SMAD3 AND SMAD4 COOPERATE WITH C-JUN C-FOS TO MEDIATE TGF-BETA-INDUCED TRANSCRIPTION/

Smad proteins transduce signals for transforming growth factor-beta (T GF-beta)-related factors'. Smad proteins activated by receptors for TG F-beta form complexes with Smad4. These com plexes are translocated in to the nucleus and regulate ligand-induced gene transcription(2-4). 12 -O-tetradecanoyl-13-acetate (TPA)-responsive gene promoter elements (T REs) are involved in the transcriptional responses of several genes to TGF-beta (refs 5-8), AP-1 transcription factors, composed of c-Jun an d c-Fos, bind to and direct transcription from TREs, which are therefo re known as AP1-binding sites(9). Here we show that Smad3 interacts di rectly with the TRE and that SmadS and Smad4 can activate TGF-beta-ind ucible transcription from the TRE in the absence of c-Jun and c-Fos, S mad3 and Smad4 also act together with c-Jun and c-Fos to activate tran scription in response to TGF-beta, through a TGF-P-inducible associati on of c-Jun with Smad3 and an interaction of Smad3 and c-Fos, These in teractions complement interactions between c-Jun and c-Fos, and betwee n Smad3 and Smad4, This mechanism of transcriptional activation by TGF -P, through functional and physical interactions between Smad3-Smad4 a nd c-Jun-c-Fos, shows that Smad signalling and MAPK/JNK signalling con verge at AP1-binding promoter sites.