dynamic regulation of tgf-b signaling by tif1γ a computational approach动态调节tif1γtgf-b信号的一种计算方法.pdf

Dynamic Regulation of Tgf-B Signaling by Tif1c: A Computational Approach 1,2 3 2 3 ´ 1 Geoffroy Andrieux , Laurent Fattet , Michel Le Borgne , Ruth Rimokh , Nathalie Theret * ´ ´ 1 Inserm U1085-IRSET, Universite de Rennes 1, Rennes, France, 2 Universite de Rennes 1, IRISA, Rennes, France, 3 Inserm U1052/CNRS 5286, Centre de Recherche en ´ Cancerologie de Lyon, Lyon, France Abstract TIF1c (Transcriptional Intermediary Factor 1 c) has been implicated in Smad-dependent signaling by Transforming Growth Factor beta (TGF-b). Paradoxically, TIF1c functions both as a transcriptional repressor or as an alternative transcription factor that promotes TGF-b signaling. Using ordinary differential-equation models, we have investigated the effect of TIF1c on the dynamics of TGF-b signaling. An integrative model that includes the formation of transient TIF1c-Smad2-Smad4 ternary complexes is the only one that can account for TGF-b signaling compatible with the different observations reported for TIF1c. In addition, our model predicts that varying TIF1c/Smad4 ratios play a critical role in the modulation of the transcriptional signal induced by TGF-b, especially for short stimulation times that mediate higher threshold responses. Chromatin immunoprecipitation analyses and quantification of the expression of TGF-b target genes as a function TIF1c/ Smad4 ratios fully validate this hypothesis. Our integrative model, which successfully unifies the seemingly opposite roles of TIF1c, also reveals how changing TIF1c/Smad4 ratios affect the cellular response to stimulation by TGF- b, accounting for a