A human Mad protein acting as a BMP-regulated transcriptional activator

Abstract

THE TGF-β/activin/BMP cytokine family signals through serine/threonine kinase receptors, but how the receptors transduce the signal is unknown. The Mad (Mothers against decapentaplegic) gene from Drosophila1 and the related Sma genes from Caenorhabditis elegans2 have been genetically implicated in signalling by members of the bone-morphogenetic-protein (BMP) subfamily. We have cloned Smad1, a human homologue of Mad and Sma. Microinjection of Smad1 messenger RNA into Xenopus embryo animal caps mimics the mesoderm-ventralizing effects of BMP4. Smad1 moves into the nucleus in response to BMP4. Smad1 has transcriptional activity when fused to a heterologous DNA-binding domain, and this activity is increased by BMP4 acting through BMP-receptor types I and II. The transactivating activity resides in the conserved carboxy-terminal domain of Smad1 and is disrupted by a nonsense mutation that corresponds to null mutations found in Mad and in the related gene DPC4, a candidate tumour-suppressor gene in human pancreatic cancer3. Additionally, we show that DPC4 contains a transcriptional activation domain. The results suggests that the Smad proteins are a new class of transcription factors that mediate responses to the TGF-β family.

References

  1. 1

    Sekelsky, J. J., Newfeld, S. J., Raftery, L. A., Chartoff, E. H. & Gelbart, W. M. Genetics 139, 1347–1358 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Savage, C. et al. Proc. natn. Acad. Sci. U.S.A. 93, 790–794 (1996).

    ADS  CAS  Article  Google Scholar 

  3. 3

    Hahn, S. A. et al. Science 271, 350–353 (1996).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Dale, L., Howes, G., Price, B. M. J. & Smith, J. C. Development 115, 573–585 (1992).

    CAS  Google Scholar 

  5. 5

    Jones, C. M., Lyons, K. M., Lapan, P. M., Wright, C. V. E. & Hogan, B. L. M. Development 115, 639–647 (1992).

    CAS  Google Scholar 

  6. 6

    Graff, J. M., Thies, R. S., Song, J. J., Celeste, A. J. & Melton, D. A. Cell 79, 169–179 (1994).

    CAS  Article  Google Scholar 

  7. 7

    Suzuki, A. et al. Proc. natn. Acad. Sci. U.S.A. 91, 10255–10259 (1994).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Harland, R. M., Proc. natn. Acad. Sci. U.S.A. 91, 10243–10246 (1994).

    ADS  CAS  Article  Google Scholar 

  9. 9

    Cárcamo, J. et al. Molec. cell. Biol. 14, 3810–3821 (1994).

    Article  Google Scholar 

  10. 10

    Ptashne, M. Nature 335, 683–689 (1988).

    ADS  CAS  Article  Google Scholar 

  11. 11

    Lillie, J. W. & Green, M. R. Nature 338, 39–44 (1989).

    ADS  CAS  Article  Google Scholar 

  12. 12

    Liu, F., Ventura, F., Doody, J. & Massagué, J. Molec. cell. Biol. 15, 3479–3486 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Rosenzweig, B. L. et al. Proc. natn. Acad. Sci. U.S.A. 92, 7632–7636 (1995).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Lennon, G. G., Auffray, C., Polymeropoulos, M. & Soares, M. B. Genomics (in the press).

  15. 15

    Rupp, R. A. & Weintraub, H. Cell 65, 927–937 (1991).

    CAS  Article  Google Scholar 

  16. 16

    Wilson, P. A. & Melton, D. A. Curr. Biol. 4, 676–686 (1994).

    CAS  Article  Google Scholar 

  17. 17

    Lamb, T. M. et al. Science 262, 713–718 (1993).

    ADS  CAS  Article  Google Scholar 

  18. 18

    Sadowski, I. & Ptashne, M. Nucleic Acids Res. 17, 7539 (1989).

    CAS  Article  Google Scholar 

  19. 19

    Wrana, J. L., Attisano, L., Wieser, R., Ventura, F. & Massagué, J. Nature 370, 341–347 (1994).

    ADS  CAS  Article  Google Scholar 

  20. 20

    Gorman, C. M., Moffat, L. F. & Howard, B. H. Molec. cell. Biol. 2, 1044–1051 (1982).

    CAS  Article  Google Scholar 

  21. 21

    Liu, F. & Green, M. R. Cell 61, 1217–1224 (1990).

    CAS  Article  Google Scholar 

  22. 22

    Hoodless, P. A. et al. Cell 85, 489–500 (1996).

    CAS  Article  Google Scholar 

  23. 23

    Graff, J. M., Bansal, A. & Melton, D. A. Cell 85, 479–487 (1996).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, F., Hata, A., Baker, J. et al. A human Mad protein acting as a BMP-regulated transcriptional activator. Nature 381, 620–623 (1996). https://doi.org/10.1038/381620a0

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing