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

Nature volume 394, pages 909–913 (1998)Cite this article

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 (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.

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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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References

  1. Heldin, C. H., Miyazono, K. & ten Dijke, P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465– 471 (1997).

    Article  ADS  CAS  Google Scholar 

  2. Lagna, G., Hata, A., Hemmati-Brivanlou, A. & Massagué, J. Partnership between DPC4 and SMAD proteins in TGF-β signalling pathways. Nature 383, 832–836 (1996).

    Article  ADS  CAS  Google Scholar 

  3. Zhang, Y., Feng, X.-H., Wu, R.-Y. & Derynck, R. Receptor-associated Mad homologues synergize as effectors of the TGF-β response. Nature 383, 168–172 ( 1996).

    Article  ADS  CAS  Google Scholar 

  4. Zhang, Y., Musci, T. & Derynck, R. The tumor suppressor Smad4/DPC 4 as a central mediator of Smad function. Curr. Biol. 7, 270– 276 (1997).

    Article  Google Scholar 

  5. de Groot, R. P. & Kruijer, W. Transcriptional activatin by TGF-β mediated by the DYAD symmetry element (DSE) and the TPA responsive element (TRE). Biochem. Biophys. Res. Commun. 168, 1074–1081 (1990).

    Article  CAS  Google Scholar 

  6. Keeton, M. R., Curriden, S. A., van Zonneveld, A. & Loskutoff, D. J. Identification of regulatory sequences in the type 1 plasminogen activator inhibitor gene responsive to transforming growth factor β. J. Biol. Chem. 266, 23048–23052 (1991).

    CAS  PubMed  Google Scholar 

  7. Jin, G. & Howe, P. H. Regulation of clusterin gene expression by transforming growth factor β. J. Biol. Chem. 272, 26620–26626 (1997).

    Article  CAS  Google Scholar 

  8. Felts, S. J., Stoflet, E. S., Eggers, C. T. & Getz, M. J. Tissue factor gene transcription in serum-stimualted fibroblasts is mediated by recruitment of c-Fos into specific AP-1 DNA-binding complexes. Biochemistry 34, 12355–12362 (1995).

    Article  CAS  Google Scholar 

  9. Angel, P. & Karin, M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim. Biophys. Acta 1072, 129–157 ( 1991).

    CAS  PubMed  Google Scholar 

  10. Wrana, J. L. et al. TGF-β signals though a heteromeric protein kinase receptor complex. Cell 71, 1003– 1014 (1992).

    Article  CAS  Google Scholar 

  11. Nakao, A. et al. TGF-β receptor-mediated signaling through Smad2, Smad3 and Smad4. EMBO J. 16, 5353– 5362 (1997).

    Article  CAS  Google Scholar 

  12. Renshaw, M. W., McWhirter, J. R. & Wang, J. Y. The human leukemia oncogene bcr-abl abrogates the anchorage requirement but not the growth factor requirement for proliferation. Mol. Cell. Biol. 15, 1286– 1293 (1995).

    Article  CAS  Google Scholar 

  13. Angel, P. et al. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49, 729–739 (1987).

    Article  CAS  Google Scholar 

  14. Wu, R.-Y., Zhang, Y., Feng, X.-H. & Derynck, R. Heteromeric and homomeric interactions correlate with signaling activity and functional cooperativity of Smad3 and Smad4/DPC4. Mol. Cell. Biol. 17, 2521–2528 (1997).

    Article  CAS  Google Scholar 

  15. Chiu, R. et al. The c-Fos protein interacts wit c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell 54, 541– 552 (1988).

    Article  CAS  Google Scholar 

  16. Yang-Yen, H. F., Chiu, R. & Karin, M. Elevationof AP-1 activity during F9 cell differentiation is due to increased c-Jun transcription. New Biol. 2, 351– 361 (1990).

    CAS  PubMed  Google Scholar 

  17. Feng, X.-H., Zhang, Wu, R.-Y. & Derynck, R. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for Smad3 in TGF-β-induced transcriptional activation. Genes Dev. 12, 2153–2163 (1998).

    Article  CAS  Google Scholar 

  18. Hata, A., Lo, R. S., Wotton, D., Lagna, G. & Massagué, J. Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4. Nature 388, 82–87 (1997).

    Article  ADS  CAS  Google Scholar 

  19. Liu, F. et al. Ahuman Mad protein acting as a BMP-regulated transcriptional activator. Nature 381, 620–623 ( 1996).

    Article  ADS  CAS  Google Scholar 

  20. Feng, X.-H., Filvaroff, E. H. & Derynck, R. TGF-β-induced down-regulation of cyclin A expression requries a functional TGF-β receptor complex. Characterization of chimeric and truncated type I and type II receptors. J. Biol. Chem. 270, 24237–24245 (1995).

    Article  CAS  Google Scholar 

  21. Yoshizumi, M. et al . Down-regulation of the cyclin A promoter by transforming growth factor-β1 is associated with a reduction in phosphorylated activating transcription factor-1 and cyclic AMP-responsive element-binding protein. J. Biol. Chem. 272, 22259– 22264 (1997).

    Article  CAS  Google Scholar 

  22. Yingling, J. M. et al . Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein. Mol. Cell. Biol. 17, 7019–7028 (1997).

    Article  CAS  Google Scholar 

  23. Zawel, L. et al. Human Smad3 and Smad4 are sequence-specific transcription activator. Mol. Cell 1, 611–176 (1998).

    Article  CAS  Google Scholar 

  24. Karin, M. The regulation of AP-1 activity by mitogen-activated protein kinases. J. Biol. Chem. 270, 16483–16486 (1995).

    Article  CAS  Google Scholar 

  25. Lloyd, A., Yancheva, N. & Wasylyk, B. Transformation suppressor activity of a Jun transcription factor lacking its activation domain. Nature 352, 635–638 (1991).

    Article  ADS  CAS  Google Scholar 

  26. Kretzschmar, M., Doody, J. & Massagué, J. Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature 389, 618–622 (1997).

    Article  ADS  CAS  Google Scholar 

  27. de Caestecker, M. P. et al. Smad2 transduces common signals from serine-threonine and tyrosine kinases. Genes Dev. 1 2, 1587 –1592 (1998).

    Article  Google Scholar 

  28. Graycar, J. L. et al . Human transforming growth factor-β3: recombinant expression, purification, and biological activities in comparison with transforming growth factor-β1 and -β2. Mol. Endocrinol. 3, 1977–1986 (1989).

    Article  CAS  Google Scholar 

  29. Sadowski, I. & Ptashne, M. Avector for expressing GAL4(1–147) fusions in mammalian cells. Nucleic Acids Res. 17, 7539 (1989).

    Article  CAS  Google Scholar 

  30. Feng, X.-H. & Derynck, R. Ligand-independent activationof TGF-β signaling pathways by heteromeric cytoplasmic domains of TGF-β receptors. J. Biol. Chem. 271, 13123– 13129 (1996).

    Article  CAS  Google Scholar 

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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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  1. Departments of Growth and Development, and Anatomy Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, 94143-0640, California, USA

    Ying Zhang, Xin-Hua Feng & Rik Derynck

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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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