EGF activates TTP expression by activation of ELK-1 and EGR-1 transcription factors

Our results demonstrate the induction of the gene coding TTP (ZFP36) by EGF through the ERK1/2-dependent pathway and implicates the transcription factor ELK-1 in this process. We show that ELK-1 regulates ZFP36 expression by two mechanisms: by binding the ZFP36 promoter directly through ETS-binding site (+ 883 to +905 bp) and by inducing expression of EGR-1, which in turn increases ZFP36 expression through sequences located between -111 and -103 bp.EGF activates TTP expression via ELK-1 and EGR-1 transcription factors.Gene ZFP36 encodes for tristetraprolin (TTP, also known as G0S24, ZFP36, TIS11, and Nup475). The gene product is the prototype of the tandem CCCH zinc finger protein family, called TIS11, which includes four structurally and sequentially related proteins - TTP, BRF-1, BRF-2 and ZFP36L3 [1]. TIS11 family members feature a conserved non-typical tandem zinc finger domain that mediates its interaction with target RNA species [2]. TTP is the most thoroughly described member of the TIS11 family, and has been identified as a nucleo-cytoplasmic protein that specifically binds mRNAs containing Adenine/Uridine-Rich Elements (AREs) in their 3'-UTRs (3'-untranslated regions) and directs them to exosome- or P-body-mediated degradation [3]. Genome-wide experiments have revealed many potential targets for TTP-mediated degradation. A more direct approach confirmed that TTP interacts with transcripts encoding for a number of cytokines (TNFα, IL-1β, IL-2, IL-6, GM-CSF), pro-inflammatory factors (iNOS, COX-2), proteins which have important roles in breast cancer invasion and metastasis (urokinase, urokinase receptor, metalloproteinase-1, VEGF), immediate-early response proteins like c-FOS and tristetraprolin itself [4-6].The activity of TTP is regulated predominantly via its phosphorylation by MAP kinases (in particular p38 and ERK1/2), kinases downstream of MAPKs (including MK2, the p38 substrate or MK3) or AKT in response to pro-inflammatory cytokines (TNFα, IL-1β, IFN