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A component of the ARC/Mediator complex required for TGFβ/Nodal signalling


The transforming growth factor β (TGFβ) family of cytokines, including Nodal, Activin and bone morphogenetic protein (BMP), have essential roles in development and tumorigenesis1,2. TGFβ molecules activate the Smad family of signal transducers, which form complexes with specific DNA-binding proteins to regulate gene expression1,2. Two discrete Smad-dependent signalling pathways have been identified: TGFβ, Activin and Nodal signal via the Smad2 (or Smad3)–Smad4 complex, whereas BMP signals via the Smad1–Smad4 complex1,2. How distinct Smad complexes regulate specific gene expression is not fully understood. Here we show that ARC105, a component of the activator-recruited co-factor (ARC)3 complex or the metazoan Mediator complex, is essential for TGFβ/Activin/Nodal/Smad2/3 signal transduction. Expression of ARC105 stimulates Activin/Nodal/Smad2 signalling in Xenopus laevis embryos, inducing axis duplication and mesendoderm differentiation, and enhances TGFβ response in human cells. Depletion of ARC105 inhibits TGFβ/Activin/Nodal/Smad2/3 signalling and Xenopus axis formation, but not BMP/Smad1 signalling. ARC105 protein binds to Smad2/3–Smad4 in response to TGFβ and is recruited to Activin/Nodal-responsive promoters in chromatin in a Smad2-dependent fashion. Thus ARC105 is a specific and key ARC/Mediator component linking TGFβ/Activin/Nodal/Smad2/3 signalling to transcriptional activation.

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Figure 1: XARC105 induces axis duplication, morphogenetic elongation and mesendoderm formation.
Figure 2: XARC105 is required for Nodal/Activin/Smad2 signalling.
Figure 3: ARC105 is required for TGFβ/Activin but not BMP signalling in 293T cells.
Figure 4: ARC105 protein associates with Smad2/3 and Smad4 in response to TGFβ in 293T cells (western blots).
Figure 5: Association between endogenous ARC/Mediator and Smad2/3-Smad4 complex and recruitment of ARC105 to chromatin via Smad2.


  1. Massague, J. How cells read TGF-β signals. Nature Rev. Mol. Cell Biol. 1, 169–178 (2000)

    CAS  Article  Google Scholar 

  2. Whitman, M. Smads and early developmental signalling by the TGFβ superfamily. Genes Dev. 12, 2445–2462 (1998)

    CAS  Article  PubMed  Google Scholar 

  3. Näär, A. M. et al. Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 398, 828–832 (1999)

    ADS  Article  PubMed  Google Scholar 

  4. Jiang, Y. W. et al. Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways. Proc. Natl Acad. Sci. USA 95, 8538–8543 (1998)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Boyer, T. G., Martin, M. E. D., Lees, E., Ricciardi, R. P. & Berk, A. J. Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein. Nature 399, 276–279 (1999)

    ADS  CAS  Article  PubMed  Google Scholar 

  6. Fondell, J. D., Ge, H. & Roeder, R. G. Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. Proc. Natl Acad. Sci. USA 93, 8329–8333 (1996)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Rachez, C. et al. Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 398, 824–828 (1999)

    ADS  CAS  Article  PubMed  Google Scholar 

  8. Gu, W. et al. A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. Mol. Cell 3, 97–108 (1999)

    CAS  Article  PubMed  Google Scholar 

  9. Ryu, S., Zhou, S., Ladurner, A. G. & Tjian, R. The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397, 446–450 (1999)

    ADS  CAS  Article  PubMed  Google Scholar 

  10. Malik, S., Gu, W., Wu, W., Qin, J. & Roeder, R. G. The USA-derived transcriptional coactivator PC2 is a submodule of TRAP/SMCC and acts synergistically with other PCs. Mol. Cell 5, 753–760 (2000)

    CAS  Article  PubMed  Google Scholar 

  11. Näär, A. M., Lemon, B. D. & Tjian, R. Transcriptional coactivator complexes. Annu. Rev. Biochem. 70, 475–501 (2001)

    Article  PubMed  Google Scholar 

  12. Rachez, C. & Freedman, L. P. Mediator complexes and transcription. Curr. Opin. Cell Biol. 13, 274–280 (2001)

    CAS  Article  PubMed  Google Scholar 

  13. Abraham, S. & Solomon, W. B. A novel glutamine-rich putative transcriptional adaptor protein (TIG-1) preferentially expressed in placental and bone-marrow tissues. Gene 255, 389–400 (2000)

    CAS  Article  PubMed  Google Scholar 

  14. Berti, L. et al. Isolation and characterization of a novel gene from the DiGeorge chromosomal region that encodes for a mediator subunit. Genomics 74, 320–332 (2001)

    CAS  Article  PubMed  Google Scholar 

  15. Harland, R. & Gerhart, J. Formation and function of Spemann's organizer. Annu. Rev. Cell Dev. Bio. 13, 611–667 (1997)

    CAS  Article  Google Scholar 

  16. Hemmati-Brivanlou, A. & Melton, D. A. A truncated activin receptor inhibits mesoderm induction and formation of axial structures in Xenopus embryos. Nature 359, 609–614 (1992)

    ADS  CAS  Article  PubMed  Google Scholar 

  17. Candia, A. F. et al. Cellular interpretation of multiple TGF-β signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signalling mediated by Smads. Development 124, 4467–4480 (1997)

    CAS  PubMed  Google Scholar 

  18. Chen, X. et al. Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85–89 (1997)

    ADS  CAS  Article  PubMed  Google Scholar 

  19. Yeo, C-Y., Chen, X. & Whitman, M. The role of FAST-1 and Smads in transcriptional regulation by activin during early Xenopus embryogenesis. J. Biol. Chem. 274, 26584–26590 (1999)

    CAS  Article  PubMed  Google Scholar 

  20. Stroschein, S. L., Wang, W., Zhou, S., Zhou, Q. & Luo, K. Negative feedback regulation of TGF-β signalling by the SnoN oncoprotein. Science 286, 771–774 (1999)

    CAS  Article  PubMed  Google Scholar 

  21. Singh, N. & Han, M. sur-2, a novel gene, functions late in the let-60 ras-mediated signalling pathway during Caenorhabditis elegans vulval induction. Genes Dev. 9, 2251–2265 (1995)

    CAS  Article  PubMed  Google Scholar 

  22. Zhang, H. & Emmons, S. W. A C. elegans mediator protein confers regulatory selectivity on lineage-specific expression of a transcription factor gene. Genes Dev. 14, 2161–2172 (2000)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Boube, M., Faucher, C., Joulia, L., Cribbs, D. L. & Bourbon, H. M. Drosophila homologs of transcriptional mediator complex subunits are required for adult cell and segment identity specification. Genes Dev. 14, 2906–2917 (2000)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Treisman, J. E. Drosophila homologue of the transcriptional coactivation complex subunits TRAP240 and TRAP230 are required for identical processes in eye-antennal disc development. Development 128, 603–615 (2001)

    CAS  PubMed  Google Scholar 

  25. Shimizu, K., Bourillot, P.-V., Nielsen, S. J., Zorn, A. M. & Gurdon, J. B. Swift is a novel BRCT domain coactivator of Smad2 in transforming growth factor β signalling. Mol. Cell Biol. 21, 3901–3912 (2001)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Bai, R.-Y. et al. SMIF, a Smad4-interacting protein that functions as a co-activator in TGFβ signalling. Nature Cell Biol. 4, 181–190 (2002)

    CAS  Article  PubMed  Google Scholar 

  27. Hsu, D. R. et al. The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol. Cell 1, 673–683 (1998)

    CAS  Article  PubMed  Google Scholar 

  28. Kato, Y., Shi, Y. & He, X. Neuralization of the Xenopus embryo by inhibition of p300/CREB-binding protein function. J. Neurosci. 19, 9364–9373 (1999)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001)

    ADS  CAS  Article  PubMed  Google Scholar 

  30. Sachs, L. M. & Shi, Y-B. Target chromatin binding and histone acetylation in vivo by thyroid hormone receptor during amphibian development. Proc. Natl Acad. Sci. USA 24, 13138–13143 (2000)

    ADS  Article  Google Scholar 

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We apologize for our inability to cite many original papers owing to space constraints. We thank Z. Chang, K. Cho, E. DeRobertis, R. Harland, A. Hata, A. Hemmati-Brivanlou, D. Kessler, K. Luo, J. Massague, J.-P. Saint-Jeannet, Y. Shi, W. Solomon, G. Thomson, T. Wang, M. Whitman, Y. Zhang and Y. Etoh for reagents; P. Dikkes for help; Y. Sun and M. Greenberg for comments; and K. Luo, Y. Shi, T. Wang, X. Wang and members of the He lab for discussion. This work is supported by postdoctoral fellowships from the Uehara Memorial Foundation (Japan) and Charles A. King Trust and the Medical Foundation to Y.K., from US Department of Defense (DOD) to R.H. A.M.N. is supported by the Bertucci Foundation. X.H. is supported by grants from the Rockefeller Brothers Fund, DOD and NIH, and is a Pew Scholar, Klingenstein Fellow, and Keck Foundation Distinguished Young Scholar.

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Correspondence to Xi He.

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Kato, Y., Habas, R., Katsuyama, Y. et al. A component of the ARC/Mediator complex required for TGFβ/Nodal signalling. Nature 418, 641–646 (2002).

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