The protein encoded by this intronless gene is a bZIPtranscription factor which can bind as a homodimer to certain promoters and gene enhancers. It can also form heterodimers with the related proteins CEBP-beta and CEBP-gamma, as well as distinct transcription factors such as c-Jun. The encoded protein is a key regulator of adipogenesis (the process of forming new fat cells) and the accumulation of lipids in those cells, as well as in the metabolism of glucose and lipids in the liver.[8] The 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 cultured cells to stop dividing.[9] In addition, CEBPA is essential for myeloid lineage commitment and therefore required both for normal mature granulocyte formation and for the development of abnormal acute myeloid leukemia.[10]
Common mutationsEdit
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 CCAAT/enhancer-binding protein alpha activity, contribute to the transformation of myeloid antecedents.[11]
It has been shown that mutation of CEBPA has been linked to good outcome in both adult and pediatric acute myeloid leukemia patients.[13]
Significance in acute myeloid leukemiaEdit
Acute myeloid leukemia is characterized by genetic abnormalities in hematopoietic progenitors. This includes excessive proliferation of blasts, and blocking the hematopoiesis of granulocytes. 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.[14]
Prognostic significance of CEBPA mutationsEdit
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.[11] Therefore, the presence of CEBPA mutations are directly associated with a more favorable course for the progression of the disease.[15]
Significance in solid tumorsEdit
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.[16][17]
Methylation of CEBPA as a prognostic biomarker in AML patientsEdit
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.[18]
^ abcGRCh38: Ensembl release 89: ENSG00000245848 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000034957 - Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.
^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.
^"CEBPA". Genetics Home Reference. April 20, 2016. Retrieved April 25, 2016.
^Olofsson LE, Orho-Melander M, William-Olsson L, Sjöholm K, Sjöström L, Groop L, Carlsson B, Carlsson LM, Olsson B (1 December 2009). "CCAAT/enhancer binding protein alpha (C/EBPalpha) in adipose tissue regulates genes in lipid and glucose metabolism and a genetic variation in C/EBPalpha is associated with serum levels of triglycerides". The Journal of Clinical Endocrinology & Metabolism. 93 (12): 4880–4886. doi:10.1210/jc.2008-0574. PMID 18765514.
^"Entrez Gene: CEBPA CCAAT/enhancer binding protein (C/EBP), alpha".
^Ohlsson E, Schuster MB, Hasemann M, Porse BT (Apr 2016). "The multifaceted functions of C/EBPalpha in normal and malignant haematopoiesis". Leukemia. 30 (4): 767–75. doi:10.1038/leu.2015.324. PMID 26601784. S2CID 24767947.
^ abLin LI, Chen CY, Lin DT, Tsay W, Tang JL, Yeh YC, et al. (2005). ""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. 11 (4): 1372–9. doi:10.1158/1078-0432.ccr-04-1816. PMID 15746035.
^ abWang 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.
^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. PMC2943755. PMID 19304957.
^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 (1): 32–40. doi:10.1038/leu.2010.222. PMID 20927134.
^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.
^Tada Y, Brena RM, Hackanson B, Morrison C, Otterson GA, Plass C (2006). "Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein alpha activity in lung cancer". J Natl Cancer Inst. 98 (6): 396–406. doi:10.1093/jnci/djj093. PMID 16537832.
^Bennett KL, Hackanson B, Smith LT, Morrison CD, Lang JC, Schuller DE, et al. (2007). "Tumor suppressor activity of CCAAT/enhancer binding protein alpha is epigenetically down-regulated in head and neck squamous cell carcinoma". Cancer Res. 67 (10): 4657–4664. doi:10.1158/0008-5472.can-06-4793. PMID 17510391.
^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 (1): 32–40. doi:10.1038/leu.2010.222. PMID 20927134.
Further readingEdit
Sladek FM, Darnell JE (1992). "Mechanisms of liver-specific gene expression". Curr. Opin. Genet. Dev. 2 (2): 256–9. doi:10.1016/S0959-437X(05)80282-5. PMID 1638120.
Marcucci G, Mrózek K, Bloomfield CD (2005). "Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics". Curr. Opin. Hematol. 12 (1): 68–75. doi:10.1097/01.moh.0000149608.29685.d1. PMID 15604894. S2CID 6183391.
Leroy H, Roumier C, Huyghe P, Biggio V, Fenaux P, Preudhomme C (March 2005). "CEBPA point mutations in hematological malignancies". Leukemia. 19 (3): 329–34. doi:10.1038/sj.leu.2403614. PMID 15674366.
External linksEdit
Human CEBPA genome location and CEBPA gene details page in the UCSC Genome Browser.
GeneReviews/NIH/NCBI/UW entry on Familial Acute Myeloid Leukemia (AML) with Mutated CEBPA
cebpa, ccaat, enhancer, binding, protein, alpha, protein, encoded, gene, humans, ccaat, enhancer, binding, protein, alpha, transcription, factor, involved, differentiation, certain, blood, cells, details, ccaat, structural, motif, gene, enhancers, ccaat, enhan. CCAAT enhancer binding protein alpha is a protein encoded by the CEBPA gene in humans 5 6 CCAAT enhancer binding protein alpha is a transcription factor involved in the differentiation of certain blood cells 7 For details on the CCAAT structural motif in gene enhancers and on CCAAT Enhancer Binding Proteins see the specific page CEBPAIdentifiersAliasesCEBPA C EBP alpha CEBP CCAAT enhancer binding protein alpha CCAAT enhancer binding protein alphaExternal IDsOMIM 116897 MGI 99480 HomoloGene 3211 GeneCards CEBPAGene location Human Chr Chromosome 19 human 1 Band19q13 11Start33 299 934 bp 1 End33 302 534 bp 1 Gene location Mouse Chr Chromosome 7 mouse 2 Band7 B2 7 21 02 cMStart34 818 718 bp 2 End34 821 353 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed innipplehuman penisskin of abdomenright lobe of livermonocyteadipose tissuesubcutaneous adipose tissuevulvaabdominal fatsynovial jointTop expressed inbrown adipose tissuesubcutaneous adipose tissuewhite adipose tissuelipright lunggallbladderskin of backleft lobe of liverright lung lobeskin of abdomenMore reference expression dataBioGPSn aGene ontologyMolecular functionDNA binding sequence specific DNA binding protein homodimerization activity DNA binding transcription activator activity RNA polymerase II specific DNA binding transcription factor activity transcription coactivator activity transcription factor binding RNA polymerase II cis regulatory region sequence specific DNA binding kinase binding protein binding transcription factor activity RNA polymerase II distal enhancer sequence specific binding DNA binding transcription factor activity RNA polymerase II specificCellular componenttranscription regulator complex RNA polymerase II transcription regulator complex nucleolus nucleus nucleoplasm intracellular membrane bounded organelleBiological processNotch signaling pathway transcription by RNA polymerase I myeloid cell differentiation regulation of transcription DNA templated cellular response to lithium ion glucose homeostasis negative regulation of cyclin dependent protein serine threonine kinase activity lung development cytokine mediated signaling pathway urea cycle regulation of transcription by RNA polymerase II cellular response to organic cyclic compound mitochondrion organization embryonic placenta development cholesterol metabolic process negative regulation of cell cycle negative regulation of transcription by RNA polymerase II cell maturation generation of precursor metabolites and energy transcription DNA templated macrophage differentiation multicellular organism development positive regulation of transcription DNA templated positive regulation of osteoblast differentiation granulocyte differentiation regulation of cell population proliferation brown fat cell differentiation lipid homeostasis white fat cell differentiation inner ear development liver development viral process negative regulation of transcription DNA templated positive regulation of fat cell differentiation positive regulation of transcription by RNA polymerase III fat cell differentiation positive regulation of proteasomal ubiquitin dependent protein catabolic process positive regulation of transcription by RNA polymerase II negative regulation of cell population proliferation transcription by RNA polymerase II cellular response to tumor necrosis factor positive regulation of DNA templated transcription initiation positive regulation of macrophage activation positive regulation of inflammatory response interleukin 6 mediated signaling pathwaySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez105012606EnsemblENSG00000245848ENSMUSG00000034957UniProtP49715P53566RefSeq mRNA NM 004364NM 001285829NM 001287424NM 001287435NM 001287514NM 001287515NM 001287521NM 001287523NM 007678RefSeq protein NP 001272758NP 001274353NP 001274364NP 004355NP 001274443NP 001274444NP 001274450NP 001274452NP 031704Location UCSC Chr 19 33 3 33 3 MbChr 7 34 82 34 82 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Function 2 Common mutations 3 Interactions 4 Clinical significance 4 1 Significance in acute myeloid leukemia 4 2 Prognostic significance of CEBPA mutations 4 3 Significance in solid tumors 4 4 Methylation of CEBPA as a prognostic biomarker in AML patients 5 See also 6 References 7 Further reading 8 External linksFunction EditThe protein encoded by this intronless gene is a bZIP transcription factor which can bind as a homodimer to certain promoters and gene enhancers It can also form heterodimers with the related proteins CEBP beta and CEBP gamma as well as distinct transcription factors such as c Jun The encoded protein is a key regulator of adipogenesis the process of forming new fat cells and the accumulation of lipids in those cells as well as in the metabolism of glucose and lipids in the liver 8 The 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 cultured cells to stop dividing 9 In addition CEBPA is essential for myeloid lineage commitment and therefore required both for normal mature granulocyte formation and for the development of abnormal acute myeloid leukemia 10 Common mutations EditThere 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 CCAAT enhancer binding protein alpha activity contribute to the transformation of myeloid antecedents 11 Interactions EditCEBPA has been shown to interact with Cyclin dependent kinase 2 12 and Cyclin dependent kinase 4 12 Clinical significance EditIt has been shown that mutation of CEBPA has been linked to good outcome in both adult and pediatric acute myeloid leukemia patients 13 Significance in acute myeloid leukemia Edit Acute myeloid leukemia is characterized by genetic abnormalities in hematopoietic progenitors This includes excessive proliferation of blasts and blocking the hematopoiesis of granulocytes 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 14 Prognostic significance of CEBPA mutations Edit 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 11 Therefore the presence of CEBPA mutations are directly associated with a more favorable course for the progression of the disease 15 Significance in solid tumors Edit 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 16 17 Methylation of CEBPA as a prognostic biomarker in AML patients Edit 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 18 See also EditCcaat enhancer binding proteinsReferences Edit a b c GRCh38 Ensembl release 89 ENSG00000245848 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000034957 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine 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 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 CEBPA Genetics Home Reference April 20 2016 Retrieved April 25 2016 Olofsson LE Orho Melander M William Olsson L Sjoholm K Sjostrom L Groop L Carlsson B Carlsson LM Olsson B 1 December 2009 CCAAT enhancer binding protein alpha C EBPalpha in adipose tissue regulates genes in lipid and glucose metabolism and a genetic variation in C EBPalpha is associated with serum levels of triglycerides The Journal of Clinical Endocrinology amp Metabolism 93 12 4880 4886 doi 10 1210 jc 2008 0574 PMID 18765514 Entrez Gene CEBPA CCAAT enhancer binding protein C EBP alpha Ohlsson E Schuster MB Hasemann M Porse BT Apr 2016 The multifaceted functions of C EBPalpha in normal and malignant haematopoiesis Leukemia 30 4 767 75 doi 10 1038 leu 2015 324 PMID 26601784 S2CID 24767947 a b Lin LI Chen CY Lin DT Tsay W Tang JL Yeh YC et al 2005 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 11 4 1372 9 doi 10 1158 1078 0432 ccr 04 1816 PMID 15746035 a b 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 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 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 1 32 40 doi 10 1038 leu 2010 222 PMID 20927134 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 Tada Y Brena RM Hackanson B Morrison C Otterson GA Plass C 2006 Epigenetic modulation of tumor suppressor CCAAT enhancer binding protein alpha activity in lung cancer J Natl Cancer Inst 98 6 396 406 doi 10 1093 jnci djj093 PMID 16537832 Bennett KL Hackanson B Smith LT Morrison CD Lang JC Schuller DE et al 2007 Tumor suppressor activity of CCAAT enhancer binding protein alpha is epigenetically down regulated in head and neck squamous cell carcinoma Cancer Res 67 10 4657 4664 doi 10 1158 0008 5472 can 06 4793 PMID 17510391 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 1 32 40 doi 10 1038 leu 2010 222 PMID 20927134 Further reading EditSladek FM Darnell JE 1992 Mechanisms of liver specific gene expression Curr Opin Genet Dev 2 2 256 9 doi 10 1016 S0959 437X 05 80282 5 PMID 1638120 Marcucci G Mrozek K Bloomfield CD 2005 Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics Curr Opin Hematol 12 1 68 75 doi 10 1097 01 moh 0000149608 29685 d1 PMID 15604894 S2CID 6183391 Leroy H Roumier C Huyghe P Biggio V Fenaux P Preudhomme C March 2005 CEBPA point mutations in hematological malignancies Leukemia 19 3 329 34 doi 10 1038 sj leu 2403614 PMID 15674366 External links EditHuman CEBPA genome location and CEBPA gene details page in the UCSC Genome Browser GeneReviews NIH NCBI UW entry on Familial Acute Myeloid Leukemia AML with Mutated CEBPA CEBPA protein human at the U S National Library of Medicine Medical Subject Headings MeSH This article incorporates text from the United States National Library of Medicine which is in the public domain Retrieved from https en wikipedia org w index php title CEBPA amp oldid 1079159100, wikipedia, wiki, book, books, library,
