%0 Journal Article
%T Dynamic Regulation of Tgf-B Signaling by Tif1¦Ã: A Computational Approach
%A Geoffroy Andrieux
%A Laurent Fattet
%A Michel Le Borgne
%A Ruth Rimokh
%A Nathalie Th¨¦ret
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0033761
%X TIF1¦Ã (Transcriptional Intermediary Factor 1 ¦Ã) has been implicated in Smad-dependent signaling by Transforming Growth Factor beta (TGF-¦Â). Paradoxically, TIF1¦Ã functions both as a transcriptional repressor or as an alternative transcription factor that promotes TGF-¦Â signaling. Using ordinary differential-equation models, we have investigated the effect of TIF1¦Ã on the dynamics of TGF-¦Â signaling. An integrative model that includes the formation of transient TIF1¦Ã-Smad2-Smad4 ternary complexes is the only one that can account for TGF-¦Â signaling compatible with the different observations reported for TIF1¦Ã. In addition, our model predicts that varying TIF1¦Ã/Smad4 ratios play a critical role in the modulation of the transcriptional signal induced by TGF-¦Â, especially for short stimulation times that mediate higher threshold responses. Chromatin immunoprecipitation analyses and quantification of the expression of TGF-¦Â target genes as a function TIF1¦Ã/Smad4 ratios fully validate this hypothesis. Our integrative model, which successfully unifies the seemingly opposite roles of TIF1¦Ã, also reveals how changing TIF1¦Ã/Smad4 ratios affect the cellular response to stimulation by TGF-¦Â, accounting for a highly graded determination of cell fate.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0033761