This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kumar, A.
Right arrow Articles by Jain, M. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kumar, A.
Right arrow Articles by Jain, M. K.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2005, p. 5893-5903, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.5893-5903.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Tumor Necrosis Factor Alpha-Mediated Reduction of KLF2 Is Due to Inhibition of MEF2 by NF-{kappa}B and Histone Deacetylases

Ajay Kumar, Zhiyong Lin, Sucharita SenBanerjee, and Mukesh K. Jain*

Program in Cardiovascular Transcriptional Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115

Received 9 December 2004/ Returned for modification 18 January 2005/ Accepted 7 April 2005

Activation of the endothelium by inflammatory cytokines is a key event in the pathogenesis of vascular disease states. Proinflammatory cytokines repress the expression of KLF2, a recently identified transcriptional inhibitor of the cytokine-mediated activation of endothelial cells. In this study the molecular basis for the cytokine-mediated inhibition of KLF2 is elucidated. Tumor necrosis factor alpha (TNF-{alpha}) potently inhibited KLF2 expression. This effect was completely abrogated by a constitutively active form of I{kappa}B{alpha}, as well as treatment with trichostatin A, implicating a role for the NF-{kappa}B pathway and histone deacetylases. Overexpression studies coupled with observations with p50/p65 null cells support an essential role for p65. A combination of promoter deletion and mutational analyses, chromatin immunoprecipitation assays, and coimmunoprecipitation studies indicates that p65 and histone deacetylases 4 cooperate to inhibit the ability of MEF2 factors to induce the KLF2 promoter. These studies identify a novel mechanism by which TNF-{alpha} can inhibit endothelial gene expression. Furthermore, the inhibition of MEF2 function by p65 and HDAC4 has implications for other cellular systems where these factors are operative.

* Corresponding author. Mailing address: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St. TH1127, Boston, MA 02115. Phone: (617) 278-0175. Fax: (617) 732-5132. E-mail: mjain{at}rics.bwh.harvard.edu.

Molecular and Cellular Biology, July 2005, p. 5893-5903, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.5893-5903.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sako, K., Fukuhara, S., Minami, T., Hamakubo, T., Song, H., Kodama, T., Fukamizu, A., Gutkind, J. S., Koh, G. Y., Mochizuki, N. (2009). Angiopoietin-1 Induces Kruppel-like Factor 2 Expression through a Phosphoinositide 3-Kinase/AKT-dependent Activation of Myocyte Enhancer Factor 2. J. Biol. Chem. 284: 5592-5601 [Abstract] [Full Text]  
  • Saavedra, M. T., Patterson, A. D., West, J., Randell, S. H., Riches, D. W., Malcolm, K. C., Cool, C. D., Nick, J. A., Dinarello, C. A. (2008). Abrogation of Anti-Inflammatory Transcription Factor LKLF in Neutrophil-Dominated Airways. Am. J. Respir. Cell Mol. Bio. 38: 679-688 [Abstract] [Full Text]  
  • Woo, C.-H., Shishido, T., McClain, C., Lim, J. H., Li, J.-D., Yang, J., Yan, C., Abe, J.-i. (2008). Extracellular Signal-Regulated Kinase 5 SUMOylation Antagonizes Shear Stress-Induced Antiinflammatory Response and Endothelial Nitric Oxide Synthase Expression in Endothelial Cells. Circ. Res. 102: 538-545 [Abstract] [Full Text]  
  • Berk, B. C. (2008). Atheroprotective Signaling Mechanisms Activated by Steady Laminar Flow in Endothelial Cells. Circulation 117: 1082-1089 [Full Text]  
  • Wu, J., Bohanan, C. S., Neumann, J. C., Lingrel, J. B. (2008). KLF2 Transcription Factor Modulates Blood Vessel Maturation through Smooth Muscle Cell Migration. J. Biol. Chem. 283: 3942-3950 [Abstract] [Full Text]  
  • Groenendijk, B. C. W., Van der Heiden, K., Hierck, B. P., Poelmann, R. E. (2007). The Role of Shear Stress on ET-1, KLF2, and NOS-3 Expression in the Developing Cardiovascular System of Chicken Embryos in a Venous Ligation Model. Physiology 22: 380-389 [Abstract] [Full Text]  
  • Atkins, G. B., Jain, M. K. (2007). Role of Kruppel-Like Transcription Factors in Endothelial Biology. Circ. Res. 100: 1686-1695 [Abstract] [Full Text]  
  • Thum, T., Bauersachs, J. (2006). Sports or statins for atheroprotection? New insight from Kruppel-like factor 2. Cardiovasc Res 72: 193-195 [Full Text]  
  • van Thienen, J. V., Fledderus, J. O., Dekker, R. J., Rohlena, J., van IJzendoorn, G. A., Kootstra, N. A., Pannekoek, H., Horrevoets, A. J.G. (2006). Shear stress sustains atheroprotective endothelial KLF2 expression more potently than statins through mRNA stabilization. Cardiovasc Res 72: 231-240 [Abstract] [Full Text]  
  • Huddleson, J. P., Ahmad, N., Lingrel, J. B. (2006). Up-regulation of the KLF2 Transcription Factor by Fluid Shear Stress Requires Nucleolin. J. Biol. Chem. 281: 15121-15128 [Abstract] [Full Text]  
  • Lin, Z., Hamik, A., Jain, R., Kumar, A., Jain, M. K. (2006). Kruppel-Like Factor 2 Inhibits Protease Activated Receptor-1 Expression and Thrombin-Mediated Endothelial Activation. Arterioscler. Thromb. Vasc. Bio. 26: 1185-1185 [Abstract] [Full Text]  
  • Das, H., Kumar, A., Lin, Z., Patino, W. D., Hwang, P. M., Feinberg, M. W., Majumder, P. K., Jain, M. K. (2006). Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Proc. Natl. Acad. Sci. USA 103: 6653-6658 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»