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.
References
[1]
Massague J (2008) TGFbeta in Cancer. Cell 134: 215–230.
[2]
Schmierer B, Hill CS (2007) TGFbeta-Smad signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8: 970–982.
[3]
Venturini L, You J, Stadler M, Galien R, Lallemand V, et al. (1999) TIF1gamma, a novel member of the transcriptional intermediary factor 1 family. Oncogene 18: 1209–1217.
[4]
Dupont S, Zacchigna L, Cordenonsi M, Soligo S, Adorno M, et al. (2005) Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell 121: 87–99.
[5]
Dupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, et al. (2009) FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell 136: 123–135.
[6]
Morsut L, Yan KP, Enzo E, Aragona M, Soligo SM, et al. (2010) Negative control of Smad activity by ectodermin/TIF1gamma patterns the mammalian embryo. Development 137: 2571–2578.
[7]
He W, Dorn DC, Erdjument-Bromage H, Tempst P, Moore MA, et al. (2006) Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway. Cell 125: 929–941.
[8]
Yan KP, Dolle P, Mark M, Lerouge T, Wendling O, et al. (2004) Molecular cloning, genomic structure, and expression analysis of the mouse transcriptional intermediary factor 1 gamma gene. Gene 334: 3–13.
[9]
Vincent DF, Yan KP, Treilleux I, Gay F, Arfi V, et al. (2009) Inactivation of TIF1gamma cooperates with Kras to induce cystic tumors of the pancreas. PLoS Genet 5: e1000575.
[10]
Aucagne R, Droin N, Paggetti J, Lagrange B, Largeot A, et al. (2011) Transcription intermediary factor 1gamma is a tumor suppressor in mouse and human chronic myelomonocytic leukemia. J Clin Invest 121: 2361–2370.
[11]
Herquel B, Ouararhni K, Khetchoumian K, Ignat M, Teletin M, et al. (2011) Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma. Proc Natl Acad Sci U S A 108: 8212–8217.
[12]
Hesling C, Fattet L, Teyre G, Jury D, Gonzalo P, et al. (2011) Antagonistic regulation of EMT by TIF1gamma and Smad4 in mammary epithelial cells. EMBO Rep 12: 665–672.
[13]
Vilar JM, Jansen R, Sander C (2006) Signal processing in the TGF-beta superfamily ligand-receptor network. PLoS Comput Biol 2: e3.
[14]
Clarke DC, Betterton MD, Liu X (2006) Systems theory of Smad signalling. Syst Biol (Stevenage) 153: 412–424.
[15]
Melke P, Jonsson H, Pardali E, ten Dijke P, Peterson C (2006) A rate equation approach to elucidate the kinetics and robustness of the TGF-beta pathway. Biophys J 91: 4368–4380.
[16]
Schmierer B, Tournier AL, Bates PA, Hill CS (2008) Mathematical modeling identifies Smad nucleocytoplasmic shuttling as a dynamic signal-interpreting system. Proc Natl Acad Sci U S A 105: 6608–6613.
[17]
Nakabayashi J, Sasaki A (2009) A mathematical model of the stoichiometric control of Smad complex formation in TGF-beta signal transduction pathway. J Theor Biol 259: 389–403.
[18]
Chung SW, Miles FL, Sikes RA, Cooper CR, Farach-Carson MC, et al. (2009) Quantitative modeling and analysis of the transforming growth factor beta signaling pathway. Biophys J 96: 1733–1750.
[19]
Zi Z, Feng Z, Chapnick DA, Dahl M, Deng D, et al. (2011) Quantitative analysis of transient and sustained transforming growth factor-beta signaling dynamics. Mol Syst Biol 7: 492.
[20]
Zi Z, Klipp E (2007) Constraint-based modeling and kinetic analysis of the Smad dependent TGF-beta signaling pathway. PLoS One 2: e936.
[21]
Elenbaas B, Spirio L, Koerner F, Fleming MD, Zimonjic DB, et al. (2001) Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev 15: 50–65.
[22]
Agricola E, Randall RA, Gaarenstroom T, Dupont S, Hill CS (2011) Recruitment of TIF1gamma to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities. Mol Cell 43: 85–96.
[23]
Bierie B, Moses HL (2006) Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 6: 506–520.
[24]
Hyytiainen M, Penttinen C, Keski-Oja J (2004) Latent TGF-beta binding proteins: extracellular matrix association and roles in TGF-beta activation. Crit Rev Clin Lab Sci 41: 233–264.
[25]
Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 116: 217–224.
[26]
Bruna A, Darken RS, Rojo F, Ocana A, Penuelas S, et al. (2007) High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 11: 147–160.
[27]
Barter MJ, Pybus L, Litherland GJ, Rowan AD, Clark IM, et al. (2010) HDAC-mediated control of ERK- and PI3K-dependent TGF-beta-induced extracellular matrix-regulating genes. Matrix Biol 29: 602–612.
[28]
Hannigan A, Smith P, Kalna G, Lo Nigro C, Orange C, et al. (2010) Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter. J Clin Invest 120: 2842–2857.
[29]
Assmann SM, Albert R (2009) Discrete dynamic modeling with asynchronous update, or how to model complex systems in the absence of quantitative information. Methods Mol Biol 553: 207–225.
[30]
Sreenath SN, Cho KH, Wellstead P (2008) Modelling the dynamics of signalling pathways. Essays Biochem 45: 1–28.
