Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-β-induced transcription

Smad proteins transduce signals for transforming growth factor-β (TGF-β)-related factors1. Smad proteins activated by receptors for TGF-β form complexes with Smad4. These complexes are translocated into the nucleus and regulate ligand-indu ced gene transcription2,3,4. 12- O-tetradecanoyl-13-acetate (TPA)-responsive gene promoter elements (TREs) are involved in the transcriptional responses of several genes to TGF-β (5–8). AP-1 transcription factors, composed of c-Jun and c-Fos, bind to and direct transcription from TREs, which are therefore known as AP1-binding sites9. Here we show that Smad3 interacts directly with the TRE and that Smad3 and Smad4 can activate TGF-β-inducible transcription from the TRE in the absence of c-Jun and c-Fos. Smad3 and Smad4 also act together with c-Jun and c-Fos to activate transcription in response to TGF-β, through a TGF-β-inducible association of c-Jun with Smad3 and an interaction of Smad3 and c-Fos. These interactions complement interactions between c-Jun and c-Fos, and between Smad3 and Smad4. This mechanism of transcriptional activation by TGF-β, through functional and physical interactions between Smad3–Smad4 and c-Jun–c-Fos, shows that Smad signalling and MAPK/JNK signalling converge at AP1-binding promoter sites.