Specificity in the response to growth factors: TGF regulation.

TGF is a paradigm morphogen during embryonic development, and a pleiotropic cytokine of adult tissues. In recent years, we have been interested in dissecting what are the cellular determinants that limit the repertoire of gene-expression programs that TGF can induce in a given cellular context. Our work has revealed the importance of p53 family members in directing TGF gene responses in embryonic development and adult epithelial cells (Cordenonsi et al., Cell 2003; Science 2007). We have also identified, and genetically validated, a new set of enzymes regulating intensity and duration of TGF signaling by causing regulative ubiquitination and de-ubiquitination of Smads (Dupont et al., Cell 2005; Cell 2009; Inui et al., Nat Cell Biol 2010; Morsut et al., Development 2010), and contributed to the concept that TGF signaling is under negative control by secreted antagonists and miRNAs (Zacchigna et al., Cell 2006; Martello et al., Nature 2007).

(Left) The pictures show mouse embryos at very early stages of development, stained for Smad target genes. Absence of the Smad inhibitor Ectodermin/Tif1g/TRIM33, enhanced endogenous TGFb signaling; mutant mice are genetically rescued by reducing the dosage of TGFb (Nodal) ligand (Morsut et al., 2010; Dupont et al., 2009). (Right) The Wnt-reporter BAT-gal mouse (Maretto et al., 2003). (Bottom) A model for R-Smad regulation by the ubiquitin system (Inui et al., 2011).
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