* 116897

CCAAT/ENHANCER-BINDING PROTEIN, ALPHA; CEBPA


Alternative titles; symbols

C/EBP-ALPHA
CEBP


HGNC Approved Gene Symbol: CEBPA

Cytogenetic location: 19q13.11     Genomic coordinates (GRCh38): 19:33,299,934-33,302,534 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
19q13.11 ?Leukemia, acute myeloid 601626 AD, SMu 3
Leukemia, acute myeloid, somatic 601626 3

TEXT

Cloning and Expression

The CCAAT/enhancer-binding protein bears sequence homology and functional similarities to liver activator protein (LAP, or CEBPB; 189965) (Descombes et al., 1990). See Landschulz et al. (1989).

Using rat Cebp-alpha to screen a human liver cDNA library, followed by screening a human placenta genomic library, Swart et al. (1997) cloned full-length CEBP-alpha. The deduced 357-amino acid protein has an N-terminal transactivation domain and a C-terminal DNA-binding and dimerization domain. Northern blot analysis detected high expression of a 2.7-kb CEBP-alpha transcript in human placenta, liver, and spleen. Lower expression was detected in colon, smooth muscle, lung, and kidney medulla, and no expression was detected in kidney cortex. CEBP-alpha was also expressed in normal and psoriatic human skin, in cultured human keratinocytes, and in rat aorta and liver. Immunohistochemical analysis detected CEBP-alpha in nuclei of epidermal keratinocytes from normal human skin and lesional psoriatic skin. Intense staining was detected in suprabasal cells, hair follicle keratinocytes, and glandular sebocytes, but not in cells of the inflammatory infiltrate or capillaries.


Gene Structure

Swart et al. (1997) determined that the CEBPA gene is intronless.


Mapping

By means of somatic cell hybrids segregating either human or rat chromosomes, Szpirer et al. (1992) mapped the CEBP gene to human chromosome 19 and rat chromosome 1. These results provided further evidence for conservation of synteny on these chromosomes (and on mouse chromosome 7). Using human/hamster somatic cell hybrids containing restricted fragments of human chromosome 19, Hendricks-Taylor et al. (1992) mapped the CEBPA gene to chromosome 19q13.1, between the GPI (172400) and TGFB1 (190180) genes. This position was confirmed by fluorescence in situ hybridization. Birkenmeier et al. (1989) mapped the Cebpa gene to mouse chromosome 7.


Gene Function

Miller et al. (1996) characterized the promoter of the human gene encoding leptin (164160), a signaling factor expressed in adipose tissue with an important role in body weight homeostasis. They found that CEBPA modulates leptin expression and suggested a function for CEBPA in treatment of human obesity.

Wang et al. (2001) found that CEBPA directly interacts with CDK2 (116953) and CDK4 (123829) and arrests cell proliferation by inhibiting these kinases. A region between amino acids 175 and 187 of CEBPA was determined to be responsible for direct inhibition of cyclin-dependent kinases and caused growth arrest in cultured cells. CEBPA inhibited CDK2 activity by blocking the association of CDK2 with cyclins. The activities of Cdk4 and Cdk2 were increased in mouse Cebpa knockout livers, leading to increased proliferation.

The myeloid transcription factor CEBPA is crucial for normal granulopoiesis, and dominant-negative mutations of the CEBPA gene are found in a significant proportion of malignant cells from patients with myeloblastic subtypes (M1 and M2) of acute myeloid leukemia (AML; 601626). Pabst et al. (2001) demonstrated that the AML1 (RUNX1; 151385)-ETO (CBFA2T1; 133435) fusion protein suppressed CEBPA expression. Helbling et al. (2004) found that the leukemic AML1-MDS1-EAI1 (AME; see 151385) fusion protein suppressed CEBPA protein. In contrast to the AML1-ETO fusion, AME failed to suppress CEBPA mRNA expression. Helbling et al. (2004) found that a putative inhibitor of CEBPA translation, calreticulin (CRT; 109091), was strongly activated after induction of AME in a cell line experimental system (14.8-fold) and in AME patient samples (12.2-fold). Moreover, inhibition of CRT by small interfering RNA restored CEBPA levels. These results identified CEBPA as a key target of the leukemic fusion protein AME and suggested that modulation of CEBPA by CRT may represent a mechanism involved in the differentiation block in AME leukemias.

Menard et al. (2002) showed that Cebpa was expressed in mouse cortical progenitor cells and could induce expression of a reporter gene containing the minimal promoter of alpha-tubulin (TUBA1A; 602529), a neuron-specific gene.

Skokowa et al. (2006) found significantly decreased or absent LEF1 (153245) expression in arrested promyelocytes from patients with congenital neutropenia (see 202700). Competitive binding and chromatin immunoprecipitation (ChIP) assays showed that LEF1 directly bound to and regulated CEBPA, suggesting that LEF1-dependent downregulation of CEBPA in congenital neutropenia leads to a maturation block in promyelocytes similar to that seen in CEBPA dominant-negative AML.

By peptide analysis of nuclear proteins that interacted with CEBPA, Bararia et al. (2008) identified TIP60 (KAT5; 601409) as a CEBPA binding partner. The interaction was confirmed by coprecipitation analysis and protein pull-down assays. TIP60 enhanced the ability of CEBPA to transactivate a TK (TK1; 188300) promoter containing 2 CCAAT sites, and the histone acetyltransferase activity of TIP60 was required for its cooperativity with CEBPA. Domain analysis revealed that TIP60 interacted with the DNA-binding and transactivation domains of CEBPA. Immunoprecipitation analysis showed that TIP60 was recruited to the promoters of CEBPA and GCSFR (CSF3R; 138971) following beta-estradiol-induced differentiation of K562 myelogenous leukemia cells, which was concomitant with histone acetylation at the CEBPA and GCSFR promoters.

Reddy et al. (2009) showed that microRNA-661 (MIR661; 613716) downregulated expression of MTA1 (603526), a gene that is upregulated in several cancers. They identified putative CEBP-alpha-binding sites in the promoter region of the MIR661 gene. Reporter gene assays showed that CEBP-alpha upregulated MIR661 expression in transfected HeLa and MDA-231 breast cancer cells. Expression of CEBP-alpha and MIR661 was inversely proportional to that of MTA1 in breast cancer cell lines, and the level of MTA1 protein was progressively upregulated with increasing metastatic potential. Overexpression of MIR661 in MDA-231 breast cancer cells inhibited cell motility, invasiveness, and anchorage-independent growth, and it reduced their ability to form tumors in a xenograft model. Reddy et al. (2009) concluded that CEBP-alpha downregulates MTA1 expression and cancer cell growth by upregulating expression of MIR661.

Di Ruscio et al. (2013) presented data demonstrating that active transcription regulates levels of genomic methylation. They identified a novel nuclear nonpolyadenylated noncoding RNA (ncRNA) arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile. They termed this ncRNA 'extracoding CEBPA' (ecCEBPA) because it encompasses the entire mRNA sequence in the same-sense orientation. ecCEBPA binds to DNMT1 (126375) and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extended the generality of this finding to numerous gene loci. Di Ruscio et al. (2013) concluded that these results delineated the nature of DNMT1-RNA interactions and suggested strategies for gene-selective demethylation of therapeutic targets in human diseases.

In mouse primary B cells, Di Stefano et al. (2014) found that transient CEBPA expression followed by Oct4 (164177), Sox2 (184429), Klf4 (602253), and Myc (190080) (collectively known as OSKM) activation induces a 100-fold increase in induced pluripotent stem (iPS) cell reprogramming efficiency, involving 95% of the population. During this conversion, pluripotency and epithelial-mesenchymal transition genes become markedly upregulated, and 60% of the cells express Oct4 within 2 days. CEBPA acts as a pathbreaker as it transiently makes the chromatin of pluripotency genes more accessible to DNaseI (125505). CEBPA also induces the expression of the dioxygenase Tet2 (612839) and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated after OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM-induced B-cell reprogramming. Because the enzyme is also required for efficient CEBPA-induced immune cell conversion, the data of Di Stefano et al. (2014) indicated that TET2 provides a mechanistic link between iPS cell reprogramming and B-cell transdifferentiation.


Molecular Genetics

Acute Myeloid Leukemia

In affected members of a family with acute myeloid leukemia (AML; 601626), Smith et al. (2004) identified a germline 1-bp deletion (212delC) in the CEBPA gene, resulting in the presence of 5 cytosine residues in a region where 6 cytosine residues are present in the wildtype sequence. Overt leukemia developed in the father at age 10 years, in the first-born son at age 30 years, and in the last-born daughter at age 18 years.

Somatic Mutations

Pabst et al. (2001) noted that in the hematopoietic system, CEBPA is exclusively expressed in myelomonocytic cells. It is specifically upregulated during granulocytic differentiation. No mature granulocytes are observed in Cebpa-mutant mice, whereas all the other blood cell types are present in normal proportions. In acute myeloid leukemia (601626), the most prominent abnormality is a block in differentiation of granulocytic blasts. With this background information, Pabst et al. (2001) studied samples from AML patients and demonstrated that CEBPA is mutated in 16% of AML-M2 patients that lack the 8;21 translocation (ETO, 133435; RUNX1, 151385). They found that 5 mutations in the N terminus truncated the full-length protein, but did not affect the 30-kD protein initiated further downstream. The mutated proteins blocked wildtype C/EBP-alpha DNA binding and transactivation of granulocyte target genes in a dominant-negative manner, and failed to induce the granulocytic differentiation. This was the first report of CEBPA mutations in human neoplasia. Pabst et al. (2001) detected 5 deletions, 2 insertions, and 4 point mutations in the CEBPA gene (see, e.g., 116897.0001-116897.0003). All deletions caused a shift into the same alternative reading frame, as the number of missing basepairs was (3n+1). The mean age at diagnosis of the patients with CEBPA mutations was 66 years. CEBPA mutations were found in 7.3% of AML patients.

Snaddon et al. (2003) stated that the t(8;21) translocation is found in 10 to 15% of cases of AML, particularly those of the M2 subtype, where it accounts for 40% of cases. Using a PCR-SSCP and sequencing approach, they screened for CEBPA mutations in 99 patients with AML type M1 or M2. They identified 9 somatic CEBPA mutations in 8 patients. All of the mutations were clustered toward the C terminus of the protein. Two patients carried biallelic mutations: one was homozygous for a 57-bp insertion at nucleotide 1137 (116897.0004) and the other was compound heterozygous for a 27-bp insertion at nucleotide 1096 (116897.0005) and a 4-bp insertion (GGCC) at nucleotide 363 (116897.0006).


Evolution

To explore the evolution of gene regulation, Schmidt et al. (2010) used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) to determine experimentally the genomewide occupancy of 2 transcription factors, CEBPA and HNF4A (600281), in the livers of 5 vertebrates: Homo sapiens, Mus musculus, Canis familiaris, Monodelphis domesticus (short-tailed opossum), and Gallus gallus. Although each transcription factor displayed highly conserved DNA binding preferences, most binding was species-specific, and aligned binding events present in all 5 species were rare. Regions near genes with expression levels that are dependent on a transcription factor were often bound by the transcription factor in multiple species yet showed no enhanced DNA sequence constraint. Binding divergence between species can be largely explained by sequence changes to the bound motifs. Among the binding events lost in one lineage, only half are recovered by another binding event within 10 kb. Schmidt et al. (2010) concluded that their results revealed large interspecies differences in transcriptional regulation and provided insight into regulatory evolution.


Nomenclature

According to the nomenclature proposed by Cao et al. (1991), the CCAAT/enhancer-binding protein is C/EBP-alpha and NF-IL6 (LAP) is C/EBP-beta, with the corresponding genes being CEBPA and CEBPB (189965). CEBPB was formerly symbolized TCF5.


Animal Model

Wang et al. (1995) found that mice homozygous for the targeted deletion of the Cebpa gene did not store hepatic glycogen and died from hypoglycemia within 8 hours after birth. In these mutant mice, the amounts of glycogen synthase (138571) mRNA were 50 to 70% of normal and the transcriptional induction of the genes for 2 gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (261680) and glucose-6-phosphatase (613742), was delayed. The hepatocytes and adipocytes of the mutant mice failed to accumulate lipid, and the expression of the gene for uncoupling protein (113730), the defining marker of brown adipose tissue, was reduced. The findings demonstrated that C/EBP-alpha is critical for the establishment and maintenance of energy homeostasis in neonates.

Flodby et al. (1996) made transgenic knockout mice in which the CEBPA gene was selectively disrupted. The homozygous mutant Cebpa -/- mice died, usually within the first 20 hours after birth and had defects in the control of hepatic growth and lung development. Histologic analysis revealed that these animals had severely disturbed liver architecture, with acinar formation, in a pattern suggestive of either regenerating liver or hepatocellular carcinoma. Pulmonary histology showed hyperproliferation of type II pneumocytes and disturbed alveolar architecture. Molecular analysis showed that accumulation of glycogen and lipids in the liver and adipose tissue is impaired and that the mutant animals are severely hypoglycemic. The authors found by Northern blot analysis that levels of c-myc and c-jun RNAs are specifically induced by several fold in the livers of these animals indicating an active proliferative state. They found by immunohistology that cyclin-stained cells are present in the liver of Cebpa -/- mice at a 5 to 10 times higher frequency than normal, also indicating abnormally active proliferation. Flodby et al. (1996) suggested that CEBPA may have an important role in the acquisition and maintenance of terminal differentiation in hepatocytes.

Mice deficient in Cebpa have defective development of adipose tissue. Wu et al. (1999) used fibroblasts from Cebpa -/- mice in combination with retroviral vectors expressing Cebpa and peroxisome proliferator-activated receptor-gamma (PPARG; 601487) to determine the precise role of CEBPA in adipogenesis. The authors found that Cebpa -/- fibroblasts underwent adipose differentiation through expression and activation of Pparg. Cebpa-deficient adipocytes accumulated less lipid and did not induce endogenous Pparg, indicating that cross-regulation between CEBPA and PPARG is important in maintaining the differentiated state. The cells also showed a complete absence of insulin (INS; 176730)-stimulated glucose transport, secondary to reduced gene expression and tyrosine phosphorylation for the Ins receptor (147670) and Ins receptor substrate-1 (147545). Wu et al. (1999) concluded that CEBPA has multiple roles in adipogenesis and that cross-regulation between PPARG and CEBPA is a key component of the transcriptional control of this cell lineage.


ALLELIC VARIANTS ( 7 Selected Examples):

.0001 LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, 7-BP DEL, NT263
  
RCV000019126

In a 42-year-old patient with secondary acute myeloid leukemia (AML; 601626) and in a 49-year-old patient with AML of the M2 subtype, Pabst et al. (2001) found deletion of 7 nucleotides (263_269del7) in the CEBPA gene, resulting in a frameshift and premature termination (Pro39fsTer159).


.0002 LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, GLU50TER
  
RCV000019127

In a 67-year-old patient with acute myeloid leukemia (AML; 601626), Pabst et al. (2001) found a 297G-T transversion in the CEBPA gene resulting in a glu50-to-ter (E50X) nonsense mutation.


.0003 LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, HIS84LEU
  
RCV000019128

In a 70-year-old patient with acute myeloid leukemia (601626), Pabst et al. (2001) found a 400A-T transversion in the CEBPA gene resulting in a his84-to-leu (H84L) missense mutation.


.0004 LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, 57-BP INS, NT1137
  
RCV000019129

In a 37-year-old man with acute myeloid leukemia (601626) of the M1 subtype, Snaddon et al. (2003) identified homozygosity for a somatic 57-bp insertion after nucleotide 1137 (1137_1138ins57) of the CEBPA gene, which was predicted to cause disruption of the leucine zipper of the protein.


.0005 LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, 27-BP INS, NT1096
  
RCV000019130

In a 72-year-old woman with acute myeloid leukemia (601626) of the M1 subtype, Snaddon et al. (2003) identified compound heterozygosity for 2 somatic mutations in the CEBPA gene: a 27-bp insertion after nucleotide 1096, which was predicted to cause disruption of the leucine zipper, and a 4-bp insertion (363_364insGGCC; 116897.0006), which resulted in a frameshift at ala71 and a truncated protein.


.0006 LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, 4-BP INS, 363GGCC
  
RCV000019131

For discussion of the somatic 4-bp insertion (363_364insGGCC) in the CEBPA gene that was found in compound heterozygous state in a patient with acute myeloid leukemia (601626) of the M1 subtype by Snaddon et al. (2003), see 116897.0005.


.0007 LEUKEMIA, ACUTE MYELOID (1 family)

LEUKEMIA, ACUTE MYELOID, SOMATIC
CEBPA, 1-BP DEL, 212C
  
RCV000019132

Acute Myeloid Leukemia

In affected members of a family with acute myeloid leukemia (AML; 601626), Smith et al. (2004) identified a germline 1-bp deletion (212delC) in the CEBPA gene, resulting in the presence of 5 cytosine residues in a region where 6 cytosine residues are present in the wildtype sequence. Overt leukemia developed in the father at age 10 years, in the first-born son at age 30 years, and in the last-born daughter at age 18 years.

Acute Myeloid Leukemia, Somatic

In bone marrow samples from 2 cases of sporadic acute myeloid leukemia (601626), Barjesteh van Waalwijk van Doorn-Khosrovani et al. (2003) identified a 1-bp deletion (212delC) in the CEBPA gene.


REFERENCES

  1. Bararia, D., Trivedi, A. K., Zada, A. A. P., Greif, P. A., Mulaw, M. A., Christopeit, M., Hiddemann, W., Bohlander, S. K., Behre, G. Proteomic identification of the MYST domain histone acetyltransferase TIP60 (HTATIP) as a co-activator of the myeloid transcription factor C/EBP-alpha. Leukemia 22: 800-807, 2008. [PubMed: 18239623, related citations] [Full Text]

  2. Barjesteh van Waalwijk van Doorn-Khosrovani, S., Erpelinck, C., Meijer, J., van Oosterhoud, S., van Putten, W. L. J., Valk, P. J. M., Beverloo, H. B., Tenen, D. G., Lowenberg, B., Delwel, R. Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. Hemat. J. 4: 31-40, 2003. [PubMed: 12692518, related citations] [Full Text]

  3. Birkenmeier, E. H., Gwynn, B., Howard, S., Jerry, J., Gordon, J. I., Landschulz, W. H., McKnight, S. L. Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev. 3: 1146-1156, 1989. [PubMed: 2792758, related citations] [Full Text]

  4. Cao, Z., Umek, R. M., McKnight, S. L. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 5: 1538-1552, 1991. [PubMed: 1840554, related citations] [Full Text]

  5. Descombes, P., Chojkier, M., Lichtsteiner, S., Falvey, E., Schibler, U. LAP, a novel member of the C/EBP gene family, encodes a liver-enriched transcriptional activator protein. Genes Dev. 4: 1541-1551, 1990. [PubMed: 2253878, related citations] [Full Text]

  6. Di Ruscio, A., Ebralidze, A. K., Benoukraf, T., Amabile, G., Goff, L. A., Terragni, J., Figueroa, M. E., De Figueiredo Pontes, L. L., Alberich-Jorda, M., Zhang, P., Wu, M., D'Alo, F., Melnick, A., Leone, G., Ebralidze, K. K., Pradhan, S., Rinn, J. L., Tenen, D. G. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 503: 371-376, 2013. [PubMed: 24107992, images, related citations] [Full Text]

  7. Di Stefano, B., Sardina, J. L., van Oevelen, C., Collombet, S., Kallin, E. M., Vicent, G. P., Lu, J., Thieffry, D., Beato, M., Graf, T. C/EBP-alpha poises B cells for rapid reprogramming into induced pluripotent stem cells. Nature 506: 235-239, 2014. [PubMed: 24336202, related citations] [Full Text]

  8. Flodby, P., Barlow, C., Kylefjord, H., Ahrlund-Richter, L., Xanthopoulos, K. G. Increased hepatic cell proliferation and lung abnormalities in mice deficient in CCAAT/enhancer binding protein alpha. J. Biol. Chem. 271: 24753-24760, 1996. [PubMed: 8798745, related citations] [Full Text]

  9. Helbling, D., Mueller, B. U., Timchenko, N. A., Hagemeijer, A., Jotterand, M., Meyer-Monard, S., Lister, A., Rowley, J. D., Huegli, B., Fey, M. F., Pabst, T. The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of calreticulin. Proc. Nat. Acad. Sci. 101: 13312-13317, 2004. [PubMed: 15326310, images, related citations] [Full Text]

  10. Hendricks-Taylor, L. R., Bachinski, L. L., Siciliano, M. J., Fertitta, A., Trask, B., de Jong, P. J., Ledbetter, D. H., Darlington, G. J. The CCAAT/enhancer binding protein (C/EBP-alpha) gene (CEBPA) maps to human chromosome 19q13.1 and the related nuclear factor NF-IL6 (C/EBP-beta) gene (CEBPB) maps to human chromosome 20q13.1. Genomics 14: 12-17, 1992. [PubMed: 1427819, related citations] [Full Text]

  11. Landschulz, W. H., Johnson, P. F., McKnight, S. L. The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite. Science 243: 1681-1688, 1989. [PubMed: 2494700, related citations] [Full Text]

  12. Menard, C., Hein, P., Paquin, A., Savelson, A., Yang, X. M., Lederfein, D., Barnabe-Heider, F., Mir, A. A., Sterneck, E., Peterson, A. C., Johnson, P. F., Vinson, C., Miller, F. D. An essential role for a MEK-C/EBP pathway during growth factor-regulated cortical neurogenesis. Neuron 36: 597-610, 2002. [PubMed: 12441050, related citations] [Full Text]

  13. Miller, S. G., De Vos, P., Guerre-Millo, M., Wong, K., Hermann, T., Staels, B., Briggs, M. R., Auwerx, J. The adipocyte specific transcription factor C/EBP-alpha modulates human ob gene expression. Proc. Nat. Acad. Sci. 93: 5507-5511, 1996. [PubMed: 8643605, related citations] [Full Text]

  14. Pabst, T., Mueller, B. U., Harakawa, N., Schoch, C., Haferlach, T., Behre, G., Hiddemann, W., Zhang, D.-E., Tenen, D. G. AML1-ETO downregulates the granulocytic differentiation factor C/EBP-alpha in t(8;21) myeloid leukemia. Nature Med. 7: 444-451, 2001. [PubMed: 11283671, related citations] [Full Text]

  15. Pabst, T., Mueller, B. U., Zhang, P., Radomska, H. S., Narravula, S., Schnittger, S., Behre, G., Hiddemann, W., Tenen, D. G. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBP-alpha), in acute myeloid leukemia. Nature Genet. 27: 263-270, 2001. [PubMed: 11242107, related citations] [Full Text]

  16. Reddy, S. D. N., Pakala, S. B., Ohshiro, K., Rayala, S. K., Kumar, R. MicroRNA-661, a c/EBP-alpha target, inhibits metastatic tumor antigen 1 and regulates its functions. Cancer Res. 69: 5639-5642, 2009. [PubMed: 19584269, images, related citations] [Full Text]

  17. Schmidt, D., Wilson, M. D., Ballester, B., Schwalie, P. C., Brown, G. D., Marshall, A., Kutter, C., Watt, S., Martinez-Jimenez, C. P., Mackay, S., Talianidis, I., Flicek, P., Odom, D. T. Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science 328: 1036-1040, 2010. [PubMed: 20378774, images, related citations] [Full Text]

  18. Skokowa, J., Cario, G., Uenalan, M., Schambach, A., Germeshausen, M., Battmer, K., Zeidler, C., Lehmann, U., Eder, M., Baum, C., Grosschedl, R., Stanulla, M., Scherr, M., Welte, K. LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nature Med. 12: 1191-1197, 2006. Note: Erratum: Nature Med. 12: 1329 only, 2006. [PubMed: 17063141, related citations] [Full Text]

  19. Smith, M. L., Cavenagh, J. D., Lister, T. A., Fitzgibbon, J. Mutation of CEBPA in familial acute myeloid leukemia. New Eng. J. Med. 351: 2403-2407, 2004. [PubMed: 15575056, related citations] [Full Text]

  20. Snaddon, J., Smith, M. L., Neat, M., Cambal-Parrales, M., Dixon-McIver, A., Arch, R., Amess, J. A., Rohatiner, A. Z., Lister, T. A., Fitzgibbon, J. Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2. Genes Chromosomes Cancer 37: 72-78, 2003. [PubMed: 12661007, related citations] [Full Text]

  21. Swart, G. W. M., van Groningen, J. J. M., van Ruissen, F., Bergers, M., Schalkwijk, J. Transcription factor C/EBP-alpha: novel sites of expression and cloning of the human gene. Biol. Chem. 378: 373-379, 1997. [PubMed: 9191024, related citations] [Full Text]

  22. Szpirer, C., Riviere, M., Cortese, R., Nakamura, T., Islam, M. Q., Levan, G., Szpirer, J. Chromosomal localization in man and rat of the genes encoding the liver-enriched transcription factors C/EBP, DBP, and HNF1/LFB-1 (CEBP, DBP, and transcription factor 1, TCF1, respectively) and of the hepatocyte growth factor/scatter factor gene (HGF). Genomics 13: 293-300, 1992. [PubMed: 1535333, related citations] [Full Text]

  23. Wang, H., Iakova, P., Wilde, M., Welm, A., Goode, T., Roesler, W. J., Timchenko, N. A. C/EBP-alpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Molec. Cell 8: 817-828, 2001. [PubMed: 11684017, related citations] [Full Text]

  24. Wang, N., Finegold, M. J., Bradley, A., Ou, C. N., Abdelsayed, S. V., Wilde, M. D., Taylor, L. R., Wilson, D. R., Darlington, G. J. Impaired energy homeostasis in C/EBP-alpha knockout mice. Science 269: 1108-1112, 1995. [PubMed: 7652557, related citations] [Full Text]

  25. Wu, Z., Rosen, E. D., Brun, R., Hauser, S., Adelmant, G., Troy, A. E., McKeon, C., Darlington, G. J., Spiegelman, B. M. Cross-regulation of C/EBP-alpha and PPAR-gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Molec. Cell 3: 151-158, 1999. [PubMed: 10078198, related citations] [Full Text]


Ada Hamosh - updated : 3/13/2014
Ada Hamosh - updated : 12/6/2013
Patricia A. Hartz - updated : 2/2/2011
Ada Hamosh - updated : 6/30/2010
Patricia A. Hartz - updated : 1/20/2010
Ada Hamosh - updated : 10/28/2008
Cassandra L. Kniffin - updated : 10/17/2006
Victor A. McKusick - updated : 3/21/2005
Victor A. McKusick - updated : 12/17/2004
Victor A. McKusick - updated : 7/18/2003
Stylianos E. Antonarakis - updated : 11/13/2001
Stylianos E. Antonarakis - updated : 3/22/1999
Jennifer P. Macke - updated : 11/20/1996
Alan F. Scott - updated : 9/17/1996
Mark H. Paalman - updated : 7/11/1996
Creation Date:
Victor A. McKusick : 10/26/1990
carol : 09/21/2022
carol : 03/06/2018
carol : 04/28/2017
carol : 02/10/2015
mcolton : 2/9/2015
carol : 11/13/2014
carol : 11/13/2014
ckniffin : 11/12/2014
alopez : 3/13/2014
alopez : 12/6/2013
carol : 2/15/2011
mgross : 2/2/2011
mgross : 2/2/2011
alopez : 7/1/2010
terry : 6/30/2010
mgross : 1/20/2010
mgross : 12/5/2008
terry : 10/28/2008
carol : 5/14/2008
wwang : 12/11/2006
wwang : 10/25/2006
ckniffin : 10/17/2006
terry : 5/17/2005
mgross : 3/21/2005
mgross : 3/21/2005
terry : 2/7/2005
tkritzer : 1/11/2005
terry : 12/17/2004
tkritzer : 7/31/2003
tkritzer : 7/30/2003
terry : 7/18/2003
mgross : 11/13/2001
mgross : 11/13/2001
alopez : 3/1/2001
carol : 2/22/2000
mgross : 3/23/1999
mgross : 3/22/1999
psherman : 9/29/1998
alopez : 9/25/1998
terry : 2/21/1998
alopez : 7/10/1997
carol : 6/23/1997
jamie : 2/4/1997
terry : 1/17/1997
jamie : 11/20/1996
mark : 9/17/1996
mark : 7/11/1996
mark : 7/11/1996
terry : 6/28/1996
mark : 10/12/1995
terry : 9/11/1995
carol : 5/26/1993
carol : 4/7/1993
carol : 10/13/1992
carol : 9/25/1992

* 116897

CCAAT/ENHANCER-BINDING PROTEIN, ALPHA; CEBPA


Alternative titles; symbols

C/EBP-ALPHA
CEBP


HGNC Approved Gene Symbol: CEBPA

SNOMEDCT: 1162928000, 91861009;   ICD10CM: C92.0, C92.00;   ICD9CM: 205.0;  


Cytogenetic location: 19q13.11     Genomic coordinates (GRCh38): 19:33,299,934-33,302,534 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
19q13.11 ?Leukemia, acute myeloid 601626 Autosomal dominant; Somatic mutation 3
Leukemia, acute myeloid, somatic 601626 3

TEXT

Cloning and Expression

The CCAAT/enhancer-binding protein bears sequence homology and functional similarities to liver activator protein (LAP, or CEBPB; 189965) (Descombes et al., 1990). See Landschulz et al. (1989).

Using rat Cebp-alpha to screen a human liver cDNA library, followed by screening a human placenta genomic library, Swart et al. (1997) cloned full-length CEBP-alpha. The deduced 357-amino acid protein has an N-terminal transactivation domain and a C-terminal DNA-binding and dimerization domain. Northern blot analysis detected high expression of a 2.7-kb CEBP-alpha transcript in human placenta, liver, and spleen. Lower expression was detected in colon, smooth muscle, lung, and kidney medulla, and no expression was detected in kidney cortex. CEBP-alpha was also expressed in normal and psoriatic human skin, in cultured human keratinocytes, and in rat aorta and liver. Immunohistochemical analysis detected CEBP-alpha in nuclei of epidermal keratinocytes from normal human skin and lesional psoriatic skin. Intense staining was detected in suprabasal cells, hair follicle keratinocytes, and glandular sebocytes, but not in cells of the inflammatory infiltrate or capillaries.


Gene Structure

Swart et al. (1997) determined that the CEBPA gene is intronless.


Mapping

By means of somatic cell hybrids segregating either human or rat chromosomes, Szpirer et al. (1992) mapped the CEBP gene to human chromosome 19 and rat chromosome 1. These results provided further evidence for conservation of synteny on these chromosomes (and on mouse chromosome 7). Using human/hamster somatic cell hybrids containing restricted fragments of human chromosome 19, Hendricks-Taylor et al. (1992) mapped the CEBPA gene to chromosome 19q13.1, between the GPI (172400) and TGFB1 (190180) genes. This position was confirmed by fluorescence in situ hybridization. Birkenmeier et al. (1989) mapped the Cebpa gene to mouse chromosome 7.


Gene Function

Miller et al. (1996) characterized the promoter of the human gene encoding leptin (164160), a signaling factor expressed in adipose tissue with an important role in body weight homeostasis. They found that CEBPA modulates leptin expression and suggested a function for CEBPA in treatment of human obesity.

Wang et al. (2001) found that CEBPA directly interacts with CDK2 (116953) and CDK4 (123829) and arrests cell proliferation by inhibiting these kinases. A region between amino acids 175 and 187 of CEBPA was determined to be responsible for direct inhibition of cyclin-dependent kinases and caused growth arrest in cultured cells. CEBPA inhibited CDK2 activity by blocking the association of CDK2 with cyclins. The activities of Cdk4 and Cdk2 were increased in mouse Cebpa knockout livers, leading to increased proliferation.

The myeloid transcription factor CEBPA is crucial for normal granulopoiesis, and dominant-negative mutations of the CEBPA gene are found in a significant proportion of malignant cells from patients with myeloblastic subtypes (M1 and M2) of acute myeloid leukemia (AML; 601626). Pabst et al. (2001) demonstrated that the AML1 (RUNX1; 151385)-ETO (CBFA2T1; 133435) fusion protein suppressed CEBPA expression. Helbling et al. (2004) found that the leukemic AML1-MDS1-EAI1 (AME; see 151385) fusion protein suppressed CEBPA protein. In contrast to the AML1-ETO fusion, AME failed to suppress CEBPA mRNA expression. Helbling et al. (2004) found that a putative inhibitor of CEBPA translation, calreticulin (CRT; 109091), was strongly activated after induction of AME in a cell line experimental system (14.8-fold) and in AME patient samples (12.2-fold). Moreover, inhibition of CRT by small interfering RNA restored CEBPA levels. These results identified CEBPA as a key target of the leukemic fusion protein AME and suggested that modulation of CEBPA by CRT may represent a mechanism involved in the differentiation block in AME leukemias.

Menard et al. (2002) showed that Cebpa was expressed in mouse cortical progenitor cells and could induce expression of a reporter gene containing the minimal promoter of alpha-tubulin (TUBA1A; 602529), a neuron-specific gene.

Skokowa et al. (2006) found significantly decreased or absent LEF1 (153245) expression in arrested promyelocytes from patients with congenital neutropenia (see 202700). Competitive binding and chromatin immunoprecipitation (ChIP) assays showed that LEF1 directly bound to and regulated CEBPA, suggesting that LEF1-dependent downregulation of CEBPA in congenital neutropenia leads to a maturation block in promyelocytes similar to that seen in CEBPA dominant-negative AML.

By peptide analysis of nuclear proteins that interacted with CEBPA, Bararia et al. (2008) identified TIP60 (KAT5; 601409) as a CEBPA binding partner. The interaction was confirmed by coprecipitation analysis and protein pull-down assays. TIP60 enhanced the ability of CEBPA to transactivate a TK (TK1; 188300) promoter containing 2 CCAAT sites, and the histone acetyltransferase activity of TIP60 was required for its cooperativity with CEBPA. Domain analysis revealed that TIP60 interacted with the DNA-binding and transactivation domains of CEBPA. Immunoprecipitation analysis showed that TIP60 was recruited to the promoters of CEBPA and GCSFR (CSF3R; 138971) following beta-estradiol-induced differentiation of K562 myelogenous leukemia cells, which was concomitant with histone acetylation at the CEBPA and GCSFR promoters.

Reddy et al. (2009) showed that microRNA-661 (MIR661; 613716) downregulated expression of MTA1 (603526), a gene that is upregulated in several cancers. They identified putative CEBP-alpha-binding sites in the promoter region of the MIR661 gene. Reporter gene assays showed that CEBP-alpha upregulated MIR661 expression in transfected HeLa and MDA-231 breast cancer cells. Expression of CEBP-alpha and MIR661 was inversely proportional to that of MTA1 in breast cancer cell lines, and the level of MTA1 protein was progressively upregulated with increasing metastatic potential. Overexpression of MIR661 in MDA-231 breast cancer cells inhibited cell motility, invasiveness, and anchorage-independent growth, and it reduced their ability to form tumors in a xenograft model. Reddy et al. (2009) concluded that CEBP-alpha downregulates MTA1 expression and cancer cell growth by upregulating expression of MIR661.

Di Ruscio et al. (2013) presented data demonstrating that active transcription regulates levels of genomic methylation. They identified a novel nuclear nonpolyadenylated noncoding RNA (ncRNA) arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile. They termed this ncRNA 'extracoding CEBPA' (ecCEBPA) because it encompasses the entire mRNA sequence in the same-sense orientation. ecCEBPA binds to DNMT1 (126375) and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extended the generality of this finding to numerous gene loci. Di Ruscio et al. (2013) concluded that these results delineated the nature of DNMT1-RNA interactions and suggested strategies for gene-selective demethylation of therapeutic targets in human diseases.

In mouse primary B cells, Di Stefano et al. (2014) found that transient CEBPA expression followed by Oct4 (164177), Sox2 (184429), Klf4 (602253), and Myc (190080) (collectively known as OSKM) activation induces a 100-fold increase in induced pluripotent stem (iPS) cell reprogramming efficiency, involving 95% of the population. During this conversion, pluripotency and epithelial-mesenchymal transition genes become markedly upregulated, and 60% of the cells express Oct4 within 2 days. CEBPA acts as a pathbreaker as it transiently makes the chromatin of pluripotency genes more accessible to DNaseI (125505). CEBPA also induces the expression of the dioxygenase Tet2 (612839) and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated after OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM-induced B-cell reprogramming. Because the enzyme is also required for efficient CEBPA-induced immune cell conversion, the data of Di Stefano et al. (2014) indicated that TET2 provides a mechanistic link between iPS cell reprogramming and B-cell transdifferentiation.


Molecular Genetics

Acute Myeloid Leukemia

In affected members of a family with acute myeloid leukemia (AML; 601626), Smith et al. (2004) identified a germline 1-bp deletion (212delC) in the CEBPA gene, resulting in the presence of 5 cytosine residues in a region where 6 cytosine residues are present in the wildtype sequence. Overt leukemia developed in the father at age 10 years, in the first-born son at age 30 years, and in the last-born daughter at age 18 years.

Somatic Mutations

Pabst et al. (2001) noted that in the hematopoietic system, CEBPA is exclusively expressed in myelomonocytic cells. It is specifically upregulated during granulocytic differentiation. No mature granulocytes are observed in Cebpa-mutant mice, whereas all the other blood cell types are present in normal proportions. In acute myeloid leukemia (601626), the most prominent abnormality is a block in differentiation of granulocytic blasts. With this background information, Pabst et al. (2001) studied samples from AML patients and demonstrated that CEBPA is mutated in 16% of AML-M2 patients that lack the 8;21 translocation (ETO, 133435; RUNX1, 151385). They found that 5 mutations in the N terminus truncated the full-length protein, but did not affect the 30-kD protein initiated further downstream. The mutated proteins blocked wildtype C/EBP-alpha DNA binding and transactivation of granulocyte target genes in a dominant-negative manner, and failed to induce the granulocytic differentiation. This was the first report of CEBPA mutations in human neoplasia. Pabst et al. (2001) detected 5 deletions, 2 insertions, and 4 point mutations in the CEBPA gene (see, e.g., 116897.0001-116897.0003). All deletions caused a shift into the same alternative reading frame, as the number of missing basepairs was (3n+1). The mean age at diagnosis of the patients with CEBPA mutations was 66 years. CEBPA mutations were found in 7.3% of AML patients.

Snaddon et al. (2003) stated that the t(8;21) translocation is found in 10 to 15% of cases of AML, particularly those of the M2 subtype, where it accounts for 40% of cases. Using a PCR-SSCP and sequencing approach, they screened for CEBPA mutations in 99 patients with AML type M1 or M2. They identified 9 somatic CEBPA mutations in 8 patients. All of the mutations were clustered toward the C terminus of the protein. Two patients carried biallelic mutations: one was homozygous for a 57-bp insertion at nucleotide 1137 (116897.0004) and the other was compound heterozygous for a 27-bp insertion at nucleotide 1096 (116897.0005) and a 4-bp insertion (GGCC) at nucleotide 363 (116897.0006).


Evolution

To explore the evolution of gene regulation, Schmidt et al. (2010) used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) to determine experimentally the genomewide occupancy of 2 transcription factors, CEBPA and HNF4A (600281), in the livers of 5 vertebrates: Homo sapiens, Mus musculus, Canis familiaris, Monodelphis domesticus (short-tailed opossum), and Gallus gallus. Although each transcription factor displayed highly conserved DNA binding preferences, most binding was species-specific, and aligned binding events present in all 5 species were rare. Regions near genes with expression levels that are dependent on a transcription factor were often bound by the transcription factor in multiple species yet showed no enhanced DNA sequence constraint. Binding divergence between species can be largely explained by sequence changes to the bound motifs. Among the binding events lost in one lineage, only half are recovered by another binding event within 10 kb. Schmidt et al. (2010) concluded that their results revealed large interspecies differences in transcriptional regulation and provided insight into regulatory evolution.


Nomenclature

According to the nomenclature proposed by Cao et al. (1991), the CCAAT/enhancer-binding protein is C/EBP-alpha and NF-IL6 (LAP) is C/EBP-beta, with the corresponding genes being CEBPA and CEBPB (189965). CEBPB was formerly symbolized TCF5.


Animal Model

Wang et al. (1995) found that mice homozygous for the targeted deletion of the Cebpa gene did not store hepatic glycogen and died from hypoglycemia within 8 hours after birth. In these mutant mice, the amounts of glycogen synthase (138571) mRNA were 50 to 70% of normal and the transcriptional induction of the genes for 2 gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (261680) and glucose-6-phosphatase (613742), was delayed. The hepatocytes and adipocytes of the mutant mice failed to accumulate lipid, and the expression of the gene for uncoupling protein (113730), the defining marker of brown adipose tissue, was reduced. The findings demonstrated that C/EBP-alpha is critical for the establishment and maintenance of energy homeostasis in neonates.

Flodby et al. (1996) made transgenic knockout mice in which the CEBPA gene was selectively disrupted. The homozygous mutant Cebpa -/- mice died, usually within the first 20 hours after birth and had defects in the control of hepatic growth and lung development. Histologic analysis revealed that these animals had severely disturbed liver architecture, with acinar formation, in a pattern suggestive of either regenerating liver or hepatocellular carcinoma. Pulmonary histology showed hyperproliferation of type II pneumocytes and disturbed alveolar architecture. Molecular analysis showed that accumulation of glycogen and lipids in the liver and adipose tissue is impaired and that the mutant animals are severely hypoglycemic. The authors found by Northern blot analysis that levels of c-myc and c-jun RNAs are specifically induced by several fold in the livers of these animals indicating an active proliferative state. They found by immunohistology that cyclin-stained cells are present in the liver of Cebpa -/- mice at a 5 to 10 times higher frequency than normal, also indicating abnormally active proliferation. Flodby et al. (1996) suggested that CEBPA may have an important role in the acquisition and maintenance of terminal differentiation in hepatocytes.

Mice deficient in Cebpa have defective development of adipose tissue. Wu et al. (1999) used fibroblasts from Cebpa -/- mice in combination with retroviral vectors expressing Cebpa and peroxisome proliferator-activated receptor-gamma (PPARG; 601487) to determine the precise role of CEBPA in adipogenesis. The authors found that Cebpa -/- fibroblasts underwent adipose differentiation through expression and activation of Pparg. Cebpa-deficient adipocytes accumulated less lipid and did not induce endogenous Pparg, indicating that cross-regulation between CEBPA and PPARG is important in maintaining the differentiated state. The cells also showed a complete absence of insulin (INS; 176730)-stimulated glucose transport, secondary to reduced gene expression and tyrosine phosphorylation for the Ins receptor (147670) and Ins receptor substrate-1 (147545). Wu et al. (1999) concluded that CEBPA has multiple roles in adipogenesis and that cross-regulation between PPARG and CEBPA is a key component of the transcriptional control of this cell lineage.


ALLELIC VARIANTS 7 Selected Examples):

.0001   LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, 7-BP DEL, NT263
SNP: rs587776848, ClinVar: RCV000019126

In a 42-year-old patient with secondary acute myeloid leukemia (AML; 601626) and in a 49-year-old patient with AML of the M2 subtype, Pabst et al. (2001) found deletion of 7 nucleotides (263_269del7) in the CEBPA gene, resulting in a frameshift and premature termination (Pro39fsTer159).


.0002   LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, GLU50TER
SNP: rs121912791, ClinVar: RCV000019127

In a 67-year-old patient with acute myeloid leukemia (AML; 601626), Pabst et al. (2001) found a 297G-T transversion in the CEBPA gene resulting in a glu50-to-ter (E50X) nonsense mutation.


.0003   LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, HIS84LEU
SNP: rs28931590, ClinVar: RCV000019128

In a 70-year-old patient with acute myeloid leukemia (601626), Pabst et al. (2001) found a 400A-T transversion in the CEBPA gene resulting in a his84-to-leu (H84L) missense mutation.


.0004   LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, 57-BP INS, NT1137
SNP: rs1555741948, ClinVar: RCV000019129

In a 37-year-old man with acute myeloid leukemia (601626) of the M1 subtype, Snaddon et al. (2003) identified homozygosity for a somatic 57-bp insertion after nucleotide 1137 (1137_1138ins57) of the CEBPA gene, which was predicted to cause disruption of the leucine zipper of the protein.


.0005   LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, 27-BP INS, NT1096
SNP: rs1555741967, ClinVar: RCV000019130

In a 72-year-old woman with acute myeloid leukemia (601626) of the M1 subtype, Snaddon et al. (2003) identified compound heterozygosity for 2 somatic mutations in the CEBPA gene: a 27-bp insertion after nucleotide 1096, which was predicted to cause disruption of the leucine zipper, and a 4-bp insertion (363_364insGGCC; 116897.0006), which resulted in a frameshift at ala71 and a truncated protein.


.0006   LEUKEMIA, ACUTE MYELOID, SOMATIC

CEBPA, 4-BP INS, 363GGCC
SNP: rs587776849, ClinVar: RCV000019131

For discussion of the somatic 4-bp insertion (363_364insGGCC) in the CEBPA gene that was found in compound heterozygous state in a patient with acute myeloid leukemia (601626) of the M1 subtype by Snaddon et al. (2003), see 116897.0005.


.0007   LEUKEMIA, ACUTE MYELOID (1 family)

LEUKEMIA, ACUTE MYELOID, SOMATIC
CEBPA, 1-BP DEL, 212C
SNP: rs137852728, gnomAD: rs137852728, ClinVar: RCV000019132

Acute Myeloid Leukemia

In affected members of a family with acute myeloid leukemia (AML; 601626), Smith et al. (2004) identified a germline 1-bp deletion (212delC) in the CEBPA gene, resulting in the presence of 5 cytosine residues in a region where 6 cytosine residues are present in the wildtype sequence. Overt leukemia developed in the father at age 10 years, in the first-born son at age 30 years, and in the last-born daughter at age 18 years.

Acute Myeloid Leukemia, Somatic

In bone marrow samples from 2 cases of sporadic acute myeloid leukemia (601626), Barjesteh van Waalwijk van Doorn-Khosrovani et al. (2003) identified a 1-bp deletion (212delC) in the CEBPA gene.


REFERENCES

  1. Bararia, D., Trivedi, A. K., Zada, A. A. P., Greif, P. A., Mulaw, M. A., Christopeit, M., Hiddemann, W., Bohlander, S. K., Behre, G. Proteomic identification of the MYST domain histone acetyltransferase TIP60 (HTATIP) as a co-activator of the myeloid transcription factor C/EBP-alpha. Leukemia 22: 800-807, 2008. [PubMed: 18239623] [Full Text: https://doi.org/10.1038/sj.leu.2405101]

  2. Barjesteh van Waalwijk van Doorn-Khosrovani, S., Erpelinck, C., Meijer, J., van Oosterhoud, S., van Putten, W. L. J., Valk, P. J. M., Beverloo, H. B., Tenen, D. G., Lowenberg, B., Delwel, R. Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. Hemat. J. 4: 31-40, 2003. [PubMed: 12692518] [Full Text: https://doi.org/10.1038/sj.thj.6200216]

  3. Birkenmeier, E. H., Gwynn, B., Howard, S., Jerry, J., Gordon, J. I., Landschulz, W. H., McKnight, S. L. Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev. 3: 1146-1156, 1989. [PubMed: 2792758] [Full Text: https://doi.org/10.1101/gad.3.8.1146]

  4. Cao, Z., Umek, R. M., McKnight, S. L. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 5: 1538-1552, 1991. [PubMed: 1840554] [Full Text: https://doi.org/10.1101/gad.5.9.1538]

  5. Descombes, P., Chojkier, M., Lichtsteiner, S., Falvey, E., Schibler, U. LAP, a novel member of the C/EBP gene family, encodes a liver-enriched transcriptional activator protein. Genes Dev. 4: 1541-1551, 1990. [PubMed: 2253878] [Full Text: https://doi.org/10.1101/gad.4.9.1541]

  6. Di Ruscio, A., Ebralidze, A. K., Benoukraf, T., Amabile, G., Goff, L. A., Terragni, J., Figueroa, M. E., De Figueiredo Pontes, L. L., Alberich-Jorda, M., Zhang, P., Wu, M., D'Alo, F., Melnick, A., Leone, G., Ebralidze, K. K., Pradhan, S., Rinn, J. L., Tenen, D. G. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 503: 371-376, 2013. [PubMed: 24107992] [Full Text: https://doi.org/10.1038/nature12598]

  7. Di Stefano, B., Sardina, J. L., van Oevelen, C., Collombet, S., Kallin, E. M., Vicent, G. P., Lu, J., Thieffry, D., Beato, M., Graf, T. C/EBP-alpha poises B cells for rapid reprogramming into induced pluripotent stem cells. Nature 506: 235-239, 2014. [PubMed: 24336202] [Full Text: https://doi.org/10.1038/nature12885]

  8. Flodby, P., Barlow, C., Kylefjord, H., Ahrlund-Richter, L., Xanthopoulos, K. G. Increased hepatic cell proliferation and lung abnormalities in mice deficient in CCAAT/enhancer binding protein alpha. J. Biol. Chem. 271: 24753-24760, 1996. [PubMed: 8798745] [Full Text: https://doi.org/10.1074/jbc.271.40.24753]

  9. Helbling, D., Mueller, B. U., Timchenko, N. A., Hagemeijer, A., Jotterand, M., Meyer-Monard, S., Lister, A., Rowley, J. D., Huegli, B., Fey, M. F., Pabst, T. The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of calreticulin. Proc. Nat. Acad. Sci. 101: 13312-13317, 2004. [PubMed: 15326310] [Full Text: https://doi.org/10.1073/pnas.0404731101]

  10. Hendricks-Taylor, L. R., Bachinski, L. L., Siciliano, M. J., Fertitta, A., Trask, B., de Jong, P. J., Ledbetter, D. H., Darlington, G. J. The CCAAT/enhancer binding protein (C/EBP-alpha) gene (CEBPA) maps to human chromosome 19q13.1 and the related nuclear factor NF-IL6 (C/EBP-beta) gene (CEBPB) maps to human chromosome 20q13.1. Genomics 14: 12-17, 1992. [PubMed: 1427819] [Full Text: https://doi.org/10.1016/s0888-7543(05)80276-9]

  11. Landschulz, W. H., Johnson, P. F., McKnight, S. L. The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite. Science 243: 1681-1688, 1989. [PubMed: 2494700] [Full Text: https://doi.org/10.1126/science.2494700]

  12. Menard, C., Hein, P., Paquin, A., Savelson, A., Yang, X. M., Lederfein, D., Barnabe-Heider, F., Mir, A. A., Sterneck, E., Peterson, A. C., Johnson, P. F., Vinson, C., Miller, F. D. An essential role for a MEK-C/EBP pathway during growth factor-regulated cortical neurogenesis. Neuron 36: 597-610, 2002. [PubMed: 12441050] [Full Text: https://doi.org/10.1016/s0896-6273(02)01026-7]

  13. Miller, S. G., De Vos, P., Guerre-Millo, M., Wong, K., Hermann, T., Staels, B., Briggs, M. R., Auwerx, J. The adipocyte specific transcription factor C/EBP-alpha modulates human ob gene expression. Proc. Nat. Acad. Sci. 93: 5507-5511, 1996. [PubMed: 8643605] [Full Text: https://doi.org/10.1073/pnas.93.11.5507]

  14. Pabst, T., Mueller, B. U., Harakawa, N., Schoch, C., Haferlach, T., Behre, G., Hiddemann, W., Zhang, D.-E., Tenen, D. G. AML1-ETO downregulates the granulocytic differentiation factor C/EBP-alpha in t(8;21) myeloid leukemia. Nature Med. 7: 444-451, 2001. [PubMed: 11283671] [Full Text: https://doi.org/10.1038/86515]

  15. Pabst, T., Mueller, B. U., Zhang, P., Radomska, H. S., Narravula, S., Schnittger, S., Behre, G., Hiddemann, W., Tenen, D. G. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBP-alpha), in acute myeloid leukemia. Nature Genet. 27: 263-270, 2001. [PubMed: 11242107] [Full Text: https://doi.org/10.1038/85820]

  16. Reddy, S. D. N., Pakala, S. B., Ohshiro, K., Rayala, S. K., Kumar, R. MicroRNA-661, a c/EBP-alpha target, inhibits metastatic tumor antigen 1 and regulates its functions. Cancer Res. 69: 5639-5642, 2009. [PubMed: 19584269] [Full Text: https://doi.org/10.1158/0008-5472.CAN-09-0898]

  17. Schmidt, D., Wilson, M. D., Ballester, B., Schwalie, P. C., Brown, G. D., Marshall, A., Kutter, C., Watt, S., Martinez-Jimenez, C. P., Mackay, S., Talianidis, I., Flicek, P., Odom, D. T. Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science 328: 1036-1040, 2010. [PubMed: 20378774] [Full Text: https://doi.org/10.1126/science.1186176]

  18. Skokowa, J., Cario, G., Uenalan, M., Schambach, A., Germeshausen, M., Battmer, K., Zeidler, C., Lehmann, U., Eder, M., Baum, C., Grosschedl, R., Stanulla, M., Scherr, M., Welte, K. LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nature Med. 12: 1191-1197, 2006. Note: Erratum: Nature Med. 12: 1329 only, 2006. [PubMed: 17063141] [Full Text: https://doi.org/10.1038/nm1474]

  19. Smith, M. L., Cavenagh, J. D., Lister, T. A., Fitzgibbon, J. Mutation of CEBPA in familial acute myeloid leukemia. New Eng. J. Med. 351: 2403-2407, 2004. [PubMed: 15575056] [Full Text: https://doi.org/10.1056/NEJMoa041331]

  20. Snaddon, J., Smith, M. L., Neat, M., Cambal-Parrales, M., Dixon-McIver, A., Arch, R., Amess, J. A., Rohatiner, A. Z., Lister, T. A., Fitzgibbon, J. Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2. Genes Chromosomes Cancer 37: 72-78, 2003. [PubMed: 12661007] [Full Text: https://doi.org/10.1002/gcc.10185]

  21. Swart, G. W. M., van Groningen, J. J. M., van Ruissen, F., Bergers, M., Schalkwijk, J. Transcription factor C/EBP-alpha: novel sites of expression and cloning of the human gene. Biol. Chem. 378: 373-379, 1997. [PubMed: 9191024] [Full Text: https://doi.org/10.1515/bchm.1997.378.5.373]

  22. Szpirer, C., Riviere, M., Cortese, R., Nakamura, T., Islam, M. Q., Levan, G., Szpirer, J. Chromosomal localization in man and rat of the genes encoding the liver-enriched transcription factors C/EBP, DBP, and HNF1/LFB-1 (CEBP, DBP, and transcription factor 1, TCF1, respectively) and of the hepatocyte growth factor/scatter factor gene (HGF). Genomics 13: 293-300, 1992. [PubMed: 1535333] [Full Text: https://doi.org/10.1016/0888-7543(92)90245-n]

  23. Wang, H., Iakova, P., Wilde, M., Welm, A., Goode, T., Roesler, W. J., Timchenko, N. A. C/EBP-alpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Molec. Cell 8: 817-828, 2001. [PubMed: 11684017] [Full Text: https://doi.org/10.1016/s1097-2765(01)00366-5]

  24. Wang, N., Finegold, M. J., Bradley, A., Ou, C. N., Abdelsayed, S. V., Wilde, M. D., Taylor, L. R., Wilson, D. R., Darlington, G. J. Impaired energy homeostasis in C/EBP-alpha knockout mice. Science 269: 1108-1112, 1995. [PubMed: 7652557] [Full Text: https://doi.org/10.1126/science.7652557]

  25. Wu, Z., Rosen, E. D., Brun, R., Hauser, S., Adelmant, G., Troy, A. E., McKeon, C., Darlington, G. J., Spiegelman, B. M. Cross-regulation of C/EBP-alpha and PPAR-gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Molec. Cell 3: 151-158, 1999. [PubMed: 10078198] [Full Text: https://doi.org/10.1016/s1097-2765(00)80306-8]


Contributors:
Ada Hamosh - updated : 3/13/2014
Ada Hamosh - updated : 12/6/2013
Patricia A. Hartz - updated : 2/2/2011
Ada Hamosh - updated : 6/30/2010
Patricia A. Hartz - updated : 1/20/2010
Ada Hamosh - updated : 10/28/2008
Cassandra L. Kniffin - updated : 10/17/2006
Victor A. McKusick - updated : 3/21/2005
Victor A. McKusick - updated : 12/17/2004
Victor A. McKusick - updated : 7/18/2003
Stylianos E. Antonarakis - updated : 11/13/2001
Stylianos E. Antonarakis - updated : 3/22/1999
Jennifer P. Macke - updated : 11/20/1996
Alan F. Scott - updated : 9/17/1996
Mark H. Paalman - updated : 7/11/1996

Creation Date:
Victor A. McKusick : 10/26/1990

Edit History:
carol : 09/21/2022
carol : 03/06/2018
carol : 04/28/2017
carol : 02/10/2015
mcolton : 2/9/2015
carol : 11/13/2014
carol : 11/13/2014
ckniffin : 11/12/2014
alopez : 3/13/2014
alopez : 12/6/2013
carol : 2/15/2011
mgross : 2/2/2011
mgross : 2/2/2011
alopez : 7/1/2010
terry : 6/30/2010
mgross : 1/20/2010
mgross : 12/5/2008
terry : 10/28/2008
carol : 5/14/2008
wwang : 12/11/2006
wwang : 10/25/2006
ckniffin : 10/17/2006
terry : 5/17/2005
mgross : 3/21/2005
mgross : 3/21/2005
terry : 2/7/2005
tkritzer : 1/11/2005
terry : 12/17/2004
tkritzer : 7/31/2003
tkritzer : 7/30/2003
terry : 7/18/2003
mgross : 11/13/2001
mgross : 11/13/2001
alopez : 3/1/2001
carol : 2/22/2000
mgross : 3/23/1999
mgross : 3/22/1999
psherman : 9/29/1998
alopez : 9/25/1998
terry : 2/21/1998
alopez : 7/10/1997
carol : 6/23/1997
jamie : 2/4/1997
terry : 1/17/1997
jamie : 11/20/1996
mark : 9/17/1996
mark : 7/11/1996
mark : 7/11/1996
terry : 6/28/1996
mark : 10/12/1995
terry : 9/11/1995
carol : 5/26/1993
carol : 4/7/1993
carol : 10/13/1992
carol : 9/25/1992