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研究生：	王文玲 Wang, Wen-Ling
論文名稱：	HDAC4參與sumoylation修飾之LAP1所抑制的COX-2基因轉錄 HDAC4 is involved in the sumoylated LAP1-mediated COX-2 gene inactivation
指導教授：	張文昌 Chang, Wen-Chang 王育民 Wang, Ju-Ming
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2009
畢業學年度：	97
語文別：	英文
論文頁數：	87
中文關鍵詞：	CEBPB 、環氧酵素二型、SUMO修飾、發炎、LAP1 、CEBPD
外文關鍵詞：	LAP1, CEBPB, CEBPD, inflammation, sumoylation, COX-2
相關次數：	點閱：146 下載：1
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在發炎組織及癌化過程中，環氧酵素二型(Cyclooxygenase-2,COX-2) 會被誘導表現增加並且扮演重要角色，將花生四烯酸(Arachidonic acid) 代謝產生前列腺素(Prostaglandins)。根據本實驗室先前的研究結果顯示，表皮生長因子(Epidermal growth factor, EGF)調控COX-2基因表現的機轉是經由誘導轉錄因子CCAAT/enhancer-binding protein delta (CEBPD)和c-Jun/c-Fos表現增加，之後兩者會結合至COX-2啟動區的C/EBP和CRE結合序列而促使 COX-2表現增加。本研究目的為進一步探討經EGF長時間刺激人類子宮頸上皮細胞癌細胞株A431細胞之後，轉錄因子CEBPB如何參與調控COX-2基因表現之機制。CEBPB屬於CCAAT/enhancer binding protein (C/EBP)家族之一員，它是ㄧ重要轉錄因子參與調控與免疫反應以及脂肪細胞和肝臟細胞生成過程中相關基因的表現。首先研究結果發現，隨著EGF處理時間增加，CEBPB mRNA及蛋白質亦被誘導表現(3~15小時)增加，同時觀察COX-2表現，發現COX-2 mRNA及蛋白質表現隨著CEBPB表現增加而減少。利用CEBPB siRNA有效抑制內生性CEBPB的表現，在EGF處理情況下可提高COX-2 基因轉錄以及加強COX-2基因啟動區活性，此外分別外送CEBPB成員的表現載體，發現不論LAP1、LAP2或LIP均可減弱EGF誘導的COX-2啟動子的活性。根據以上結果推測在EGF處理長時間的情況下，延遲增加的CEBPB可能扮演一個轉錄抑制者角色而抑制COX-2基因表現。此外實驗證明，隨著EGF處理A431細胞時間增加可誘導LAP1和LAP2表現並且增加它們的SUMO修飾(sumoylation)。進一步以COX-2啟動區之報告基因分析SUMO修飾的LAP1和LAP2對COX-2基因活性之影響，結果顯示只有LAP1而非LAP2是透過SUMO修飾的機制而抑制COX-2基因表現。然而，在EGF處理的延遲時期，LAP1、LAP2和LIP的表現以及它們結合至C/EBP和CRE/E box結合序列的量均明顯增加，同時發現HDAC4亦可結合至此兩個序列上且模式與CEBPBs是一致的。進一步觀察HDAC4和SUMO1在細胞內分布，發現EGF會促進此兩蛋白在細胞核和細胞質之間移動，接著分析HDAC4的功能，則證實它可與LAP1相互作用並負向調控COX-2基因表現，而LAP1K174A是LAP1 sumoylation修飾缺失的突變株則喪失與HDAC4的交互作用且無法抑制COX-2基因啟動子活性。同時，利用細胞內核染色質免疫沉澱法(ChIP assay)分析得知SUMO修飾缺失的突變種，LAP1K174A和CEBPDK120A會減弱HDAC4結合至COX-2啟動區的能力。綜合以上結果得知，經EGF長時間處理A431細胞之後，SUMO修飾的CEBPD和LAP1會結合至COX-2啟動區並且促使更多HDAC4聚集進而達到抑制COX-2基因的表現。

Transcriptional activation of the cyclooxygenase-2 (COX-2) plays an important role in the synthesis of prostaglandins (PGs) from arachidonic acid during inflammation and carcinogenesis. Our previous work indicated that epidermal growth factor (EGF)-induced COX-2 expression is mediated through the induction of the function of CCAAT/enhancer-binding protein delta (CEBPD) and c-Jun/c-Fos for the binding to the C/EBP and CRE/E box motifs of the COX-2 promoter. The aim of the present study is to characterize CCAAT/enhancer-binding protein beta (CEBPB) involving in the regulation of the COX-2 transcription upon EGF treatment in A431 cells. CEBPB, one of the CEBP family members, is a crucial gene regulator for appropriate innate immunity, adipogenesis and liver regeneration. In this study, we found that both CEBPB mRNA and protein expression were increased in long-term EGF exposure (3~15 h). The EGF-induced increases of CEBPB mRNA and protein expression were correlated with a decrease of COX-2 mRNA and protein expression. Inhibiting CEBPBs by siRNA enhanced COX-2 transcripts and COX-2 activity determined by COX-2 reporter system upon EGF treatment. Moreover, ectopic expression of all the CEBPB isoforms, LAP1, LAP2 or LIP, attenuated EGF-induced COX-2 promoter activity. We speculated that the lagging increases of CEBPBs might act as a transcriptional repressor to turn off the expression of COX-2 gene upon long-term EGF treatment. Furthermore, long-term EGF treatment increased the expression of LAP1 and LAP2 and their sumoylation in A431 cells. Only the sumoylated LAP1 (suLAP1), but not sumoylated LAP2, was responsible for COX-2 gene repression. In the lagging stage of EGF treatment, the LAP1 LAP2 and LIP bound to the CEBP and CRE/E box motifs as determined by DNA binding assay. The HDAC4 also bound to these two responsive elements and coincided with the CEBPBs’ binding abilities. In addition, EGF enhanced the nucleocytoplasmic redistribution of HDAC4 and SUMO1. We further demonstrated that HDAC4 interacted with LAP1 and negatively regulated COX-2 transcripts. The LAP1K174A, a sumoylation-defective LAP1 mutant, did not interact with HDAC4 and reversed LAP1-inhibited COX-2 promoter activity. Furthermore, both LAP1K174A and CEBPDK120A, a sumoylation-defective CEBPD mutant, attenuated the binding of HDAC4 onto the COX-2 promoter. Collectively, sumoylated CEBPD and LAP1 bound stably to COX-2 promoter that facilitated the recruitment of HDAC4 and consequently inhibited the expression of COX-2 in A431 cells of long-term EGF exposure.

Abstract	I
Abstract in Chinese	III
Acknowledgement	V
Contents	VI
List of Figures	X
Abbreviations	XII

Chapter 1: Introduction
I.	Cyclooxygenase (COX)	1
1.	Cyclooxygenase-1 (COX-1)	1
2.	Cyclooxygenase-2 (COX-2)	2
3.	Cyclooxygenase-3 (COX-3)	3
II.	CCAAT/Enhancer Binding Proteins (C/EBPs) 	4
1.	Protein structure	4
2.	Cellular functions	4
3.	The characteristics of CEBPB	5
4.	The regulation of COX-2 gene expression by CEBPs	5
III.	Histone Deacetylases (HDACs)	6
1.	Classification	6
2.	Gene regulation	7
IV.	Small Ubiquitin-Related Modifier (SUMO)	8
1.	The SUMO family	8
2.	SUMO conjugation (Sumoylation)	9
V.	Aims	10

Chapter 2: Materials and Methods
I.	Materials	12
II.	Plasmids	13
III.	Methods	13
1.	Cell Culture and EGF Treatment	13
2.	RNA Extraction and Reverse Transcription-PCR	13
3.	Preparation of Cell Lysate	14
4.	Preparation of Nuclear Extracts	15
5.	Western Blotting	15
6.	Small Interfering RNA’s Assay	16
7.	Plasmid Construction	16
8.	Transfection and Reporter Gene Assay	17
9.	In vivo SUMO Modification Assay	18
10.	Co-Immunoprecipitation Assay	18
11.	DNA Affinity Precipitation Assay (DAPA)	19
12.	Electrophoretic Mobility Shift Assay (EMSA)	19
13.	Chromatin IP and re-Chromatin IP Assay	20
14.	Immunofluorescence Assay	20
15.	Statistical analysis	21


Chapter 3: Results
A.	Expression of CEBPBs is induced after long-term EGF treatment in A431 cells
1.	Gene expression analysis of COX-2 and CEBPBs upon EGF treatment	22
B.	CEBPB participation in repression of EGF-induced COX-2 expression
1.	Effect of CEBPBs on COX-2 gene expression by using CEBPB siRNA	23
2.	Effect of individual CEBPB isoform on COX-2 promoter activity	23
C.	Sumoylation of LAP1 is enhanced upon long-term EGF treatment, and the sumoylation mutant of LAP1 attenuates its repressive ability on the COX-2 promoter
1.	Identification of sumoylation of individual CEBPB isoform by using in vivo-sumoylation assay	24
2.	Increase sumoylation of LAP1 and LAP2 upon EGF-treatment in a time-dependent manner	25
3.	Effects of the sumoylation mutants of LAP1 and LAP2 on COX-2 promoter activity	26
4.	Essential role of sumoylated LAP1, but not LAP2, in EGF-regulating COX-2 promoter activity	26
5.	Verification of SUMO1 on LAP1-mediated repression of COX-2 expression	27
D.	CEBPB isoforms and HDAC4 can bind to the CEBP and CRE motifs of the COX-2 promoter
1.	DNA binding clarification of CEBPB isoforms to the CEBP and CRE sites on COX-2 promoter	28
2.	Identification of the other transcriptional repression factors involved in regulating COX-2 gene expression	28
3.	Effect of EGF on the cellular localization of HDAC4 and SUMO1 in cells	29
E.	HDAC4, but not HDAC1, plays a functional role in silencing COX-2
1.	Effects of HDAC4 and HDAC1 on COX-2 promoter activity	30
2.	Identification of HDAC4 acting as a repressor on COX-2 expression	31
F.	suLAP1 cooperates with HDAC4 to repress COX-2 promoter activity
1.	Identification the cooperation effect between HDAC4 and suLAP1 on COX-2 promoter	31
2.	Analysis of the interaction activity of HDAC4 and suLAP1	32
G.	suCEBPD and suLAP1 cooperatively function in the repression of the COX-2 promoter activity
1.	Analysis of in vivo DNA binding patterns of CEBPB, CEBPD, SUMO1, and HDAC4 upon EGF treatment	33
2.	Pivotal role of sumoylation of CEBPD and LAP1 in HDAC4 recruitment	34
3.	Determination of the cooperation between suCEBPD and suLAP1 in COX-2 gene regulation	34

Chapter 4: Discussion	35
References	42
Publications	85
Curriculum Vitae	86
	


List of Figures
Figure 1. Expression of COX-2 and CEBPs upon long-term EGF treatment in A431 cells	59
Figure 2. CEBPBs participate in silencing COX-2 gene expression	60
Figure 3. LAP1 and LAP2, but not LIP, are conjugated by SUMO1 and the sumoylated HA/LAP1 is decreased by SUMO1 siRNA.	62
Figure 4. Sumoylation of LAP1 and LAP2 are enhanced upon long-term EGF treatment	64
Figure 5. Sumoylation mutant of LAP1, but not LAP2, attenuates its repressive ability on the COX-2 promoter	65
Figure 6. LAP1 lose its repression ability on COX-2 reporter when loss-of SUMO1	67
Figure 7. Bindings of CEBPBs parallel with HDAC4 binding upon long-term EGF treatment	68
Figure 8. EGF treatment induces HDAC4 and SUMO1 nuclear shuttling	70
Figure 9. Overexpression of HDAC4, but not HDAC1, attenuates COX-2 promoter activity	72
Figure 10. HDAC4 plays a negative role in regulating COX-2 transcription	73
Figure 11. HDAC4 is involved in the suLAP1-mediated repression of COX-2 promoter activity	74
Figure 12. LAP1 has higher capability to interact with HDAC4 than LAP1K174A	75
Figure 13. SUMO1-conjuated CEBPD and CEBPB recruit HDAC4 to COX-2 promoter in vivo under long-term EGF treatment	76
Figure 14. suLAP1 and suCEBPD play a negative coordinating role in the transcriptional regulation of COX-2 gene	77
Figure 15. HDAC4 does not affect the sumoylation of LAP1 and LAP2	78
Figure 16. The involvement of CEBPD and LAP1 in the EGF-regulated COX-2 transcription	79
Appendix 1. COX enzymes in prostaglandin synthesis	80
Appendix 2. Regulatory elements in the human COX-2 promoters	81
Appendix 3. Inducers of COX-2 gene expression	82
Appendix 4. Examples of target genes regulated by the C/EBP family	83
Appendix 5. Human CEBPB protein isoforms	84
                                    

Alberini, C.M. (2009). Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89, 121-145.
Aung, H.T., Schroder, K., Himes, S.R., Brion, K., van Zuylen, W., Trieu, A., Suzuki, H., Hayashizaki, Y., Hume, D.A., Sweet, M.J., et al. (2006). LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression. FASEB J. 20, 1315-1327.
Ayer, D.E., Lawrence, Q.A., and Eisenman, R.N. (1995). Mad-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Cell 80, 767-776.
Basile, V., Mantovani, R., and Imbriano, C. (2006). DNA damage promotes histone deacetylase 4 nuclear localization and repression of G2/M promoters, via p53 C-terminal lysines. J. Biol. Chem. 281, 2347-2357.
Bolden, J.E., Peart, M.J., and Johnstone, R.W. (2006). Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5, 769-784.
Calella, A.M., Nerlov, C., Lopez, R.G., Sciarretta, C., von Bohlen und Halbach, O., Bereshchenko, O., and Minichiello, L. (2007). Neurotrophin/Trk receptor signaling mediates C/EBPalpha, -beta and NeuroD recruitment to immediate-early gene promoters in neuronal cells and requires C/EBPs to induce immediate-early gene transcription. Neural Dev. 2, 4
Callejas, N.A., Bosca, L., Williams, C.S., Du, B.R., and Martin-Sanz, P. (2000). Regulation of cyclooxygenase 2 expression in hepatocytes by CCAAT/enhancer-binding proteins. Gastroenterology 119, 493-501.
Cao, D., Bromberg, P.A., and Samet, J.M. (2007). COX-2 expression induced by diesel particles involves chromatin modification and degradation of HDAC1. Am. J. Respir. Cell Mol. Biol. 37, 232-239.
Cao, Y., and Prescott, S.M. (2002). Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J. Cell. Physiol. 190, 279-286.
Chandrasekharan, N.V., Dai, H., Roos, K.L., Evanson, N.K., Tomsik, J., Elton, T.S., and Simmons, D.L. (2002). COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc. Natl. Acad. Sci. USA 99, 13926-13931.
Chandrasekharan, N.V., and Simmons, D.L. (2004). The cyclooxygenases. Genome Biol. 5, 241.
Chauchereau, A., Mathieu, M., de Saintignon, J., Ferreira, R., Pritchard, L.L., Mishal, Z., Dejean, A., and Harel-Bellan, A. (2004). HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF. Oncogene 23, 8777-8784.
Chen, J.J., Huang, W.C., and Chen, C.C. (2005a). Transcriptional regulation of cyclooxygenase-2 in response to proteasome inhibitors involves reactive oxygen species-mediated signaling pathway and recruitment of CCAAT/enhancer-binding protein delta and CREB-binding protein. Mol. Biol. Cell. 16, 5579-5591.
Chen, L.C., Chen, B.K., Chang, J.M., and Chang, W.C. (2004). Essential role of c-Jun induction and coactivator p300 in epidermal growth factor-induced gene expression of cyclooxygenase-2 in human epidermoid carcinoma A431 cells. Biochim. Biophys. Acta. 1683, 38-48.
Chen, L.C., Chen, B.K., and Chang, W.C. (2005b). Activating protein 1-mediated cyclooxygenase-2 expression is independent of N-terminal phosphorylation of c-Jun. Mol. Pharmacol. 67, 2057-2069.
Chun, K.S., and Surh, Y.J. (2004). Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. Biochem. Pharmacol. 68, 1089-1100.
Cho, Y.H., Lee, C.H., and Kim, S.G. (2003). Potentiation of lipopolysaccharide-inducible cyclooxygenase 2 expression by C2-ceramide via c-Jun N-terminal kinase-mediated activation of CCAAT/enhancer binding protein beta in macrophages. Mol. Pharmacol. 63, 512-523.
Cieslik, K.A., Zhu, Y., Shtivelband, M., and Wu, K.K. (2005). Inhibition of p90 ribosomal S6 kinase-mediated CCAAT/enhancer-binding protein beta activation and cyclooxygenase-2 expression by salicylate. J. Biol. Chem. 280, 18411-18417.
Cok, S.J., Acton, S.J., and Morrison, A.R. (2003). The proximal region of the 3'-untranslated region of cyclooxygenase-2 is recognized by a multimeric protein complex containing HuR, TIA-1, TIAR, and the heterogeneous nuclear ribonucleoprotein U. J. Biol. Chem. 278, 36157-36162.
Crepaldi, L., Lackner, C., Corti, C., and Ferraguti, F. (2007). Transcriptional activators and repressors for the neuron-specific expression of a metabotropic glutamate receptor. J. Biol. Chem. 282, 17877-17889.
Dannenberg, A.J., Lippman, S.M., Mann, J.R., Subbaramaiah, K., and DuBois, R.N. (2005). Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J. Clin. Oncol. 23, 254-266.
Darlington, G.J., Ross, S.E., and MacDougald, O.A. (1998). The role of C/EBP genes in adipocyte differentiation. The Journal of biological chemistry 273, 30057-30060.
de Ruijter, A.J., van Gennip, A.H., Caron, H.N., Kemp, S., and van Kuilenburg, A.B. (2003). Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J. 370, 737-749.
Deng, W.G., Zhu, Y., and Wu, K.K. (2003). Up-regulation of p300 binding and p50 acetylation in tumor necrosis factor-alpha-induced cyclooxygenase-2 promoter activation. J. Biol. Chem. 278, 4770-4777.
Deng, W.G., Zhu, Y., and Wu, K.K. (2004). Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators. Blood 103, 2135-2142.
DeWitt, D.L., and Smith, W.L. (1988). Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc. Natl. Acad. Sci. USA 85, 1412-1416.
Di-Poi, N., Desvergne, B., Michalik, L., and Wahli, W. (2005). Transcriptional repression of peroxisome proliferator-activated receptor beta/delta in murine keratinocytes by CCAAT/enhancer-binding proteins. J. Biol. Chem. 280, 38700-38710.
Dixon, D.A., Kaplan, C.D., McIntyre, T.M., Zimmerman, G.A., and Prescott, S.M. (2000). Post-transcriptional control of cyclooxygenase-2 gene expression. The role of the 3'-untranslated region. J. Biol. Chem. 275, 11750-11757.
Diehl, A.M. (1998). Roles of CCAAT/enhancer-binding proteins in regulation of liver regenerative growth. J. Biol. Chem. 273, 30843-30846.
Dubois, R.N., Abramson, S.B., Crofford, L., Gupta, R.A., Simon, L.S., Van De Putte, L.B., and Lipsky, P.E. (1998). Cyclooxygenase in biology and disease. FASEB J. 12, 1063-1073.
Eaton, E.M., Hanlon, M., Bundy, L., and Sealy, L. (2001). Characterization of C/EBPbeta isoforms in normal versus neoplastic mammary epithelial cells. J. Cell. Physiol. 189, 91-105.
Eaton, E.M., and Sealy, L. (2003). Modification of CCAAT/enhancer-binding protein-beta by the small ubiquitin-like modifier (SUMO) family members, SUMO-2 and SUMO-3. J. Biol. Chem. 278, 33416-33421.
Eliopoulos, A.G., Dumitru, C.D., Wang, C.C., Cho, J., and Tsichlis, P.N. (2002). Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J. 21, 4831-4840.
Fischle, W., Emiliani, S., Hendzel, M.J., Nagase, T., Nomura, N., Voelter, W., and Verdin, E. (1999). A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p. J. Biol. Chem. 274, 11713-11720.
Gao, L., Cueto, M.A., Asselbergs, F., and Atadja, P. (2002). Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 277, 25748-25755.
Garavito, R.M., and DeWitt, D.L. (1999). The cyclooxygenase isoforms: structural insights into the conversion of arachidonic acid to prostaglandins. Biochim. Biophys. Acta 1441, 278-287.
Gasparini, G., Longo, R., Sarmiento, R., and Morabito, A. (2003). Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol. 4, 605-615.
Geiss-Friedlander, R., and Melchior, F. (2007). Concepts in sumoylation: a decade on. Nat. Rev. Mol. Cell Biol. 8, 947-956.
Ghisletti, S., Huang, W., Ogawa, S., Pascual, G., Lin, M.E., Willson, T.M., Rosenfeld, M.G., and Glass, C.K. (2007). Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol. Cell 25, 57-70.
Gill, G. (2005). Something about SUMO inhibits transcription. Curr. Opin. Genet. Dev. 15, 536-541.
Gorgoni, B., Maritano, D., Marthyn, P., Righi, M., and Poli, V. (2002). C/EBP beta gene inactivation causes both impaired and enhanced gene expression and inverse regulation of IL-12 p40 and p35 mRNAs in macrophages. J. Immunol. 168, 4055-4062.
Gregoire, S., and Yang, X.J. (2005). Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors. Mol. Cell. Biol. 25, 2273-2287.
Grimm, S.L., Contreras, A., Barcellos-Hoff, M.H., and Rosen, J.M. (2005). Cell cycle defects contribute to a block in hormone-induced mammary gland proliferation in CCAAT/enhancer-binding protein (C/EBPbeta)-null mice. J. Biol. Chem. 280, 36301-36309.
Grozinger, C.M., and Schreiber, S.L. (2000). Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proc. Natl. Acad. Sci. USA 97, 7835-7840.
Gunawardena, R.W., Fox, S.R., Siddiqui, H., and Knudsen, E.S. (2007). SWI/SNF activity is required for the repression of deoxyribonucleotide triphosphate metabolic enzymes via the recruitment of mSin3B. J. Biol. Chem. 282, 20116-20123.
Guo, D., Li, M., Zhang, Y., Yang, P., Eckenrode, S., Hopkins, D., Zheng, W., Purohit, S., Podolsky, R.H., Muir, A., et al. (2004). A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat. Genet. 36, 837-841.
Gupta, R.A., and Dubois, R.N. (2001). Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat. Rev. Cancer 1, 11-21.
Harper, K.A., and Tyson-Capper, A.J. (2008). Complexity of COX-2 gene regulation. Biochem. Soc. Trans. 36, 543-545.
Hemler, M., and Lands, W.E. (1976). Purification of the cyclooxygenase that forms prostaglandins. Demonstration of two forms of iron in the holoenzyme. J. Biol. Chem. 251, 5575-5579.
Herschman, H.R. (1996). Prostaglandin synthase 2. Biochim. Biophys. Acta 1299, 125-140.
Hla, T., and Neilson, K. (1992). Human cyclooxygenase-2 cDNA. Proc. Natl. Acad. Sci. USA 89, 7384-7388.
Hohaus, S., Petrovick, M.S., Voso, M.T., Sun, Z., Zhang, D.E., and Tenen, D.G. (1995). PU.1 (Spi-1) and C/EBP alpha regulate expression of the granulocyte-macrophage colony-stimulating factor receptor alpha gene. Mol. Cell. Biol. 15, 5830-5845.
Inoue, H., Yokoyama, C., Hara, S., Tone, Y., and Tanabe, T. (1995). Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element. J. Biol. Chem. 270, 24965-24971.
Jiang, Y.J., Lu, B., Choy, P.C., and Hatch, G.M. (2003). Regulation of cytosolic phospholipase A2, cyclooxygenase-1 and -2 expression by PMA, TNFalpha, LPS and M-CSF in human monocytes and macrophages. Mol. Cell. Biochem. 246, 31-38.
Johnson, E.S. (2004). Protein modification by SUMO. Annu. Rev. Biochem. 73, 355-382.
Jones, D.A., Carlton, D.P., McIntyre, T.M., Zimmerman, G.A., and Prescott, S.M. (1993). Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J. Biol. Chem. 268, 9049-9054.
Jones, P.L., and Shi, Y.B. (2003). N-CoR-HDAC corepressor complexes: roles in transcriptional regulation by nuclear hormone receptors. Curr. Top. Microbiol. Immunol. 274, 237-268.
Kao, H.Y., Verdel, A., Tsai, C.C., Simon, C., Juguilon, H., and Khochbin, S. (2001). Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7. J. Biol. Chem. 276, 47496-47507.
Karim, S., Berrou, E., Levy-Toledano, S., Bryckaert, M., and MacLouf, J. (1997). Regulatory role of prostaglandin E2 in induction of cyclo-oxygenase-2 by a thromboxane A2 analogue (U46619) and basic fibroblast growth factor in porcine aortic smooth-muscle cells. Biochem. J. 326 ( Pt 2), 593-599.
Kim, J., Cantwell, C.A., Johnson, P.F., Pfarr, C.M., and Williams, S.C. (2002). Transcriptional activity of CCAAT/enhancer-binding proteins is controlled by a conserved inhibitory domain that is a target for sumoylation. J. Biol. Chem. 277, 38037-38044.
Kim, Y., and Fischer, S.M. (1998). Transcriptional regulation of cyclooxygenase-2 in mouse skin carcinoma cells. Regulatory role of CCAAT/enhancer-binding proteins in the differential expression of cyclooxygenase-2 in normal and neoplastic tissues. J. Biol. Chem. 273, 27686-27694.
Kowenz-Leutz, E., and Leutz, A. (1999). A C/EBP beta isoform recruits the SWI/SNF complex to activate myeloid genes. Mol. Cell 4, 735-743.
Kowenz-Leutz, E., Twamley, G., Ansieau, S., and Leutz, A. (1994). Novel mechanism of C/EBP beta (NF-M) transcriptional control: activation through derepression. Genes Dev. 8, 2781-2791.
Kujubu, D.A., Fletcher, B.S., Varnum, B.C., Lim, R.W., and Herschman, H.R. (1991). TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J. Biol. Chem. 266, 12866-12872.
Lai, P.H., Wang, W.L., Ko, C.Y., Lee, Y.C., Yang, W.M., Shen, T.W., Chang, W.C., and Wang, J.M. (2008). HDAC1/HDAC3 modulates PPARG2 transcription through the sumoylated CEBPD in hepatic lipogenesis. Biochim. Biophys. Acta 1783, 1803-1814.
Lamb, J., Ramaswamy, S., Ford, H.L., Contreras, B., Martinez, R.V., Kittrell, F.S., Zahnow, C.A., Patterson, N., Golub, T.R., and Ewen, M.E. (2003). A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 114, 323-334.
Lane, M.D., Tang, Q.Q., and Jiang, M.S. (1999). Role of the CCAAT enhancer binding proteins (C/EBPs) in adipocyte differentiation. Biochem. Biophys. Res. Commun. 266, 677-683.
Lekstrom-Himes, J., and Xanthopoulos, K.G. (1998). Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J. Biol. Chem. 273, 28545-28548.
Martin, S., Wilkinson, K.A., Nishimune, A., and Henley, J.M. (2007). Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction. Nat. Rev. Neurosci. 8, 948-959.
Matsuoka, H., Fujimura, T., Hayashi, M., Matsuda, K., Ishii, Y., Aramori, I., and Mutoh, S. (2007). Disruption of HDAC4/N-CoR complex by histone deacetylase inhibitors leads to inhibition of IL-2 gene expression. Biochem. Pharmacol. 74, 465-476.
McCauslin, C.S., Heath, V., Colangelo, A.M., Malik, R., Lee, S., Mallei, A., Mocchetti, I., and Johnson, P.F. (2006). CAAT/enhancer-binding protein delta and cAMP-response element-binding protein mediate inducible expression of the nerve growth factor gene in the central nervous system. J. Biol. Chem. 281, 17681-17688.
Meinecke, I., Cinski, A., Baier, A., Peters, M.A., Dankbar, B., Wille, A., Drynda, A., Mendoza, H., Gay, R.E., Hay, R.T., et al. (2007). Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Proc. Natl. Acad. Sci. USA 104, 5073-5078.
Merlie, J.P., Fagan, D., Mudd, J., and Needleman, P. (1988). Isolation and characterization of the complementary DNA for sheep seminal vesicle prostaglandin endoperoxide synthase (cyclooxygenase). J. Biol. Chem. 263, 3550-3553.
Miyamoto, T., Ogino, N., Yamamoto, S., and Hayaishi, O. (1976). Purification of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes. J. Biol. Chem. 251, 2629-2636.
Mukhopadhyay, D., Houchen, C.W., Kennedy, S., Dieckgraefe, B.K., and Anant, S. (2003). Coupled mRNA stabilization and translational silencing of cyclooxygenase-2 by a novel RNA binding protein, CUGBP2. Mol. Cell 11, 113-126.
Muller, S., Hoege, C., Pyrowolakis, G., and Jentsch, S. (2001). SUMO, ubiquitin's mysterious cousin. Nat. Rev. Mol. Cell Biol. 2, 202-210.
Nakajima, T., Kinoshita, S., Sasagawa, T., Sasaki, K., Naruto, M., Kishimoto, T., and Akira, S. (1993). Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc. Natl. Acad. Sci. USA 90, 2207-2211.
Nie, M., Pang, L., Inoue, H., and Knox, A.J. (2003). Transcriptional regulation of cyclooxygenase 2 by bradykinin and interleukin-1beta in human airway smooth muscle cells: involvement of different promoter elements, transcription factors, and histone h4 acetylation. Mol. Cell. Biol. 23, 9233-9244.
Nishiyori, A., Tashiro, H., Kimura, A., Akagi, K., Yamamura, K., Mori, M., and Takiguchi, M. (1994). Determination of tissue specificity of the enhancer by combinatorial operation of tissue-enriched transcription factors. Both HNF-4 and C/EBP beta are required for liver-specific activity of the ornithine transcarbamylase enhancer. J. Biol. Chem. 269, 1323-1331.
Oelgeschlager, M., Nuchprayoon, I., Luscher, B., and Friedman, A.D. (1996). C/EBP, c-Myb, and PU.1 cooperate to regulate the neutrophil elastase promoter. Mol. Cell. Biol. 16, 4717-4725.
Ossipow, V., Descombes, P., and Schibler, U. (1993). CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials. Proc. Natl. Acad. Sci. USA 90, 8219-8223.
Oyesanya, R.A., Lee, Z.P., Wu, J., Chen, J., Song, Y., Mukherjee, A., Dent, P., Kordula, T., Zhou, H., and Fang, X. (2008). Transcriptional and post-transcriptional mechanisms for lysophosphatidic acid-induced cyclooxygenase-2 expression in ovarian cancer cells. FASEB J. 22, 2639-2651.
Park, M.A., Seok, Y.J., Jeong, G., and Lee, J.S. (2008). SUMO1 negatively regulates BRCA1-mediated transcription, via modulation of promoter occupancy. Nucleic Acids Res. 36, 263-283.
Pham, H., Chong, B., Vincenti, R., and Slice, L.W. (2008). Ang II and EGF synergistically induce COX-2 expression via CREB in intestinal epithelial cells. J. Cell. Physiol. 214, 96-109.
Picot, D., Loll, P.J., and Garavito, R.M. (1994). The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 367, 243-249.
Ramji, D.P., and Foka, P. (2002). CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem. J. 365, 561-575.
Rosas-Acosta, G., Russell, W.K., Deyrieux, A., Russell, D.H., and Wilson, V.G. (2005). A universal strategy for proteomic studies of SUMO and other ubiquitin-like modifiers. Mol. Cell. Proteomics 4, 56-72.
Saitoh, H., and Hinchey, J. (2000). Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J. Biol. Chem. 275, 6252-6258.
Sampey, A.V., Monrad, S., and Crofford, L.J. (2005). Microsomal prostaglandin E synthase-1: the inducible synthase for prostaglandin E2. Arthritis Res. Ther. 7, 114-117.
Saunders, M.A., Sansores-Garcia, L., Gilroy, D.W., and Wu, K.K. (2001). Selective suppression of CCAAT/enhancer-binding protein beta binding and cyclooxygenase-2 promoter activity by sodium salicylate in quiescent human fibroblasts. J. Biol. Chem. 276, 18897-18904.
Schrem, H., Klempnauer, J., and Borlak, J. (2004). Liver-enriched transcription factors in liver function and development. Part II: the C/EBPs and D site-binding protein in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation. Pharmacol. Rev. 56, 291-330.
Schroer, K., Zhu, Y., Saunders, M.A., Deng, W.G., Xu, X.M., Meyer-Kirchrath, J., and Wu, K.K. (2002). Obligatory role of cyclic adenosine monophosphate response element in cyclooxygenase-2 promoter induction and feedback regulation by inflammatory mediators. Circulation 105, 2760-2765.
Sheng, H., Williams, C.S., Shao, J., Liang, P., DuBois, R.N., and Beauchamp, R.D. (1998). Induction of cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway. J. Biol. Chem. 273, 22120-22127.
Shimokawa, T., and Ra, C. (2003). C/EBP alpha and Ets protein family members regulate the human myeloid IgA Fc receptor (Fc alpha R, CD89) promoter. J. Immunol. 170, 2564-2572.
Shuman, J.D., Sebastian, T., Kaldis, P., Copeland, T.D., Zhu, S., Smart, R.C., and Johnson, P.F. (2004). Cell cycle-dependent phosphorylation of C/EBPbeta mediates oncogenic cooperativity between C/EBPbeta and H-RasV12. Mol. Cell. Biol. 24, 7380-7391.
Smith, L.T., Hohaus, S., Gonzalez, D.A., Dziennis, S.E., and Tenen, D.G. (1996). PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. Blood 88, 1234-1247.
Spurling, C.C., Godman, C.A., Noonan, E.J., Rasmussen, T.P., Rosenberg, D.W., and Giardina, C. (2008). HDAC3 overexpression and colon cancer cell proliferation and differentiation. Mol. Carcinog. 47, 137-147.
Subbaramaiah, K., and Dannenberg, A.J. (2007). Cyclooxygenase-2 transcription is regulated by human papillomavirus 16 E6 and E7 oncoproteins: evidence of a corepressor/coactivator exchange. Cancer Res. 67, 3976-3985.
Subbaramaiah, K., Norton, L., Gerald, W., and Dannenberg, A.J. (2002). Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. J. Biol. Chem. 277, 18649-18657.
Subbaramaiah, K., Telang, N., Ramonetti, J.T., Araki, R., DeVito, B., Weksler, B.B., and Dannenberg, A.J. (1996). Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells. Cancer Res. 56, 4424-4429.
Sudarsanam, P., and Winston, F. (2000). The Swi/Snf family nucleosome-remodeling complexes and transcriptional control. Trends Genet. 16, 345-351.
Sully, G., Dean, J.L., Wait, R., Rawlinson, L., Santalucia, T., Saklatvala, J., and Clark, A.R. (2004). Structural and functional dissection of a conserved destabilizing element of cyclo-oxygenase-2 mRNA: evidence against the involvement of AUF-1 [AU-rich element/poly(U)-binding/degradation factor-1], AUF-2, tristetraprolin, HuR (Hu antigen R) or FBP1 (far-upstream-sequence-element-binding protein 1). Biochem. J. 377, 629-639.
Sureban, S.M., Murmu, N., Rodriguez, P., May, R., Maheshwari, R., Dieckgraefe, B.K., Houchen, C.W., and Anant, S. (2007). Functional antagonism between RNA binding proteins HuR and CUGBP2 determines the fate of COX-2 mRNA translation. Gastroenterology 132, 1055-1065.
Tanabe, T., and Tohnai, N. (2002). Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins Other Lipid Mediat. 68-69, 95-114.
Thomas, B., Berenbaum, F., Humbert, L., Bian, H., Bereziat, G., Crofford, L., and Olivier, J.L. (2000). Critical role of C/EBPdelta and C/EBPbeta factors in the stimulation of the cyclooxygenase-2 gene transcription by interleukin-1beta in articular chondrocytes. Eur. J. Biochem. 267, 6798-6809.
Timchenko, N.A., Welm, A.L., Lu, X., and Timchenko, L.T. (1999). CUG repeat binding protein (CUGBP1) interacts with the 5' region of C/EBPbeta mRNA and regulates translation of C/EBPbeta isoforms. Nucleic Acids Res. 27, 4517-4525.
Tong, X., Van Dross, R.T., Abu-Yousif, A., Morrison, A.R., and Pelling, J.C. (2007). Apigenin prevents UVB-induced cyclooxygenase 2 expression: coupled mRNA stabilization and translational inhibition. Mol. Cell. Biol. 27, 283-296.
Wadleigh, D.J., Reddy, S.T., Kopp, E., Ghosh, S., and Herschman, H.R. (2000). Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. J. Biol. Chem. 275, 6259-6266.
Waltregny, D., Glenisson, W., Tran, S.L., North, B.J., Verdin, E., Colige, A., and Castronovo, V. (2005). Histone deacetylase HDAC8 associates with smooth muscle alpha-actin and is essential for smooth muscle cell contractility. FASEB J. 19, 966-968.
Wang, A.H., and Yang, X.J. (2001). Histone deacetylase 4 possesses intrinsic nuclear import and export signals. Mol. Cell. Biol. 21, 5992-6005.
Wang, J.M., Ko, C.Y., Chen, L.C., Wang, W.L., and Chang, W.C. (2006). Functional role of NF-IL6beta and its sumoylation and acetylation modifications in promoter activation of cyclooxygenase 2 gene. Nucleic Acids Res. 34, 217-231.
Wang, N.D., Finegold, M.J., Bradley, A., Ou, C.N., Abdelsayed, S.V., Wilde, M.D., Taylor, L.R., Wilson, D.R., and Darlington, G.J. (1995). Impaired energy homeostasis in C/EBP alpha knockout mice. Science 269, 1108-1112.
Wang, S.C., Lien, H.C., Xia, W., Chen, I.F., Lo, H.W., Wang, Z., Ali-Seyed, M., Lee, D.F., Bartholomeusz, G., Ou-Yang, F., et al. (2004). Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell 6, 251-261.
Weichert, W., Roske, A., Gekeler, V., Beckers, T., Ebert, M.P., Pross, M., Dietel, M., Denkert, C., and Rocken, C. (2008). Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis. Lancet Oncol. 9, 139-148.
Williamson, E.A., Xu, H.N., Gombart, A.F., Verbeek, W., Chumakov, A.M., Friedman, A.D., and Koeffler, H.P. (1998). Identification of transcriptional activation and repression domains in human CCAAT/enhancer-binding protein epsilon. J. Biol. Chem. 273, 14796-14804.
Wu, K.K., Liou, J.Y., and Cieslik, K. (2005). Transcriptional Control of COX-2 via C/EBPbeta. Arterioscler. Thromb. Vasc. Biol. 25, 679-685.
Xie, W., and Herschman, H.R. (1995). v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. J. Biol. Chem. 270, 27622-27628.
Xie, W.L., Chipman, J.G., Robertson, D.L., Erikson, R.L., and Simmons, D.L. (1991). Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc. Natl. Acad. Sci. USA a 88, 2692-2696.
Xiong, W., Hsieh, C.C., Kurtz, A.J., Rabek, J.P., and Papaconstantinou, J. (2001). Regulation of CCAAT/enhancer-binding protein-beta isoform synthesis by alternative translational initiation at multiple AUG start sites. Nucleic Acids Res. 29, 3087-3098.
Yang, S.H., and Sharrocks, A.D. (2004). SUMO promotes HDAC-mediated transcriptional repression. Mol. Cell 13, 611-617.
Yokoyama, C., Takai, T., and Tanabe, T. (1988). Primary structure of sheep prostaglandin endoperoxide synthase deduced from cDNA sequence. FEBS Lett. 231, 347-351.
Yokoyama, C., and Tanabe, T. (1989). Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme. Biochem. Biophys. Res. Commun. 165, 888-894.
Zhang, C.L., McKinsey, T.A., Lu, J.R., and Olson, E.N. (2001). Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor. J. Biol. Chem. 276, 35-39.
Zhang, C.L., McKinsey, T.A., and Olson, E.N. (2002). Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation. Mol. Cell. Biol. 22, 7302-7312.
Zhang, D.E., Hetherington, C.J., Meyers, S., Rhoades, K.L., Larson, C.J., Chen, H.M., Hiebert, S.W., and Tenen, D.G. (1996). CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter. Mol. Cell. Biol. 16, 1231-1240.
Zhang, D.E., Zhang, P., Wang, N.D., Hetherington, C.J., Darlington, G.J., and Tenen, D.G. (1997). Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc. Natl. Acad. Sci. U S A 94, 569-574.
Zhao, X., Ito, A., Kane, C.D., Liao, T.S., Bolger, T.A., Lemrow, S.M., Means, A.R., and Yao, T.P. (2001). The modular nature of histone deacetylase HDAC4 confers phosphorylation-dependent intracellular trafficking. J. Biol. Chem. 276, 35042-35048.
Zhao, X., Sternsdorf, T., Bolger, T.A., Evans, R.M., and Yao, T.P. (2005). Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol. Cell. Biol. 25, 8456-8464.
Zhu, S., Yoon, K., Sterneck, E., Johnson, P.F., and Smart, R.C. (2002a). CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling. Proceedings of the National Academy of Sciences of the United States of America 99, 207-212.
Zhu, Y., Saunders, M.A., Yeh, H., Deng, W.G., and Wu, K.K. (2002b). Dynamic regulation of cyclooxygenase-2 promoter activity by isoforms of CCAAT/enhancer-binding proteins. J Biol Chem 277, 6923-6928.
Zhu, S., Oh, H.S., Shim, M., Sterneck, E., Johnson, P.F., and Smart, R.C. (1999). C/EBPbeta modulates the early events of keratinocyte differentiation involving growth arrest and keratin 1 and keratin 10 expression. Mol. Cell. Biol. 19, 7181-7190.

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