ABSTRACT

Tumor necrosis factor (TNF) affects the growth, differentiation, and function of a multitude of cell types and is viewed as a potent mediator of inflammation and cellular immune responses. In order to delineate functional domains that control TNF gene transcription, we have analyzed a 5` flanking region of the human TNF promoter spanning base pairs -115 to -98. This region contains a PEA3/Ets-1 binding motif 5` GAGGA 3` in direct juxtaposition to an AP-1/ATF-like palindromic sequence motif 5` TGAGCTCA 3`. Specific binding of Ets and Jun to their respective elements is demonstrated by competition analysis as well as by supershift assays. As shown by promoter deletion analysis, these two binding sites were essential for both basal promoter activity and responsiveness to the phorbol ester phorbol 12-myristate 13-acetate. Co-transfection of c-ets or c-jun expression plasmids along with TNF promoter-CAT reporter constructs revealed the participation of both transcription factors in the regulation of TNF gene transcription. Correspondingly, site-specific mutation of either Ets or Jun sites led to a complete loss of responsiveness to the respective transcription factor. These data suggest an essential role of Ets for the activation of TNF gene transcription.

FOOTNOTES

*

This work was supported by the Deutsche Forschungsgemeinschaft and the Deutsche Krebshilfe. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence should be addressed: Institut für Medizinische Mikrobiologie und Hygiene, Technische Universität München, Trogerstr. 32, 81675 München, FRG. Tel.: 49-89-4140-4141; Fax: 49-89-4140-4942.

()

The abbreviations used are: TNF, tumor necrosis factor; AP-1, activator protein 1; CREB, cAMP-responsive element-binding protein; CAT, chloramphenicol acetyltransferase; EMSA, electrophoretic mobility shift assay; PMA, phorbol 12-myristate 13-acetate; ATF, activating transcription factor.

()

B. Krämer, K. Wiegmann, and M. Krönke, unpublished observation.

()

B. Krämer, K. Wiegmann, and M. Krönke, unpublished results.

ACKNOWLEDGEMENTS

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				S. J. Skinner, K. M. Deleault, R. Fecteau, and S. A. Brooks Extracellular Signal-regulated Kinase Regulation of Tumor Necrosis Factor-{alpha} mRNA Nucleocytoplasmic Transport Requires TAP-NxT1 Binding and the AU-rich Element J. Biol. Chem., February 8, 2008; 283(6): 3191 - 3199. [Abstract] [Full Text] [PDF]

				H. Qiao, M. V. Andrade, F. A. Lisboa, K. Morgan, and M. A. Beaven Fc{epsilon}R1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells Blood, January 15, 2006; 107(2): 610 - 618. [Abstract] [Full Text] [PDF]

				A. R. Suriano, A. N. Sanford, N. Kim, M. Oh, S. Kennedy, M. J. Henderson, K. Dietzmann, and K. E. Sullivan GCF2/LRRFIP1 Represses Tumor Necrosis Factor Alpha Expression Mol. Cell. Biol., October 15, 2005; 25(20): 9073 - 9081. [Abstract] [Full Text] [PDF]

				S.-B. Lee and J. S. Schorey Activation and Mitogen-Activated Protein Kinase Regulation of Transcription Factors Ets and NF-{kappa}B in Mycobacterium-Infected Macrophages and Role of These Factors in Tumor Necrosis Factor Alpha and Nitric Oxide Synthase 2 Promoter Function Infect. Immun., October 1, 2005; 73(10): 6499 - 6507. [Abstract] [Full Text] [PDF]

				X. Tang, D. L. Marciano, S. E. Leeman, and S. Amar LPS induces the interaction of a transcription factor, LPS-induced TNF-{alpha} factor, and STAT6(B) with effects on multiple cytokines PNAS, April 5, 2005; 102(14): 5132 - 5137. [Abstract] [Full Text] [PDF]

				C. Brown, J. Gaspar, A. Pettit, R. Lee, X. Gu, H. Wang, C. Manning, C. Voland, S. R. Goldring, M. B. Goldring, et al. ESE-1 Is a Novel Transcriptional Mediator of Angiopoietin-1 Expression in the Setting of Inflammation J. Biol. Chem., March 26, 2004; 279(13): 12794 - 12803. [Abstract] [Full Text] [PDF]

				H. Higuchi, A. Grambihler, A. Canbay, S. F. Bronk, and G. J. Gores Bile Acids Up-regulate Death Receptor 5/TRAIL-receptor 2 Expression via a c-Jun N-terminal Kinase-dependent Pathway Involving Sp1 J. Biol. Chem., January 2, 2004; 279(1): 51 - 60. [Abstract] [Full Text] [PDF]

				H. Wang, J. Hicks, P. Khanbolooki, S.-J. Kim, C. Yan, Y. Wang, and D. Boyd Transgenic Mice Demonstrate Novel Promoter Regions for Tissue-Specific Expression of the Urokinase Receptor Gene Am. J. Pathol., August 1, 2003; 163(2): 453 - 464. [Abstract] [Full Text] [PDF]

				J. Zhang, S. Wang, R. A. Wesley, and R. L. Danner Adjacent Sequence Controls the Response Polarity of Nitric Oxide-sensitive Sp Factor Binding Sites J. Biol. Chem., August 1, 2003; 278(31): 29192 - 29200. [Abstract] [Full Text] [PDF]

				M. Santos, P. Perez, C. Segrelles, S. Ruiz, J. L. Jorcano, and J. M. Paramio Impaired NF-kappa B Activation and Increased Production of Tumor Necrosis Factor alpha in Transgenic Mice Expressing Keratin K10 in the Basal Layer of the Epidermis J. Biol. Chem., April 4, 2003; 278(15): 13422 - 13430. [Abstract] [Full Text] [PDF]

				X. Tang, M. J. Fenton, and S. Amar Identification and functional characterization of a novel binding site on TNF-alpha promoter PNAS, April 1, 2003; 100(7): 4096 - 4101. [Abstract] [Full Text] [PDF]

				J. Ye, L. Wang, X. Zhang, V. Tantishaiyakul, and Y. Rojanasakul Inhibition of TNF-alpha gene expression and bioactivity by site-specific transcription factor-binding oligonucleotides Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L386 - L394. [Abstract] [Full Text] [PDF]

				R. Castellano, C. Van Lint, V. Peri, E. Veithen, Y. Morel, R. Costello, D. Olive, and Y. Collette Mechanisms Regulating Expression of the Tumor Necrosis Factor-related light Gene. ROLE OF CALCIUM-SIGNALING PATHWAY IN THE TRANSCRIPTIONAL CONTROL J. Biol. Chem., November 1, 2002; 277(45): 42841 - 42851. [Abstract] [Full Text] [PDF]

				T. A. Sanchez, J. L. Booth, and J. P. Metcalf Tumor necrosis factor-alpha activation by adenovirus E1A 13S CR3 occurs in a cell-dependent and cell-independent manner Am J Physiol Lung Cell Mol Physiol, September 1, 2002; 283(3): L619 - L627. [Abstract] [Full Text] [PDF]

				K. Subbaramaiah, L. Norton, W. Gerald, and A. J. Dannenberg Cyclooxygenase-2 Is Overexpressed in HER-2/neu-positive Breast Cancer. EVIDENCE FOR INVOLVEMENT OF AP-1 AND PEA3 J. Biol. Chem., May 17, 2002; 277(21): 18649 - 18657. [Abstract] [Full Text] [PDF]

				S. Fujiie, K. Hieshima, D. Izawa, T. Nakayama, R. Fujisawa, H. Ohyanagi, and O. Yoshie Proinflammatory cytokines induce liver and activation-regulated chemokine/macrophage inflammatory protein-3{alpha}/CCL20 in mucosal epithelial cells through NF-{kappa}B Int. Immunol., October 1, 2001; 13(10): 1255 - 1263. [Abstract] [Full Text] [PDF]

				E. Y. Tsai, J. V. Falvo, A. V. Tsytsykova, A. K. Barczak, A. M. Reimold, L. H. Glimcher, M. J. Fenton, D. C. Gordon, I. F. Dunn, and A. E. Goldfeld A Lipopolysaccharide-Specific Enhancer Complex Involving Ets, Elk-1, Sp1, and CREB Binding Protein and p300 Is Recruited to the Tumor Necrosis Factor Alpha Promoter In Vivo Mol. Cell. Biol., August 15, 2000; 20(16): 6084 - 6094. [Abstract] [Full Text]

				J. An, R. C. J. Ribeiro, P. Webb, J.-A. Gustafsson, P. J. Kushner, J. D. Baxter, and D. C. Leitman Estradiol repression of tumor necrosis factor-alpha transcription requires estrogen receptor activation function-2 and is enhanced by coactivators PNAS, December 21, 1999; 96(26): 15161 - 15166. [Abstract] [Full Text] [PDF]

				C Rohowsky-Kochan, D Molinaro, A Choudhry, M Kahn, and S D Cook Impaired interleukin-12 production in multiple sclerosis patients Multiple Sclerosis, October 1, 1999; 5(5): 327 - 334. [Abstract] [PDF]

				J. H. Ko, E. Miyoshi, K. Noda, A. Ekuni, R. Kang, Y. Ikeda, and N. Taniguchi Regulation of the GnT-V Promoter by Transcription Factor Ets-1 in Various Cancer Cell Lines J. Biol. Chem., August 13, 1999; 274(33): 22941 - 22948. [Abstract] [Full Text] [PDF]

				G. Jayaraman, R. Srinivas, C. Duggan, E. Ferreira, S. Swaminathan, K. Somasundaram, J. Williams, C. Hauser, M. Kurkinen, R. Dhar, et al. p300/cAMP-responsive Element-binding Protein Interactions with Ets-1 and Ets-2 in the Transcriptional Activation of the Human Stromelysin Promoter J. Biol. Chem., June 11, 1999; 274(24): 17342 - 17352. [Abstract] [Full Text] [PDF]

				A. Martin-Villalba, I. Herr, I. Jeremias, M. Hahne, R. Brandt, J. Vogel, J. Schenkel, T. Herdegen, and K.-M. Debatin CD95 Ligand (Fas-L/APO-1L) and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Mediate Ischemia-Induced Apoptosis in Neurons J. Neurosci., May 15, 1999; 19(10): 3809 - 3817. [Abstract] [Full Text] [PDF]

				D. V. Kuprash, I. A. Udalova, R. L. Turetskaya, D. Kwiatkowski, N. R. Rice, and S. A. Nedospasov Similarities and Differences Between Human and Murine TNF Promoters in Their Response to Lipopolysaccharide J. Immunol., April 1, 1999; 162(7): 4045 - 4052. [Abstract] [Full Text] [PDF]

				T. Ishizuka, K. Chayama, K. Takeda, E. Hamelmann, N. Terada, G. M. Keller, G. L. Johnson, and E. W. Gelfand Mitogen-Activated Protein Kinase Activation Through Fc{epsilon} Receptor I and Stem Cell Factor Receptor Is Differentially Regulated by Phosphatidylinositol 3-Kinase and Calcineurin in Mouse Bone Marrow-Derived Mast Cells J. Immunol., February 15, 1999; 162(4): 2087 - 2094. [Abstract] [Full Text] [PDF]

				C. Pelletier, N. Varin-Blank, J. Rivera, B. Iannascoli, F. Marchand, B. David, A. Weyer, and U. Blank Fc{epsilon}RI-Mediated Induction of TNF-{alpha} Gene Expression in the RBL-2H3 Mast Cell Line: Regulation by a Novel NF-{kappa}B-Like Nuclear Binding Complex J. Immunol., November 1, 1998; 161(9): 4768 - 4776. [Abstract] [Full Text] [PDF]

				L. H. McKinlay, M. J. Tymms, R. S. Thomas, A. Seth, S. Hasthorpe, P. J. Hertzog, and I. Kola The Role of Ets-1 in Mast Cell Granulocyte-Macrophage Colony-Stimulating Factor Expression and Activation J. Immunol., October 15, 1998; 161(8): 4098 - 4105. [Abstract] [Full Text] [PDF]

				I. A. Udalova, J. C. Knight, V. Vidal, S. A. Nedospasov, and D. Kwiatkowski Complex NF-kappa B Interactions at the Distal Tumor Necrosis Factor Promoter Region in Human Monocytes J. Biol. Chem., August 14, 1998; 273(33): 21178 - 21186. [Abstract] [Full Text] [PDF]

				A. Zagariya, S. Mungre, R. Lovis, M. Birrer, S. Ness, B. Thimmapaya, and R. Pope Tumor Necrosis Factor Alpha Gene Regulation: Enhancement of C/EBPbeta -Induced Activation by c-Jun Mol. Cell. Biol., May 1, 1998; 18(5): 2815 - 2824. [Abstract] [Full Text]

				G. Gri, D. Savio, G. Trinchieri, and X. Ma Synergistic Regulation of the Human Interleukin-12 p40 Promoter by NFkappa B and Ets Transcription Factors in Epstein-Barr Virus-transformed B Cells and Macrophages J. Biol. Chem., March 13, 1998; 273(11): 6431 - 6438. [Abstract] [Full Text] [PDF]

				J. Yao, N. Mackman, T. S. Edgington, and S.-T. Fan Lipopolysaccharide Induction of the Tumor Necrosis Factor-alpha Promoter in Human Monocytic Cells. REGULATION BY Egr-1, c-Jun, AND NF-kappa B TRANSCRIPTION FACTORS J. Biol. Chem., July 11, 1997; 272(28): 17795 - 17801. [Abstract] [Full Text] [PDF]

				T. Ishizuka, N. Terada, P. Gerwins, E. Hamelmann, A. Oshiba, G. R. Fanger, G. L. Johnson, and E. W. Gelfand Mast cell tumor necrosis factor alpha  production is regulated by MEK kinases PNAS, June 10, 1997; 94(12): 6358 - 6363. [Abstract] [Full Text] [PDF]

				T. M. Schlaeger, S. Bartunkova, J. A. Lawitts, G. Teichmann, W. Risau, U. Deutsch, and T. N. Sato Uniform vascular-endothelial-cell-specific gene expression in both embryonic and adult transgenic mice PNAS, April 1, 1997; 94(7): 3058 - 3063. [Abstract] [Full Text] [PDF]

				J. Kwon, S. J. Lee, and E. N. Benveniste A 3' cis-Acting Element Is Involved in Tumor Necrosis Factor-alpha Gene Expression in Astrocytes J. Biol. Chem., September 13, 1996; 271(37): 22383 - 22390. [Abstract] [Full Text] [PDF]

				R. Gum, E. Lengyel, J. Juarez, J. H. Chen, H. Sato, M. Seiki, and D. Boyd Stimulation of 92-kDa Gelatinase B Promoter Activity by ras Is Mitogen-activated Protein Kinase Kinase 1-independent and Requires Multiple Transcription Factor Binding Sites Including Closely Spaced PEA3/ets and AP-1 Sequences J. Biol. Chem., May 3, 1996; 271(18): 10672 - 10680. [Abstract] [Full Text] [PDF]

				A. Hultgardh-Nilsson, B. Cercek, J.-W. Wang, S. Naito, C. Lovdahl, B. Sharifi, J. S. Forrester, and J. A. Fagin Regulated Expression of the Ets-1 Transcription Factor in Vascular Smooth Muscle Cells In Vivo and In Vitro Circ. Res., April 1, 1996; 78(4): 589 - 595. [Abstract] [Full Text]

				A. Altmeyer, L. Klampfer, A. R. Goodman, and J. Vilcek Promoter Structure and Transcriptional Activation of the Murine TSG-14 Gene Encoding a Tumor Necrosis Factor/Interleukin-1-inducible Pentraxin Protein J. Biol. Chem., October 27, 1995; 270(43): 25584 - 25590. [Abstract] [Full Text] [PDF]

				S. Rudders, J. Gaspar, R. Madore, C. Voland, F. Grall, A. Patel, A. Pellacani, M. A. Perrella, T. A. Libermann, and P. Oettgen ESE-1 Is a Novel Transcriptional Mediator of Inflammation That Interacts with NF-kappa B to Regulate the Inducible Nitric-oxide Synthase Gene J. Biol. Chem., January 26, 2001; 276(5): 3302 - 3309. [Abstract] [Full Text] [PDF]

				J. H. Steer, K. M. Kroeger, L. J. Abraham, and D. A. Joyce Glucocorticoids Suppress Tumor Necrosis Factor-alpha Expression by Human Monocytic THP-1 Cells by Suppressing Transactivation through Adjacent NF-kappa B and c-Jun-Activating Transcription Factor-2 Binding Sites in the Promoter J. Biol. Chem., June 9, 2000; 275(24): 18432 - 18440. [Abstract] [Full Text] [PDF]