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 language | English (US) |
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Pages (from-to) | 6084-6094 |
Number of pages | 11 |
Journal | Molecular and cellular biology |
Volume | 20 |
Issue number | 16 |
DOIs | |
State | Published - 2000 |
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology