Abstract
Engagement of the tumor necrosis factor-alpha (TNF-alpha) receptors by the TNF-alpha ligand results in the rapid induction of TNF-alpha gene expression. The study presented here shows that autoregulation of TNF-alpha gene transcription by selective signaling through tumor necrosis factor receptor 1 (TNFR1) requires p38 mitogen-activated protein (MAP) kinase activity and the binding of the transcription factors ATF-2 and Jun to the TNF-alpha cAMP-response element (CRE) promoter element. Consistent with these findings, TNFR1 engagement results in increased p38 MAP kinase activity and p38-dependent phosphorylation of ATF-2. Furthermore, overexpression of MADD (MAP kinase-activating death domain protein), an adapter protein that binds to the death domain of TNFR1 and activates MAP kinase cascades, results in CRE-dependent induction of TNF-alpha gene expression. Thus, the TNF-alpha CRE site is the target of TNFR1 stimulation and mediates the autoregulation of TNF-alpha gene transcription.
Highlights
The tumor necrosis factor (TNF)1-␣ gene encodes a pleiotropic cytokine involved in multiple immunological responses [1]
tumor necrosis factor receptor 1 (TNFR1)-mediated Phosphorylation of ATF-2 Is Dependent upon p38 mitogen-activated protein (MAP) Kinase—Since ATF-2 becomes transcriptionally active upon phosphorylation by p38 MAP kinase, we studied the role of p38 MAP kinase activity in TNFR1-stimulated TNF-␣ gene expression and ATF-2 phosphorylation in L929 cells
We have shown that TNFR1 engagement leads to TNF-␣ gene transcription through the p38-dependent phosphorylation and binding of ATF-2/Jun to the TNF-␣ cAMP-response element (CRE) promoter element
Summary
The tumor necrosis factor (TNF)1-␣ gene encodes a pleiotropic cytokine involved in multiple immunological responses [1]. This TNF-␣ CRE site is critical in the regulation of TNF-␣ by multiple signal transduction pathways and binds ATF-2 and Jun proteins [19, 20], which become transcriptionally active upon phosphorylation by the p38 and JNK members of the MAP kinase family of protein kinases [17]. This induction is dependent upon p38 MAP kinase activity and the binding of ATF-2/Jun proteins to the TNF-␣ CRE.
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