title: Transforming growth factor β regulates P-body formation through induction of the mRNA decay factor tristetraprolin.
abstract: 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.
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Blanco
authors.forename: Sandhya
authors.initials: S
authors.lastname: Sanduja
authors.forename: Natasha G
authors.initials: NG
authors.lastname: Deane
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.forename: Dan A
authors.initials: DA
authors.lastname: Dixon
mesh_terms: D020413:3' Untranslated Regions; D063307:AU Rich Elements; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence; D003106:Colon / Q000166:cytology; D022083:Cytoplasmic Structures / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000502:physiology*; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D012333:RNA, Messenger; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; D051816:Tristetraprolin