least partially, to diethylnitrosamine-induced hepatocellular carcinoma formation. These observations suggest a tumor suppressor role of C/EBPa in hepatocellular carcinoma (Tan et al., 2005).
Entity Head and neck squamous cell cancer
Disease It has been reported that C/EBPa expression is down-regulated in squamous cell cancers in head and neck region. This down-regulation correlates with the degree of C/EBPa promoter methylation (Bennett et al., 2007).


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Genes Dev. 2001 Dec 1;15(23):3208-16.
PMID 11731483
The proline-histidine-rich CDK2/CDK4 interaction region of C/EBPalpha is dispensable for C/EBPalpha-mediated growth regulation in vivo.
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Mol Cell Biol. 2006 Feb;26(3):1028-37.
PMID 16428455
Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA).
Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S, Thomas X, Raffoux E, Lamandin C, Castaigne S, Fenaux P, Dombret H; ALFA Group.
Blood. 2002 Oct 15;100(8):2717-23.
PMID 12351377
CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors.
Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG.
Mol Cell Biol. 1998 Jul;18(7):4301-14.
PMID 9632814
CCAAT/enhancer-binding proteins: structure, function and regulation.
Ramji DP, Foka P.
Biochem J. 2002 Aug 1;365(Pt 3):561-75. (REVIEW)
PMID 12006103
C/EBPα induces highly efficient macrophage transdifferentiation of B lymphoma and leukemia cell lines and impairs their tumorigenicity.
Rapino F, Robles EF, Richter-Larrea JA, Kallin EM, Martinez-Climent JA, Graf T.
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PMID 23545498
Another pedigree with familial acute myeloid leukemia and germline CEBPA mutation.
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PMID 18946494
CCAAT/enhancer-binding protein-α suppresses lung tumor development in mice through the p38α MAP kinase pathway.
Sato A, Yamada N, Ogawa Y, Ikegami M.
PLoS One. 2013;8(2):e57013. doi: 10.1371/journal.pone.0057013. Epub 2013 Feb 20.
PMID 23437297
Recruitment of p300 by C/EBPbeta triggers phosphorylation of p300 and modulates coactivator activity.
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EMBO J. 2003 Feb 17;22(4):882-92.
PMID 12574124
Heterogeneous patterns of CEBPalpha mutation status in the progression of myelodysplastic syndrome and chronic myelomonocytic leukemia to acute myelogenous leukemia.
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Clin Cancer Res. 2005 Mar 1;11(5):1821-6.
PMID 15756005
Diminished expression of C/EBPalpha in skin carcinomas is linked to oncogenic Ras and reexpression of C/EBPalpha in carcinoma cells inhibits proliferation.
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Cancer Res. 2005 Feb 1;65(3):861-7.
PMID 15705884
Mutation of CEBPA in familial acute myeloid leukemia.
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PMID 15575056
Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2.
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PMID 12661007
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PMID 16537832
CCAAT/enhancer binding protein alpha knock-in mice exhibit early liver glycogen storage and reduced susceptibility to hepatocellular carcinoma.
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Cancer Res. 2005 Nov 15;65(22):10330-7.
PMID 16288022
C/EBPα expression is downregulated in human nonmelanoma skin cancers and inactivation of C/EBPα confers susceptibility to UVB-induced skin squamous cell carcinomas.
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PMID 21346772
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Anticancer Res. 2003 Jan-Feb;23(1A):351-4.
PMID 12680236
CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia.
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Blood. 2003 Feb 1;101(3):1141-8. Epub 2002 Oct 3.
PMID 12393450
Impaired energy homeostasis in C/EBP alpha knockout mice.
Wang ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD, Taylor LR, Wilson DR, Darlington GJ.
Science. 1995 Aug 25;269(5227):1108-12.
PMID 7652557
Impaired proliferation and tumorigenicity induced by CCAAT/enhancer-binding protein.
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PMID 8640762
Stepwise reprogramming of B cells into macrophages.
Xie H, Ye M, Feng R, Graf T.
Cell. 2004 May 28;117(5):663-76.
PMID 15163413
C/EBPbeta and GATA-1 synergistically regulate activity of the eosinophil granule major basic protein promoter: implication for C/EBPbeta activity in eosinophil gene expression.
Yamaguchi Y, Nishio H, Kishi K, Ackerman SJ, Suda T.
Blood. 1999 Aug 15;94(4):1429-39.
PMID 10438731
In prostate cancer cells the interaction of C/EBPalpha with Ku70, Ku80, and poly(ADP-ribose) polymerase-1 increases sensitivity to DNA damage.
Yin H, Glass J.
J Biol Chem. 2006 Apr 28;281(17):11496-505. Epub 2006 Feb 20.
PMID 16490787
Down regulation of PSA by C/EBPalpha is associated with loss of AR expression and inhibition of PSA promoter activity in the LNCaP cell line.
Yin H, Radomska HS, Tenen DG, Glass J.
BMC Cancer. 2006 Jun 14;6:158.
PMID 16774685
Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice.
Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG.
Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):569-74.
PMID 9012825
C/EBPalpha redirects androgen receptor signaling through a unique bimodal interaction.
Zhang J, Gonit M, Salazar MD, Shatnawi A, Shemshedini L, Trumbly R, Ratnam M.
Oncogene. 2010 Feb 4;29(5):723-38. doi: 10.1038/onc.2009.373. Epub 2009 Nov 9.
PMID 19901962
Expression and sub-cellular localization of the CCAAT/enhancer binding protein alpha in relation to postnatal development and malignancy of the prostate.
Zhang J, Wilkinson JE, Gonit M, Keck R, Selman S, Ratnam M.
Prostate. 2008 Aug 1;68(11):1206-14. doi: 10.1002/pros.20779.
PMID 18481268


This paper should be referenced as such :
TV Tian, T Graf
CEBPA (CCAAT/enhancer binding protein (C/EBP), alpha)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(4):249-255.
Free journal version : [ pdf ]   [ DOI ]
On line version :
History of this paper:
Smith, LL. CEBPA (CCAAT enhancer binding protein alpha). Atlas Genet Cytogenet Oncol Haematol. 2006;10(4):218-221.

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 14 ]
  t(14;19)(q32;q13) IGH/CEBPA
Acute myeloid leukemia with myelodysplasia related changes
Classification of myelodysplastic syndromes 2015
Chronic myelogenous leukaemia (CML)
i(17q) solely in myeloid malignancies
t(3;21)(q26;q22) RUNX1/MECOM
t(6;9)(p22;q34) DEK/NUP214
t(6;9)(p22;q34) DEK/NUP214 in Childhood
t(8;14)(q11;q32) IGH/CEBPD
t(14;14)(q11;q32) CEBPE/IGH::inv(14)(q11q32) CEBPE/IGH
t(2;19)(p12;q13.3) IGK/BCL3::t(14;19)(q32;q13.3) IGH/BCL3::t(19;22)(q13.3;q11) BCL3/IGL
t(14;19)(q32;p13) IGH/EPOR::t(14;19)(q32;p13) IGH/BRD4 ?
t(14;19)(q32;q13) IGH/CEBPA
t(14;20)(q32;q13) IGH/CEBPB

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Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)1050
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
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canSAR (ICR) (select the gene name)
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