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

An Erratum to this article was published on 03 December 1998

Abstract

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 (58). 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.

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Figure 1: Smad3/Smad4 and c-Jun–c-Fos cooperate to induce tra nscription from the AP-1 promoter.
Figure 2: Interaction between Smad3 and c-Jun or c-Fos.
Figure 3: Smad3–Smad4 and c-Jun–c-Fos participate in a nucleoprotein complex with the consensus AP1-binding sequence.
Figure 4: Dominant-negative inhibition of TGF-β- and Smad3/4-induced transcription from the AP1-binding site by truncated c-Jun or Smad3.
Figure 5: Domains of c-Jun and Smad3.

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Acknowledgements

This research was supported by the NIH (R.D.) and postdoctoral fellowships from the American Lung Association (to Y.Z.) and the American Cancer Society (to X-H.F.). We thank J.Massagué, J. Wrana and L. Attisano, M. Karin, D. Loskutoff, J. Wang, K. Yamamoto, P. Kushner, X.-F. Wang, P. ten Dijke, M.Green, M. Ptashne and R. Tijan for valuable reagents, and M. Cronin and L. Choy for reading of the manuscript.

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Correspondence to Rik Derynck.

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Zhang, Y., Feng, XH. & Derynck, R. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-β-induced transcription. Nature 394, 909–913 (1998). https://doi.org/10.1038/29814

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