Transforming growth factor β regulates P-body formation through induction of the mRNA decay factor tristetraprolin.

Blanco FF, Sanduja S, Deane NG, Blackshear PJ, Dixon DA
Mol Cell Biol. 2014 34 (2): 180-95

PMID: 24190969 · PMCID: PMC3911289 · DOI:10.1128/MCB.01020-13

Transforming growth factor β (TGF-β) 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-β inhibited ARE-mRNA expression. This effect of TGF-β was promoted through increased assembly of cytoplasmic RNA processing (P) bodies where ARE-mRNA localization was observed. P-body formation was dependent on TGF-β/Smad signaling, as Smad3 deletion abrogated P-body formation. In concert with increased P-body formation, TGF-β induced expression of the ARE-binding protein tristetraprolin (TTP), which colocalized to P bodies. TTP expression was necessary for TGF-β-dependent P-body formation and promoted growth inhibition by TGF-β. The significance of this was observed in vivo, where colonic epithelium deficient in TGF-β/Smad signaling or TTP expression showed attenuated P-body levels. These results provide new insight into TGF-β's antiproliferative properties and identify TGF-β as a novel mRNA stability regulator in intestinal epithelium through its ability to promote TTP expression and subsequent P-body formation.

MeSH Terms (22)

3' Untranslated Regions Animals AU Rich Elements Binding Sites Cell Line Cell Proliferation Cellular Senescence Colon Cytoplasmic Structures Intestinal Mucosa Mice Mice, Knockout Promoter Regions, Genetic Rats RNA, Messenger RNA Processing, Post-Transcriptional RNA Stability Signal Transduction Smad3 Protein Transcriptional Activation Transforming Growth Factor beta Tristetraprolin

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