title: Dynamic regulation of Tgf-B signaling by Tif1γ: a computational approach.
abstract: TIF1γ (Transcriptional Intermediary Factor 1 γ) has been implicated in Smad-dependent signaling by Transforming Growth Factor beta (TGF-β). Paradoxically, TIF1γ functions both as a transcriptional repressor or as an alternative transcription factor that promotes TGF-β signaling. Using ordinary differential-equation models, we have investigated the effect of TIF1γ on the dynamics of TGF-β signaling. An integrative model that includes the formation of transient TIF1γ-Smad2-Smad4 ternary complexes is the only one that can account for TGF-β signaling compatible with the different observations reported for TIF1γ. In addition, our model predicts that varying TIF1γ/Smad4 ratios play a critical role in the modulation of the transcriptional signal induced by TGF-β, especially for short stimulation times that mediate higher threshold responses. Chromatin immunoprecipitation analyses and quantification of the expression of TGF-β target genes as a function TIF1γ/Smad4 ratios fully validate this hypothesis. Our integrative model, which successfully unifies the seemingly opposite roles of TIF1γ, also reveals how changing TIF1γ/Smad4 ratios affect the cellular response to stimulation by TGF-β, accounting for a highly graded determination of cell fate.
authors.affiliation: Inserm U1085-IRSET, Université de Rennes 1, Rennes, France.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Andrieux
authors.forename: Laurent
authors.initials: L
authors.lastname: Fattet
authors.forename: Michel
authors.initials: M
authors.lastname: Le Borgne
authors.forename: Ruth
authors.initials: R
authors.lastname: Rimokh
authors.forename: Nathalie
authors.initials: N
authors.lastname: Théret
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D051899:Smad2 Protein; D051901:Smad4 Protein; C511956:TRIM33 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta