A lipopolysaccharide-specific enhancer complex involving Ets, Elk-l, Spl, and CREB binding protein and p300 is recruited to the tumor necrosis factor alpha promoter in vivo

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, A. E. Goldfeld

Research output: Contribution to journalArticle

215 Scopus citations

Abstract

The tumor necrosis factor alpha (TNF-α) gene is rapidly activated by lipopolysaccbaride (LPS). Here, we show that extracellular signal-regulated kinase (ERK) kinase activity but not calcineurin phosphatase activity is required for LPS-stimulated TNF-α gene expression. In LPS-stimulated macrophages, the ERK substrates Ets and Elk-1 bind to the TNF-α promoter in vivo. Strikingly, Ets and Elk-1 bind to two TNF-α nuclear factor of activated T cells (NFAT)-binding sites, which are required for calcineurin and NFAT-dependent TNF-α gene expression in lymphocytes. The transcription factors ATF-2, c-jun, Egr-1, and Sp1 are also inducibly recruited to the TNF-α promoter in vivo, and the binding sites for each of these activators are required for LPS-stimulated TNF-α gene expression. Furthermore, assembly of the LPS-stimulated TNF-α enhancer complex is dependent upon the coactivator proteins CREB binding protein and p300. The finding that a distinct set of transcription factors associates with a fixed set of binding sites on the TNF-α promoter in response to LPS stimulation lends new insights into the mechanisms by which complex patterns of gene regulation are achieved.

Original languageEnglish (US)
Pages (from-to)6084-6094
Number of pages11
JournalMolecular and cellular biology
Volume20
Issue number16
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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