Fattet L, Ay AS, Bonneau B, Jallades L, Mikaelian I, Treilleux I, Gillet G, Hesling C, Rimokh R

TIF1γ, a new actor of TGFβ signaling, inhibits the Smad4-mediated TGFβ response by interaction with Smad2/3 or ubiquitination of Smad4. We have shown that TIF1γ participates in TGFβ signaling as a negative regulator of Smad4 during the TGFβ-induced epithelial-to-mesenchymal transition in mammary epithelial cells and during terminal differentiation of mammary ...

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alveolar epithelial cells and lactation. We demonstrate here that TIF1γ is sumoylated and interacts with Ubc9, the only known SUMO-conjugating enzyme. Four functional sumoylation sites lie within the middle domain of TIF1γ, the Smad interaction domain. We show that a sumoylation-defective TIF1γ mutant significantly reduces TIF1γ inhibition of Smad complexes and that of the Smad-mediated TGFβ transcriptional response. Moreover, chromatin immunoprecipitation experiments indicate that TIF1γ sumoylation is required to limit Smad4 binding on the PAI-1 TGFβ target gene promoter. Ectopic expression of TIF1γ in mammary epithelial cells inhibits TGFβ-induced EMT, an effect relieved by expression of non-sumoylated TIF1γ. Taken together, our results identify a new TGFβ regulatory layer, whereby sumoylation strengthens the TIF1γ repressive action on canonical TGFβ signaling.

Date: Jun. 20, 2013

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