Human Trefoil Factor 3 induces the transcription of its own promoter through STAT3

Abstract

Human trefoil factor 3 (hTFF3) is a small peptide of potential therapeutic value. The mechanisms underlying the transcriptional regulation of hTFF3 remain unclear. The purpose of this study was to identify the core functional elements for the self-induction action of hTFF3 and transcription factors. First, truncated promoters were constructed to identify the functional regions of the hTFF3 promoter. Next, point mutation, chromatin immunoprecipitation, RNA interference, and gene overexpression experiments were performed to analyze the transcriptional binding sites responsible for the self-induced transcription of hTFF3. Our results revealed the −1450 bp to −1400 bp fragment of the hTFF3 promoter was the functional region for the self-induction action of hTFF3. Bioinformatics analysis confirmed that a STAT3 binding site is present in the −1417 bp to −1409 bp region. Subsequently, site-directed mutagenesis analysis determined that this STAT3 binding site was critical for the self-induction effect of hTFF3. ChIP experiments confirmed that STAT3 binds to the hTFF3 promoter. STAT3 overexpression and knockdown experiments revealed that STAT3 enhanced the self-induction effect and the expression of hTFF3. This study confirmed that hTFF3 exhibits self-induction action, and that STAT3 is the key transcription factor to maintain the function of self-induction.

Gastric TFF1 Expression from Acute to Chronic Helicobacter Infection

“…The regulatory cross-talk among the three Trefoil peptides was already described (Taupin et al, 1999 ), nevertheless our analysis highlights such crosstalk upon Helicobacter infection. Interestingly, in hyper-expressing clone TFF1 is so strongly induced that its level cannot be explained as the mere sum of dox-induced plus H. pylori- induced mRNA; such result could be justified with an auto-induction mechanism, already described for TFF2 and TFF3 (Bulitta et al, 2002 ; Sun et al, 2016 ), and we are currently examining this possibility.…”

Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy

“…Trefoil factor 3 (TFF3) is a small peptide that has essential roles in restitution, such as cell migration to heal superficial lesions, and in regeneration, including differentiation and proliferation in the repair of the epithelia. [1][2][3] It has been suggested that TFF3 is expressed in all mucus-secreting tissues, including the renal tubules. 4 The TFF3 expression increases in various organs as the consequence of tissue damage such as inflammation or fibrosis.…”

TFF3 is a ligand for LINGO2 that de-represses EGFR to control disease outcome during colitis and gastrointestinal nematode infection

“…TFF3-mediated cytoprotective functions are well-documented and are associated with activation of EGFR and ERK in various cell lines derived from pancreas, lung, and colon 3,24,25 26 . While TFF3 can regulate the transcription factor STAT3 by promoting Stat3 phosphorylation and STAT3 transcriptional activation of TFF3 and other STAT3-dependent genes 27,28 , these effects are not mediated by direct binding of TFF3 to the EGFR 29 . To determine if TFF3 instead impacts EGFR signaling and subsequent STAT3-dependent signaling through LINGO2, we used a murine intestinal adenocarcinoma cell line (MC38) that expresses all four LINGO family member genes, with LINGO2 showing highest expression ( Figure 2A).…”