Transforming Growth Factor β Regulates P-Body Formation through Induction of the mRNA Decay Factor Tristetraprolin

Abstract

dTransforming growth factor ␤ (TGF-␤) is a potent growth regulator and tumor suppressor in normal intestinal epithelium. Likewise, epithelial cell growth is controlled by rapid decay of growth-related mRNAs mediated through 3= untranslated region (UTR) AU-rich element (ARE) motifs. We demonstrate that treatment of nontransformed intestinal epithelial cells with TGF-␤ inhibited ARE-mRNA expression. This effect of TGF-␤ was promoted through increased assembly of cytoplasmic RNA processing (P) bodies where ARE-mRNA localization was observed. P-body formation was dependent on TGF-␤/Smad signaling, as Smad3 deletion abrogated P-body formation. In concert with increased P-body formation, TGF-␤ induced expression of the ARE-binding protein tristetraprolin (TTP), which colocalized to P bodies. TTP expression was necessary for TGF-␤-dependent P-body formation and promoted growth inhibition by TGF-␤. The significance of this was observed in vivo, where colonic epithelium deficient in TGF-␤/Smad signaling or TTP expression showed attenuated P-body levels. These results provide new insight into TGF-␤'s antiproliferative properties and identify TGF-␤ as a novel mRNA stability regulator in intestinal epithelium through its ability to promote TTP expression and subsequent P-body formation.

Transforming Growth Factor β Activation Primes Canonical Wnt Signaling Through Down‐Regulation of Axin‐2

“…Bioinformatic analysis revealed the presence of several AU‐rich elements (AREs) located in the 3′‐untranslated region (3′‐UTR) of the Axin‐2 transcript (see Supplementary Figure 2C, http://onlinelibrary.wiley.com/doi/10.1002/art.40437/abstract). Recruitment of TTP‐1 to ARE‐containing transcripts leads to destabilization and degradation . Concordantly, siRNA‐mediated silencing of mRNA for TTP‐1 in SSc fibroblasts increased expression of mRNA for Axin‐2 and Dkk‐1 relative to nontargeting (scrambled) siRNA by 151% ( P < 0.05) and 142% ( P < 0.05), respectively, and in healthy control fibroblasts treated with TGFβ by 162.1% ( P < 0.01) and 161.5% ( P < 0.01), respectively (Figure G).…”

“…The degradation of the majority of eukaryotic mRNAs occurs through poly(A) tail shortening and is mediated by the recruitment of the RNA‐degrading exosome complex . TTP‐1, a TGFβ‐responsive ARE‐binding protein, can facilitate the recruitment of the exosome complex and enhance mRNA decay in transcripts containing 3′‐UTR ARE motifs, including TNF , c‐ myc , and CCND1 . Consistent with the presence of ARE motifs located within the 3′‐UTR of the Axin‐2 gene, silencing of TTP‐1 expression led to a significant up‐regulation of both Axin‐2 mRNA and protein expression.…”

The IκB kinase complex is a regulator of mRNA stability

“…It was previously shown that mRNAs of cytokines are enriched for AU‐rich elements in their 3′ UTRs (Hao & Baltimore, ). AREs are known to regulate RNA stability in both positive and negative manner (Blanco et al , ; Zid & O'Shea, ; Halstead et al , ). To determine whether AREs in the 3′ UTR would be overrepresented in the above‐mentioned groups of transcripts, we analysed the occurrence of the annotated AREs, using 1,000 randomly selected 3′ UTRs as control (Table EV7).…”

AST IV inhibits H2O2-induced human umbilical vein endothelial cell apoptosis by suppressing Nox4 expression through the TGF-β1/Smad2 pathway

“…expression through the TGF-β1/Smad2 pathway the nucleus and modulates the transcription of TGF-β1 target genes (13,14). Previous studies have demonstrated that TGF-β1/ Smad2 possesses potent proliferative activity in various cell types (15)(16)(17), whereas others have demonstrated that it induces apoptosis in a number of cells (18)(19)(20).…”