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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''CCAAT/enhancer-binding protein alpha''' is a [[protein]] that in humans is encoded by the ''CEBPA'' [[gene]].<ref name="pmid1535333">{{cite journal | vauthors = Szpirer C, Riviere M, Cortese R, Nakamura T, Islam MQ, Levan G, Szpirer J | title = 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) | journal = Genomics | volume = 13 | issue = 2 | pages = 293–300 | date = July 1992 | pmid = 1535333 | pmc =  | doi = 10.1016/0888-7543(92)90245-N }}</ref><ref name="pmid1840554">{{cite journal | vauthors = Cao Z, Umek RM, McKnight SL | title = Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells | journal = Genes Dev | volume = 5 | issue = 9 | pages = 1538–52 | date = October 1991 | pmid = 1840554 | pmc =  | doi = 10.1101/gad.5.9.1538 }}</ref> CCAAT/enhancer-binding protein alpha is a [[transcription factor]] involved in the differentiation of certain [[Blood cell]]s.<ref>{{Cite web|url=https://ghr.nlm.nih.gov/gene/CEBPA|title=CEBPA|last=|first=|date=April 20, 2016|website=Genetics Home Reference|publisher=|access-date=April 25, 2016}}</ref> For details on the CCAAT motif in [[Enhancer (genetics)|gene enhancers]] and on CCAAT/Enhancer Binding Proteins see the specific [[Ccaat-enhancer-binding proteins|page]].
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image = PBB_Protein_CEBPA_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1nqw.
| PDB = {{PDB2|1nwq}}
| Name = CCAAT/enhancer binding protein (C/EBP), alpha
| HGNCid = 1833
| Symbol = CEBPA
| AltSymbols =; C/EBP-alpha; CEBP
| OMIM = 116897
| ECnumber = 
| Homologene = 3211
| MGIid = 99480
| Function = {{GNF_GO|id=GO:0003705 |text = RNA polymerase II transcription factor activity, enhancer binding}} {{GNF_GO|id=GO:0008134 |text = transcription factor binding}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046983 |text = protein dimerization activity}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006091 |text = generation of precursor metabolites and energy}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006366 |text = transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0019221 |text = cytokine and chemokine mediated signaling pathway}} {{GNF_GO|id=GO:0030099 |text = myeloid cell differentiation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1050
    | Hs_Ensembl = 
    | Hs_RefseqProtein = NP_004355
    | Hs_RefseqmRNA = NM_004364
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 
    | Hs_GenLoc_start = 
    | Hs_GenLoc_end = 
    | Hs_Uniprot = 
    | Mm_EntrezGene = 12606
    | Mm_Ensembl = ENSMUSG00000034957
    | Mm_RefseqmRNA = NM_007678
    | Mm_RefseqProtein = NP_031704
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 7
    | Mm_GenLoc_start = 34828063
    | Mm_GenLoc_end = 34830688
    | Mm_Uniprot = Q3U2H8
  }}
}}
'''CCAAT/enhancer binding protein (C/EBP), alpha''', also known as '''CEBPA''', is a human [[gene]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
The protein encoded by this intronless gene is a [[BZIP domain|bZIP]] [[transcription factor]] which can bind as a homodimer to certain promoters and enhancers. It can also form heterodimers with the related proteins CEBP-beta and CEBP-gamma, as well as distinct transcription factors such as Jun. The encoded protein has been shown to bind to the promoter and modulate the expression of the gene encoding leptin, a protein that plays an important role in body weight homeostasis. Also, the encoded protein can interact with CDK2 and CDK4, thereby inhibiting these kinases and causing growth arrest in cultured cells.<ref>{{cite web | title = Entrez Gene: CEBPA CCAAT/enhancer binding protein (C/EBP), alpha| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1050| accessdate = }}</ref> In addition, CEBPA is essential for myeloid lineage commitment and therefore required both for normal mature granulocyte formation and for the development of abnormal AML.<ref>Ohlsson E, Schuster MB, Hasemann M, Porse BT. The multifaceted functions of C/EBPalpha in normal and malignant haematopoiesis. Leukemia. 2016 Apr;30(4):767-75. PubMed {{PMID|26601784}}.</ref>
{{PBB_Summary
| section_title =
| summary_text = The protein encoded by this intronless gene is a bZIP transcription factor which can bind as a homodimer to certain promoters and enhancers. It can also form heterodimers with the related proteins CEBP-beta and CEBP-gamma. The encoded protein has been shown to bind to the promoter and modulate the expression of the gene encoding leptin, a protein that plays an important role in body weight homeostasis. Also, the encoded protein can interact with CDK2 and CDK4, thereby inhibiting these kinases and causing growth arrest in cultured cells.<ref>{{cite web | title = Entrez Gene: CEBPA CCAAT/enhancer binding protein (C/EBP), alpha| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1050| accessdate = }}</ref>
}}


==See also==
== Common mutations ==
*[[Ccaat-enhancer-binding proteins]]
There are two major categories which CEBPA mutations can be categorized into. One category of mutations prevent CCAAT/enhancer-binding protein alpha DNA binding by altering its COOH-terminal basic leucine zipper domain. The other category of mutations disrupt the translation of the CCAAT/enhancer-binding protein alpha NH<sub>2</sub> terminus. CEBPA mutations, which result in diminished CCATT/enhancer-binding protein alpha activity, contribute to the transformation of myeloid antecedents.<ref name=":0">Lin LI, Chen CY, Lin DT, Tsay W, Tang JL, Yeh YC, et al. Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res 2005;'''11''':1372–9.</ref>


==References==
== Interactions ==
{{reflist|2}}


==Further reading==
CEBPA has been shown to [[Protein-protein interaction|interact]] with [[Cyclin-dependent kinase 2]]<ref name="pmid11684017">{{cite journal | vauthors = Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA | title = C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4 | journal = Mol. Cell | volume = 8 | issue = 4 | pages = 817–28 | date = October 2001 | pmid = 11684017 | doi = 10.1016/S1097-2765(01)00366-5 }}</ref> and [[Cyclin-dependent kinase 4]].<ref name=pmid11684017/>
 
== Clinical significance ==
 
It has been shown that mutation of CEBPA has been linked to good outcome in both adult and pediatric [[acute myeloid leukemia]] patients.<ref name="pmid19304957">{{cite journal | vauthors = Ho PA, Alonzo TA, Gerbing RB, Pollard J, Stirewalt DL, Hurwitz C, Heerema NA, Hirsch B, Raimondi SC, Lange B, Franklin JL, Radich JP, Meshinchi S | title = Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group | journal = Blood | volume = 113 | issue = 26 | pages = 6558–66 | date = June 2009 | pmid = 19304957 | pmc = 2943755 | doi = 10.1182/blood-2008-10-184747 }}</ref>
 
=== Significance in acute myeloid leukemia ===
Acute myeloid leukemia is characterized by genetic abnormalities in hematopoietic progenitors. This includes excessive proliferation of blasts, and blocking the [[hematopoiesis]] of [[Granulocyte|ganulocytes]]. It has been shown that suppression of CEBPA expression and blocking of CCAAT/enhancer-binding protein alpha stops the differentiation of myeloid progenitors. For this reason, CCAAT/enhancer-binding protein alpha's role during granulocyte differentiation and CEBPA's role as a [[tumor suppressor]] gene is critically important in the prognosis of acute myeloid leukemia.<ref>Lin TC, Hou HA, Chou WC, Ou DL, Yu SL, Tien HF ''et al''. (2011). CEBPA methylation as a prognostic biomarker in patients with ''de novo'' acute myeloid leukemia. Leukemia25: 32–40.</ref>
 
=== Prognostic significance of CEBPA mutations ===
CCAAT/enhancer-binding protein alpha, the [[transcription factor]] that is encoded by CEBPA, is very important in the differentiation of immature granulocytes. Mutation of the CEBPA gene has been shown to play a crucial role in leukemogenesis and prognosis in acute myeloid leukemia patients. In recent studies CEBPA mutations were found in between 7% and 15% of patients with acute myeloid leukemia. The three different types of mutations seen in these AML patients include germ-line N-terminal mutation, N-terminal [[frameshift mutation]], and C-terminal mutation. These mutations are most frequently found in acute myeloid leukemia M1 or acute myeloid leukemia M2. Many reports link CEBPA mutations with a favorable outcome in acute myeloid leukemia. This is because these mutations are likely to induce [[Cellular differentiation|differentiation]] arrest in these patients. Patients with CEBPA mutations have longer remission duration and survival time than those without the mutations.<ref name=":0" /> Therefore, the presence of CEBPA mutations are directly associated with a more favorable course for the progression of the disease.<ref>El-Sharnouby JA, Ahmed LM, Taha AM, Kamal O. Prognostic significance of CEBPA mutations and BAALC expression in acute myeloid leukemia Egyptian patients with normal karyotype. Egypt J Immunol. 2010;15:131–143.</ref>
 
=== Significance in solid tumors ===
Recently it has been shown that epigenetic modification of the distal promoter region of CEBPA has resulted in [[downregulation]] of CEBPA expression in pancreatic cancer cells, lung cancer, and head and neck [[squamous cell carcinoma]].<ref>Tada Y, Brena RM, Hackanson B, Morrison C, Otterson GA, Plass C. Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein alpha activity in lung cancer. J Natl Cancer Inst 2006; 98: 396–406.</ref><ref>Bennett KL, Hackanson B, Smith LT, Morrison CD, Lang JC, Schuller DE et al. Tumor suppressor activity of CCAAT/enhancer binding protein alpha is epigenetically down-regulated in head and neck squamous cell carcinoma. Cancer Res 2007; 67: 4657–4664.</ref>
 
=== Methylation of CEBPA as a prognostic biomarker in AML patients ===
A recent study has found that higher levels of CEBPA [[methylation]] are directly proportionate with treatment response. The complete response rate increased proportionately with the level of CEBPA methylation. For this reason it has been proposed that methylation of CEBPA could be a very useful biomarker in acute myeloid leukemia [[prognosis]].<ref>Lin TC, Hou HA, Chou WC, Ou DL, Yu SL, Tien HF et al. (2011). CEBPA methylation as a prognostic [[biomarker]] in patients with de novo acute myeloid leukemia. Leukemia 25: 32–40.</ref>
 
== See also ==
[[Ccaat-enhancer-binding proteins]]
 
== References ==
{{reflist}}
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Sladek FM, Darnell JE | title = Mechanisms of liver-specific gene expression. | journal = Curr. Opin. Genet. Dev. | volume = 2 | issue = 2 | pages = 256–9 | year = 1992 | pmid = 1638120 | doi = 10.1016/S0959-437X(05)80282-5 }}
| citations =
* {{cite journal | vauthors = Marcucci G, Mrózek K, Bloomfield CD | title = Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. | journal = Curr. Opin. Hematol. | volume = 12 | issue = 1 | pages = 68–75 | year = 2005 | pmid = 15604894 | doi = 10.1097/01.moh.0000149608.29685.d1 }}
*{{cite journal | author=Sladek FM, Darnell JE |title=Mechanisms of liver-specific gene expression. |journal=Curr. Opin. Genet. Dev. |volume=2 |issue= 2 |pages= 256-9 |year= 1992 |pmid= 1638120 |doi= }}
* {{cite journal | vauthors = Leroy H, Roumier C, Huyghe P, Biggio V, Fenaux P, Preudhomme C | title = CEBPA point mutations in hematological malignancies | journal = Leukemia | volume = 19 | issue = 3 | pages = 329–34 | date = March 2005 | pmid = 15674366 | doi = 10.1038/sj.leu.2403614 }}
*{{cite journal | author=Marcucci G, Mrózek K, Bloomfield CD |title=Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. |journal=Curr. Opin. Hematol. |volume=12 |issue= 1 |pages= 68-75 |year= 2005 |pmid= 15604894 |doi= }}
*{{cite journal | author=Leroy H, Roumier C, Huyghe P, ''et al.'' |title=CEBPA point mutations in hematological malignancies. |journal=Leukemia |volume=19 |issue= 3 |pages= 329-34 |year= 2005 |pmid= 15674366 |doi= 10.1038/sj.leu.2403614 }}
}}
{{refend}}
{{refend}}


== External links ==
== External links ==
* {{UCSC gene info|CEBPA}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cebpa-aml  GeneReviews/NIH/NCBI/UW entry on Familial Acute Myeloid Leukemia (AML) with Mutated CEBPA]
* {{MeshName|CEBPA+protein,+human}}
* {{MeshName|CEBPA+protein,+human}}
{{PDB Gallery|geneid=1050}}


{{Transcription factors|g1}}
{{NLM content}}
{{NLM content}}
{{protein-stub}}
 
{{DEFAULTSORT:Cebpa}}
[[Category:Transcription factors]]
[[Category:Transcription factors]]
{{Transcription factors}}
{{WikiDoc Sources}}

Revision as of 09:31, 30 August 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

CCAAT/enhancer-binding protein alpha is a protein that in humans is encoded by the CEBPA gene.[1][2] CCAAT/enhancer-binding protein alpha is a transcription factor involved in the differentiation of certain Blood cells.[3] For details on the CCAAT motif in gene enhancers and on CCAAT/Enhancer Binding Proteins see the specific page.

Function

The protein encoded by this intronless gene is a bZIP transcription factor which can bind as a homodimer to certain promoters and enhancers. It can also form heterodimers with the related proteins CEBP-beta and CEBP-gamma, as well as distinct transcription factors such as Jun. The encoded protein has been shown to bind to the promoter and modulate the expression of the gene encoding leptin, a protein that plays an important role in body weight homeostasis. Also, the encoded protein can interact with CDK2 and CDK4, thereby inhibiting these kinases and causing growth arrest in cultured cells.[4] In addition, CEBPA is essential for myeloid lineage commitment and therefore required both for normal mature granulocyte formation and for the development of abnormal AML.[5]

Common mutations

There are two major categories which CEBPA mutations can be categorized into. One category of mutations prevent CCAAT/enhancer-binding protein alpha DNA binding by altering its COOH-terminal basic leucine zipper domain. The other category of mutations disrupt the translation of the CCAAT/enhancer-binding protein alpha NH2 terminus. CEBPA mutations, which result in diminished CCATT/enhancer-binding protein alpha activity, contribute to the transformation of myeloid antecedents.[6]

Interactions

CEBPA has been shown to interact with Cyclin-dependent kinase 2[7] and Cyclin-dependent kinase 4.[7]

Clinical significance

It has been shown that mutation of CEBPA has been linked to good outcome in both adult and pediatric acute myeloid leukemia patients.[8]

Significance in acute myeloid leukemia

Acute myeloid leukemia is characterized by genetic abnormalities in hematopoietic progenitors. This includes excessive proliferation of blasts, and blocking the hematopoiesis of ganulocytes. It has been shown that suppression of CEBPA expression and blocking of CCAAT/enhancer-binding protein alpha stops the differentiation of myeloid progenitors. For this reason, CCAAT/enhancer-binding protein alpha's role during granulocyte differentiation and CEBPA's role as a tumor suppressor gene is critically important in the prognosis of acute myeloid leukemia.[9]

Prognostic significance of CEBPA mutations

CCAAT/enhancer-binding protein alpha, the transcription factor that is encoded by CEBPA, is very important in the differentiation of immature granulocytes. Mutation of the CEBPA gene has been shown to play a crucial role in leukemogenesis and prognosis in acute myeloid leukemia patients. In recent studies CEBPA mutations were found in between 7% and 15% of patients with acute myeloid leukemia. The three different types of mutations seen in these AML patients include germ-line N-terminal mutation, N-terminal frameshift mutation, and C-terminal mutation. These mutations are most frequently found in acute myeloid leukemia M1 or acute myeloid leukemia M2. Many reports link CEBPA mutations with a favorable outcome in acute myeloid leukemia. This is because these mutations are likely to induce differentiation arrest in these patients. Patients with CEBPA mutations have longer remission duration and survival time than those without the mutations.[6] Therefore, the presence of CEBPA mutations are directly associated with a more favorable course for the progression of the disease.[10]

Significance in solid tumors

Recently it has been shown that epigenetic modification of the distal promoter region of CEBPA has resulted in downregulation of CEBPA expression in pancreatic cancer cells, lung cancer, and head and neck squamous cell carcinoma.[11][12]

Methylation of CEBPA as a prognostic biomarker in AML patients

A recent study has found that higher levels of CEBPA methylation are directly proportionate with treatment response. The complete response rate increased proportionately with the level of CEBPA methylation. For this reason it has been proposed that methylation of CEBPA could be a very useful biomarker in acute myeloid leukemia prognosis.[13]

See also

Ccaat-enhancer-binding proteins

References

  1. ↑ Szpirer C, Riviere M, Cortese R, Nakamura T, Islam MQ, Levan G, Szpirer J (July 1992). "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 (2): 293–300. doi:10.1016/0888-7543(92)90245-N. PMID 1535333.
  2. ↑ Cao Z, Umek RM, McKnight SL (October 1991). "Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells". Genes Dev. 5 (9): 1538–52. doi:10.1101/gad.5.9.1538. PMID 1840554.
  3. ↑ "CEBPA". Genetics Home Reference. April 20, 2016. Retrieved April 25, 2016.
  4. ↑ "Entrez Gene: CEBPA CCAAT/enhancer binding protein (C/EBP), alpha".
  5. ↑ Ohlsson E, Schuster MB, Hasemann M, Porse BT. The multifaceted functions of C/EBPalpha in normal and malignant haematopoiesis. Leukemia. 2016 Apr;30(4):767-75. PubMed PMID 26601784.
  6. ↑ 6.0 6.1 Lin LI, Chen CY, Lin DT, Tsay W, Tang JL, Yeh YC, et al. Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res 2005;11:1372–9.
  7. ↑ 7.0 7.1 Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA (October 2001). "C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4". Mol. Cell. 8 (4): 817–28. doi:10.1016/S1097-2765(01)00366-5. PMID 11684017.
  8. ↑ Ho PA, Alonzo TA, Gerbing RB, Pollard J, Stirewalt DL, Hurwitz C, Heerema NA, Hirsch B, Raimondi SC, Lange B, Franklin JL, Radich JP, Meshinchi S (June 2009). "Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group". Blood. 113 (26): 6558–66. doi:10.1182/blood-2008-10-184747. PMC 2943755. PMID 19304957.
  9. ↑ Lin TC, Hou HA, Chou WC, Ou DL, Yu SL, Tien HF et al. (2011). CEBPA methylation as a prognostic biomarker in patients with de novo acute myeloid leukemia. Leukemia25: 32–40.
  10. ↑ El-Sharnouby JA, Ahmed LM, Taha AM, Kamal O. Prognostic significance of CEBPA mutations and BAALC expression in acute myeloid leukemia Egyptian patients with normal karyotype. Egypt J Immunol. 2010;15:131–143.
  11. ↑ Tada Y, Brena RM, Hackanson B, Morrison C, Otterson GA, Plass C. Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein alpha activity in lung cancer. J Natl Cancer Inst 2006; 98: 396–406.
  12. ↑ Bennett KL, Hackanson B, Smith LT, Morrison CD, Lang JC, Schuller DE et al. Tumor suppressor activity of CCAAT/enhancer binding protein alpha is epigenetically down-regulated in head and neck squamous cell carcinoma. Cancer Res 2007; 67: 4657–4664.
  13. ↑ Lin TC, Hou HA, Chou WC, Ou DL, Yu SL, Tien HF et al. (2011). CEBPA methylation as a prognostic biomarker in patients with de novo acute myeloid leukemia. Leukemia 25: 32–40.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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