Engagement of tumor necrosis factor (TNF) receptor 1 leads to ATF-2- and p38 mitogen-activated protein kinase-dependent TNF-α gene expression

Abstract

Engagement of the tumor necrosis factor-α (TNF-α) receptors by the TNF-α ligand results in the rapid induction of TNF-α gene expression. The study presented here shows that autoregulation of TNF-α 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-α 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-α gene expression. Thus, the TNF-α CRE site is the target of TNFR1 stimulation and mediates the autoregulation of TNF-α gene transcription.