CEBPA

CCAAT/強化子結合蛋白α，簡稱C/EBP-α或CEBPA是一種由人類CEBPA基因編碼的蛋白質。^[6][7]CEBPA是參與某些血球分化的轉錄因子。^[8]有關基因強化子中的CCAAT結構基序和CCAAT/強化子結合蛋白的詳細資訊，請參見特定頁面。

CEBPA
識別號
別名	CEBPA；, C/EBP-alpha, CEBP, CCAAT/enhancer binding protein alpha, CCAAT enhancer binding protein alpha
外部ID	OMIM：116897 MGI：99480 HomoloGene：3211 GeneCards：CEBPA
相關疾病
急性骨髓性白血病[1]
基因位置（人類） 染色體 19號染色體[2] 基因座 19q13.11 起始 33,299,934 bp[2] 終止 33,302,534 bp[2]
基因位置（小鼠） 染色體 小鼠7號染色體[3] 基因座 7 B2|7 21.02 cM 起始 34,818,718 bp[3] 終止 34,821,353 bp[3]
基因本體 分子功能 • DNA結合 • sequence-specific DNA binding • protein homodimerization activity • DNA-binding transcription activator activity, RNA polymerase II-specific • DNA結合轉錄因子活性 • 轉錄共活化因子活性 • 轉錄因子結合 • RNA polymerase II cis-regulatory region sequence-specific DNA binding • 激酶結合 • 血漿蛋白結合 • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding • DNA-binding transcription factor activity, RNA polymerase II-specific 細胞組分 • 轉錄調節複合物 • RNA polymerase II transcription regulator complex • 核仁 • 細胞核 • 核質 • 細胞內膜結合胞器 生物學過程 • Notch信號通路 • 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 • 尿素循環 • 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 • 內耳的發生 • 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 pathway Sources:Amigo / QuickGO
直系同源
物種	人類	小鼠
Entrez	1050	12606
Ensembl	ENSG00000245848	ENSMUSG00000034957
UniProt	P49715	P53566
mRNA​序列	NM_004364 ​NM_001285829 ​NM_001287424 ​NM_001287435	NM_001287514 ​NM_001287515 ​NM_001287521 ​NM_001287523 ​NM_007678
蛋白序列	NP_001272758 ​NP_001274353 ​NP_001274364 ​NP_004355	NP_001274443 ​NP_001274444 ​NP_001274450 ​NP_001274452 ​NP_031704
基因位置​（UCSC）	Chr 19: 33.3 – 33.3 Mb	Chr 7: 34.82 – 34.82 Mb
PubMed​查找	[4]	[5]
維基資料
檢視/編輯人類 檢視/編輯小鼠

功能

這種無內含子基因編碼的蛋白質是一種bZIP轉錄因子，它可以作為同源二聚體與某些啟動子和基因強化子結合。它還可以與相關蛋白C/EBP-β和C/EBP-γ以及不同的轉錄因子如c-Jun形成異二聚體。編碼的蛋白質是脂肪細胞生成和這些細胞中脂質積累以及肝臟中葡萄糖和脂質代謝的關鍵調節因子。^[9]該蛋白質已被證明與啟動子結合併調節編碼瘦蛋白的基因的表現，瘦蛋白是一種在體重穩態中起重要作用的蛋白質。此外，編碼的蛋白質可以與CDK2和CDK4相互作用，從而抑制這些激酶並導致培養的細胞停止分裂。^[10]此外，CEBPA對骨髓譜系定型至關重要，因此對於正常成熟顆粒球的形成和異常急性骨髓性白血病的發展都是必需的。^[11]

常見突變

CEBPA突變可分為兩大類。一類突變通過改變其COOH末端鹼性白胺酸拉鏈結構域來阻止CEBPA的DNA結合。另一類突變破壞了CEBPA的NH₂末端的轉譯。 CEBPA突變導致CEBPA活性降低，有助於骨髓前體的轉化。^[12]

相互作用

CEBPA已被證明與週期素依賴性激酶2相互作用^[13]和週期素依賴性激酶4。^[13]

臨床意義

CEBPA的突變已被證明與成人和兒童急性骨髓性白血病患者的良好結果有關。^[14]

在急性骨髓性白血病中的意義

急性骨髓性白血病的特徵在於造血祖細胞的遺傳異常。這包括原始細胞的過度增殖，以及阻止顆粒球的造血。已經表明，抑制CEBPA表現和阻斷CEBPA會阻止骨髓祖細胞的分化。出於這個原因，CEBPA在顆粒球分化過程中的作用和CEBPA作為腫瘤抑制基因的作用在急性髓細胞白血病的預後中至關重要。^[15]

CEBPA突變的預後意義

CEBPA在未成熟顆粒球的分化中非常重要。CEBPA基因的突變已被證明在急性骨髓性白血病患者的白血病發生和預後中起關鍵作用。在最近的研究中，在7%到15%的急性骨髓性白血病患者中發現了CEBPA突變。在這些急性骨髓性白血病患者中看到的三種不同類型的突變包括種系N末端突變、N末端框移突變和C末端突變。這些突變最常見於急性骨髓性白血病M1或M2。許多報道將CEBPA突變與急性骨髓細胞白血病的良好結果聯繫起來。這是因為這些突變可能會導致這些患者的分化停滯。有CEBPA突變的患者比沒有突變的患者有更長的緩解持續時間和生存時間。^[12]因此，CEBPA突變的存在與疾病進展的更有利過程直接相關。^[16]

在實體瘤中的意義

最近顯示，CEBPA遠端啟動子區域的表觀遺傳修飾導致胰腺癌細胞、肺癌和頭頸部鱗狀細胞癌中CEBPA表現下調。^[17][18]

CEBPA的甲基化作為急性骨髓性白血病患者的預後生物標記

最近的一項研究發現，較高水平的CEBPA甲基化與治療反應成正比。完全反應率與CEBPA甲基化水平成比例增加。出於這個原因，有人提出CEBPA的甲基化可能是急性髓細胞白血病預後中非常有用的生物標記。^[19]

參考文獻

1. 與CEBPA相關的疾病；在維基數據上查看/編輯參考.
2. GRCh38: Ensembl release 89: ENSG00000245848 - Ensembl, May 2017
3. GRCm38: Ensembl release 89: ENSMUSG00000034957 - Ensembl, May 2017
4. Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
6. Szpirer C, Riviere M, Cortese R, Nakamura T, Islam MQ, 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. July 1992, 13 (2): 293–300. PMID 1535333. doi:10.1016/0888-7543(92)90245-N.
7. Cao Z, Umek RM, McKnight SL. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. October 1991, 5 (9): 1538–52. PMID 1840554. doi:10.1101/gad.5.9.1538 .
8. CEBPA. Genetics Home Reference. April 20, 2016 [April 25, 2016].
9. Olofsson LE, Orho-Melander M, William-Olsson L, Sjöholm K, Sjöström L, Groop L, Carlsson B, Carlsson LM, Olsson B. 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. 1 December 2009, 93 (12): 4880–4886. PMID 18765514. doi:10.1210/jc.2008-0574 .
10. Entrez Gene: CEBPA CCAAT/enhancer binding protein (C/EBP), alpha.
11. Ohlsson E, Schuster MB, Hasemann M, Porse BT. The multifaceted functions of C/EBPalpha in normal and malignant haematopoiesis. Leukemia. Apr 2016, 30 (4): 767–75. PMID 26601784. S2CID 24767947. doi:10.1038/leu.2015.324.
12. 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 (4): 1372–9. PMID 15746035. doi:10.1158/1078-0432.ccr-04-1816 .
13. Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA. C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Mol. Cell. October 2001, 8 (4): 817–28. PMID 11684017. doi:10.1016/S1097-2765(01)00366-5 .
14. 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. Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. Blood. June 2009, 113 (26): 6558–66. PMC 2943755 . PMID 19304957. doi:10.1182/blood-2008-10-184747.
15. Lin TC, Hou HA, Chou WC, Ou DL, Yu SL, Tien HF, et al. CEBPA methylation as a prognostic biomarker in patients with de novo acute myeloid leukemia. Leukemia. 2011, 25 (1): 32–40. PMID 20927134. doi:10.1038/leu.2010.222 .
16. 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.
17. 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 (6): 396–406. PMID 16537832. doi:10.1093/jnci/djj093 .
18. 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 (10): 4657–4664. PMID 17510391. doi:10.1158/0008-5472.can-06-4793 .
19. Lin TC, Hou HA, Chou WC, Ou DL, Yu SL, Tien HF, et al. CEBPA methylation as a prognostic biomarker in patients with de novo acute myeloid leukemia. Leukemia. 2011, 25 (1): 32–40. PMID 20927134. doi:10.1038/leu.2010.222 .

閱讀

• Sladek FM, Darnell JE. Mechanisms of liver-specific gene expression.. Curr. Opin. Genet. Dev. 1992, 2 (2): 256–9. PMID 1638120. doi:10.1016/S0959-437X(05)80282-5.
• Marcucci G, Mrózek K, Bloomfield CD. Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics.. Curr. Opin. Hematol. 2005, 12 (1): 68–75. PMID 15604894. S2CID 6183391. doi:10.1097/01.moh.0000149608.29685.d1.
• Leroy H, Roumier C, Huyghe P, Biggio V, Fenaux P, Preudhomme C. CEBPA point mutations in hematological malignancies. Leukemia. March 2005, 19 (3): 329–34. PMID 15674366. doi:10.1038/sj.leu.2403614 .

外部連結

• Human CEBPA genome location and CEBPA gene details page in the UCSC Genome Browser（英語：UCSC Genome Browser）.
• GeneReviews/NIH/NCBI/UW entry on Familial Acute Myeloid Leukemia (AML) with Mutated CEBPA （頁面存檔備份，存於網際網路檔案館）
• 醫學主題詞表（MeSH）：CEBPA+protein,+human