CCAAT增強子結合蛋白

CCAAT增強子結合蛋白，簡稱C/EBP，是一個由六個成員組成的轉錄因子家族，從C/EBPα到C/EBPζ命名。它們通過與其啟動子的相互作用促進某些基因的表達。一旦與DNA結合，C/EBP就可以招募所謂的共活化因子（例如CBP^[2]^[3]），進而可以打開染色質結構或招募基礎轉錄因子。

功能

C/EBP蛋白與CCAAT（胞嘧啶-胞嘧啶-腺苷-腺苷-胸苷）盒基序相互作用，該基序存在於幾個基因啟動子中。它們的特點是在C端具有高度保守的鹼性白氨酸拉鏈（bZIP）結構域。該結構域與含有白氨酸拉鏈結構域的家族（c-Fos和c-jun）的其他轉錄因子一樣，參與二聚化和DNA結合。 C/EBP的bZIP結構域結構由一個α螺旋組成，當它二聚化時形成一個「盤繞」結構。C/EBP家族的成員可以與其他C/EBP和其他轉錄因子形成同源二聚體或異源二聚體，這些轉錄因子可能包含或不包含白氨酸拉鏈結構域。二聚化是使C/EBP通過DNA大溝中的迴文序列特異性結合DNA所必需的。C/EBP蛋白在N端也含有活化結構域和調節結構域。

這些蛋白質存在於肝細胞、脂肪細胞、造血球、脾、腎、大腦和許多其他器官中。 C/EBP 蛋白參與不同的細胞反應，例如控制細胞增殖、生長和分化、代謝和免疫。幾乎所有C/EBP家族的成員都可以通過其活化結構域與基礎轉錄裝置的成分相互作用來誘導轉錄（C/EBPγ是一個例外，它缺乏功能性轉錄活化結構域）。它們的表達在多個水平上受到調節，包括通過激素、絲裂原、細胞因子、營養和其他因素。

這種蛋白質在哺乳動物的神經系統中表達，在神經細胞的發育和功能中起重要作用。C/EBPβ在神經元分化、學習、記憶過程、神經膠質和神經元細胞功能以及神經營養因子表達中發揮作用。

基因轉錄

C/EBPα、C/EBPβ、C/EBPγ和C/EBPδ基因沒有內含子。C/EBP-ζ有四個外顯子；C/EBPε有兩個，由於啟動子和剪接的替代使用，導致四個同工型。對於C/EBPα和C/EBPβ，可以通過交替使用起始密碼子來產生不同大小的多肽。這被認為是由於核糖體掃描機制較弱。C/EBPα的mRNA可以轉錄成兩種多肽。對於C/EBPβ，製備了三種不同的多肽：LAP*（38kDa）、LAP（35kDa）和LIP（20kDa）。轉譯最多的異構體是LAP，然後是LAP*和LIP。LIP可以通過形成非功能性異二聚體作為其他C/EBP的抑制劑。

調節

C/EBPβ功能受多種機制調節，包括磷酸化、乙酰化、活化、自動調節和通過其他轉錄因子、致癌元件或趨化因子的抑制。C/EBPβ可以與CREB、NF-κB和其他蛋白質相互作用，從而產生反式活化潛力。

C/EBPβ的磷酸化可具有活化或抑制作用。例如，人C/EBPβ中蘇氨酸235的磷酸化或小鼠和大鼠C/EBPβ中蘇氨酸188的磷酸化對C/EBPβ反式活化能力很重要。C/EBPβ在其調節域中的磷酸化也可以調節其功能。

在秀麗隱杆線蟲中表明，cebp-1 mRNA 3'非轉譯區的多個順式元件有助於CEBP-1在神經元發育中的表達。^[4]

臨床意義

在脂肪生成細胞中的作用

C/EBPβ和δ在脂肪細胞分化的早期階段（脂肪細胞生成）被短暫誘導，而C/EBPα在脂肪細胞生成的末期被上調。體外和體內研究表明，每一種都在這一過程中發揮着重要作用。例如，來自缺乏C/EBPβ和C/EBPδ的小鼠的小鼠胚胎纖維母細胞（MEF）顯示出對脂肪形成刺激的反應受損的脂肪細胞分化。^[5]相反，即使在沒有脂肪細胞形成刺激的情況下，3T3-L1前脂肪細胞中C/EBPβ和δ的異位表達也會促進脂肪細胞生成。^[6]^[7]C/EBPβ和δ促進脂肪細胞生成，至少部分是通過誘導「主」脂肪生成轉錄因子C/EBPα和PPAR-γ的表達。

C/EBPα是脂肪細胞生成和正常脂肪細胞功能所必需的。例如，在除肝臟（需要避免產後致死）外的所有組織中缺乏C/EBPα的小鼠顯示出異常的脂肪組織形成。^[8]此外，各種纖維母細胞系中C/EBPα的異位表達促進脂肪細胞生成。^[9]C/EBPα可能通過誘導PPAR-γ的表達來促進脂肪細胞生成。^[10]

在骨質疏鬆症的作用

C/EBPβ已被發現在骨質疏鬆症的發展中起作用。 C/EBPβ蛋白（LAP）的全長同種型活化MafB基因，而短同種型（LIP）抑制它。MafB基因活化抑制破骨細胞的形成。因此，LAP的上調減少了破骨細胞的數量，這削弱了骨質疏鬆過程，而LIP的上調則相反，增加了骨量的損失。

LAP/LIP平衡由mTOR蛋白決定。抑制mTOR的表達可以阻止破骨細胞的活性。^[11]

在癌症中的作用

CCAAT/增強子結合蛋白通常參與生長停滯和分化，這被解釋為表明這些蛋白具有腫瘤抑制活性。然而，CCAAT/增強子結合蛋白的過度表達與膠質母細胞瘤的不良預後相關，並促進宮頸癌的基因組不穩定性，暗示其具有致癌作用。然而，重要的是，C/EBPδ在胰腺導管腺癌中充當腫瘤抑制因子。這是特別令人感興趣的，因為在胰腺癌的背景下僅發現了少數腫瘤抑制因子。^[12]因此，CCAAT/增強子結合蛋白在癌症中的功能明顯依賴於環境，但在很大程度上抑制了腫瘤。

參考文獻

^ Miller M, Shuman JD, Sebastian T, Dauter Z, Johnson PF. Structural basis for DNA recognition by the basic region leucine zipper transcription factor CCAAT/enhancer-binding protein alpha. The Journal of Biological Chemistry. Apr 2003, 278 (17): 15178–84. PMID 12578822. doi:10.1074/jbc.M300417200 .
^ Kovács KA, Steinmann M, Magistretti PJ, Halfon O, Cardinaux JR. CCAAT/enhancer-binding protein family members recruit the coactivator CREB-binding protein and trigger its phosphorylation. The Journal of Biological Chemistry. Sep 2003, 278 (38): 36959–65. PMID 12857754. doi:10.1074/jbc.M303147200 .
^ Ramji DP, Foka P. CCAAT/enhancer-binding proteins: structure, function and regulation. The Biochemical Journal. Aug 2002, 365 (Pt 3): 561–75. PMC 1222736 . PMID 12006103. doi:10.1042/BJ20020508.
^ Sharifnia P, Kim KW, Wu Z, Jin Y. Distinct cis elements in the 3' UTR of the C. elegans cebp-1 mRNA mediate its regulation in neuronal development. Developmental Biology. September 2017, 429 (1): 240–248. PMC 5828015 . PMID 28673818. doi:10.1016/j.ydbio.2017.06.022.
^ Tanaka T, Yoshida N, Kishimoto T, Akira S. Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. The EMBO Journal. Dec 1997, 16 (24): 7432–43. PMC 1170343 . PMID 9405372. doi:10.1093/emboj/16.24.7432.
^ Cao Z, Umek RM, McKnight SL. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes & Development. Sep 1991, 5 (9): 1538–52. PMID 1840554. doi:10.1101/gad.5.9.1538 .
^ Yeh WC, Cao Z, Classon M, McKnight SL. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes & Development. Jan 1995, 9 (2): 168–81. PMID 7531665. doi:10.1101/gad.9.2.168 .
^ Linhart HG, Ishimura-Oka K, DeMayo F, Kibe T, Repka D, Poindexter B, Bick RJ, Darlington GJ. C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. Proceedings of the National Academy of Sciences of the United States of America. Oct 2001, 98 (22): 12532–7. Bibcode:2001PNAS...9812532L. PMC 60088 . PMID 11606718. doi:10.1073/pnas.211416898 .
^ Freytag SO, Paielli DL, Gilbert JD. Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells. Genes & Development. Jul 1994, 8 (14): 1654–63. PMID 7958846. doi:10.1101/gad.8.14.1654 .
^ Clarke SL, Robinson CE, Gimble JM. CAAT/enhancer binding proteins directly modulate transcription from the peroxisome proliferator-activated receptor gamma 2 promoter. Biochemical and Biophysical Research Communications. Nov 1997, 240 (1): 99–103. PMID 9367890. doi:10.1006/bbrc.1997.7627.
^ [1] （頁面存檔備份，存於互聯網檔案館）, Oxytocin Controls Differentiation of Human Mesenchymal Stem Cells and Reverses Osteoporosis
^ Hartl L, Duitman J, Aberson HL, Chen K, Dijk F, Roelofs JJ, Dings MP, Hooijer GK, Hernanda PY, Pan Q, Busch OR, Besselink MG, Boerman T, Peppelenbosch MP, Bijlsma MF, Spek CA. CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells. Cancers (Basel). Sep 2020, 12 (9): 2546. PMC 7564797 . PMID 32906832. doi:10.3390/cancers12092546 .

外部連結

醫學主題詞表（MeSH）：CCAAT-Enhancer-Binding+Proteins

[1] Miller M, Shuman JD, Sebastian T, Dauter Z, Johnson PF. Structural basis for DNA recognition by the basic region leucine zipper transcription factor CCAAT/enhancer-binding protein alpha. The Journal of Biological Chemistry. Apr 2003, 278 (17): 15178–84. PMID 12578822. doi:10.1074/jbc.M300417200 .

[CCAAT-2] Kovács KA, Steinmann M, Magistretti PJ, Halfon O, Cardinaux JR. CCAAT/enhancer-binding protein family members recruit the coactivator CREB-binding protein and trigger its phosphorylation. The Journal of Biological Chemistry. Sep 2003, 278 (38): 36959–65. PMID 12857754. doi:10.1074/jbc.M303147200 .

[enhancer-binding_proteins-3] Ramji DP, Foka P. CCAAT/enhancer-binding proteins: structure, function and regulation. The Biochemical Journal. Aug 2002, 365 (Pt 3): 561–75. PMC 1222736 . PMID 12006103. doi:10.1042/BJ20020508.

[4] Sharifnia P, Kim KW, Wu Z, Jin Y. Distinct cis elements in the 3' UTR of the C. elegans cebp-1 mRNA mediate its regulation in neuronal development. Developmental Biology. September 2017, 429 (1): 240–248. PMC 5828015 . PMID 28673818. doi:10.1016/j.ydbio.2017.06.022.

[adipocyte-5] Tanaka T, Yoshida N, Kishimoto T, Akira S. Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. The EMBO Journal. Dec 1997, 16 (24): 7432–43. PMC 1170343 . PMID 9405372. doi:10.1093/emboj/16.24.7432.

[C/EBP_isoforms-6] Cao Z, Umek RM, McKnight SL. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes & Development. Sep 1991, 5 (9): 1538–52. PMID 1840554. doi:10.1101/gad.5.9.1538 .

[Cascade-7] Yeh WC, Cao Z, Classon M, McKnight SL. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes & Development. Jan 1995, 9 (2): 168–81. PMID 7531665. doi:10.1101/gad.9.2.168 .

[C/EBPalpha-8] Linhart HG, Ishimura-Oka K, DeMayo F, Kibe T, Repka D, Poindexter B, Bick RJ, Darlington GJ. C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. Proceedings of the National Academy of Sciences of the United States of America. Oct 2001, 98 (22): 12532–7. Bibcode:2001PNAS...9812532L. PMC 60088 . PMID 11606718. doi:10.1073/pnas.211416898 .

[Ectopic-9] Freytag SO, Paielli DL, Gilbert JD. Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells. Genes & Development. Jul 1994, 8 (14): 1654–63. PMID 7958846. doi:10.1101/gad.8.14.1654 .

[CAAT/enhancer-10] Clarke SL, Robinson CE, Gimble JM. CAAT/enhancer binding proteins directly modulate transcription from the peroxisome proliferator-activated receptor gamma 2 promoter. Biochemical and Biophysical Research Communications. Nov 1997, 240 (1): 99–103. PMID 9367890. doi:10.1006/bbrc.1997.7627.

[Oxytoxin-11] [1] （頁面存檔備份，存於互聯網檔案館）, Oxytocin Controls Differentiation of Human Mesenchymal Stem Cells and Reverses Osteoporosis

[CAAT/enhancer_in_cancer-12] Hartl L, Duitman J, Aberson HL, Chen K, Dijk F, Roelofs JJ, Dings MP, Hooijer GK, Hernanda PY, Pan Q, Busch OR, Besselink MG, Boerman T, Peppelenbosch MP, Bijlsma MF, Spek CA. CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells. Cancers (Basel). Sep 2020, 12 (9): 2546. PMC 7564797 . PMID 32906832. doi:10.3390/cancers12092546 .

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]