Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-β involves functional cooperation with p300/CBP transcriptional coactivators

Oncogene volume 19, pages 3546–3555 (2000)Cite this article

Abstract

Transforming growth factor-β (TGF-β) stimulation of Type I collagen gene (COL1A2) transcription involves the Smad signal transduction pathway, but the mechanisms of Smad-mediated transcriptional activation are not fully understood. We now demonstrate that the ubiquitous transcriptional coactivators p300 and CREB-binding protein (CBP) enhanced basal as well as TGF-β- or Smad3-induced COL1A2 promoter activity, and stimulated the expression of endogenous Type I collagen. The adenoviral E1A oncoprotein abrogated stimulation of COL1A2 activity in transfected fibroblasts, and reduced the basal level of collagen gene expression. This effect was due to specific interaction of E1A with cellular p300/CBP because (a) a mutant form of E1A defective in p300 binding failed to abrogate stimulation, and (b) forced expression of p300/CBP restored the ability of TGF-β to stimulate COL1A2 promoter activity in the presence of E1A. The effect of p300 on COL1A2 transcription appeared to be due, in part, to its intrinsic acetyltransferase activity, as stimulation induced by a histone acetyltransferase-deficient mutant p300 was substantially reduced. Transactivation of COL1A2 by p300 involved the Smad signaling pathway, as Smad4-deficient cells failed to respond to p300, and stimulation was rescued by overexpression of Smad4. Furthermore, minimal constructs containing only the Smad-binding CAGACA element of COL1A2 were transactivated by p300 in the presence of TGF-β. These results indicate, for the first time, that the multifunctional p300/CBP coactivators play a major role in Smad-dependent TGF-β stimulation of collagen gene expression in fibroblasts.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Arany Z, Newsome D, Oldread E, Livingston DM and Eckner R. . 1995 Nature 374: 81–84.

  • Arany Z, Sellers WR, Livingston DM and Eckner R. . 1994 Cell 77: 799–800.

  • Bannister AJ and Kouzarides T. . 1996 Nature 384: 641–643.

  • Boyes J, Byfield P, Nakatani Y and Ogryzko VV. . 1998 Nature 396: 594–598.

  • Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G and Whitman M. . 1997 Nature 389: 85–89.

  • Chen S-J, Yuan W, Mori Y, Levenson A, Trojanowska M and Varga J. . 1999 J. Invest. Dermatol. 112: 49–57.

  • Chen S-J, Yuan W, Lo S, Trojanowska M and Varga J. . 2000 J. Cell. Physiol. 183: 381–392.

  • Chirivia JC, Kwok RP, Lamb N, Hagiwara M, Montmony MR and Goodman RH. . 1993 Nature 365: 855–859.

  • Coussens LM, Yokoyama K and Chiu R. . 1994 J. Cell. Physiol. 160: 435–444.

  • Datto MB, Hu PP, Kowalik TF, Yingling J and Wang XF. . 1997 Mol. Cell. Biol. 17: 2030–2037.

  • Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S and Gauthier J-M. . 1998 EMBO J. 17: 3091–3100.

  • Dyson N and Harlow E. . 1992 Cancer Surv. 12: 161–195.

  • Eckner R, Ewen ME, Newsome D, Gerdes M, DeCaprio JA, Lawrence JB and Livingston DM. . 1994 Genes Dev. 8: 869–884.

  • Ewen ME, Wing YG, Lawrence JB and Livingston DM. . 1991 Cell. 66: 1155–1164.

  • Feng XH, Zhang Y, Wu RY and Derynck R. . 1998 Genes Dev. 12: 2153–2163.

  • Giles RH, Peters DJM and Breuning MH. . 1998 Trends Genet. 14: 178–183.

  • Gorman CM, Moffat LF and Howard BH. . 1982 Mol. Cell. Biol. 2: 1044–1051.

  • Gu W and Roeder RG. . 1997 Cell 90: 595–606.

  • Hamamori Y, Sartorelli V, Ogryzko V, Puri PL, Wu HY, Wang JY, Nakatani Y and Kedes L. . 1999 Cell 96: 405–413.

  • Hannon GJ, Demetrick D and Beach D. . 1993 Genes Dev. 7: 2378–2391.

  • Heldin CH, Miyazono K and Dijke P. . 1997 Nature 390: 465–471.

  • Ihn H, LeRoy EC and Trojanowska M. . 1997 J. Biol. Chem. 272: 24666–24672.

  • Imhof A, Yang X-J, Ogryzko VV, Nakatani Y, Wolffe AP and Ge H. . 1997 Curr. Biol. 7: 689–692.

  • Janknecht R, Wells NJ and Hunter T. . 1998 Genes Dev. 12: 2114–2119.

  • Kawabata M, Inoue H, Hanyu A, Imamura T and Miyazono K. . 1998 EMBO J. 17: 4056–4065.

  • Kawabata M and Miyazono K. . 1999 J. Biochem. 125: 9–16.

  • Kawasaki H, Song J, Eckner R, Ugai H, Chiu R, Tiara K, Shi Y, Jones N and Yokoyama KK. . 1998 Genes Dev. 12: 233–245.

  • Kitabayashi I, Eckner R, Arany Z, Chiu R, Gachelin G, Livingston DM and Yokoyama KK. . 1995 EMBO J. 14: 3496–3509.

  • Kon A, Vindevoghel L, Kouba DJ, Fujimura Y, Uitto J and Mauviel A. . 1999 Oncogene 18: 1837–1844.

  • Kraus VB, Moran E and Nevins JR. . 1992 Mol. Cell. Biol. 12: 4391–4399.

  • Kretzschmar M and Massague J. . 1998 Curr. Opin. Genet. Dev. 8: 103–111.

  • Labbe E, Silvestri C, Hoodless PA, Wrana JL and Attisano L. . 1998 Mol. Cell. 2: 109–120.

  • Li L, Artlett CM, Jimenez SA, Hall DJ and Varga J. . 1995 Gene 164: 229–234.

  • Liu B, Dou C-L, Prabhu L and Lai E. . 1999 Mol. Cell. Biol. 19: 424–430.

  • Liu F, Pouponnot C and Massague J. . 1997a Genes Dev. 11: 3157–3167.

  • Liu X, Sun Y, Constantinescu SN, Karam E, Weinberg RA and Lodish HF. . 1997b Proc. Natl. Acad. Sci. USA. 94: 10669–10674.

  • Lundblad JR, Kwok RP, Laurance ME, Harter ML and Goodman RH. . 1995 Nature 374: 85–88.

  • Massague J. . 1998 Annu. Rev. Biochem. 67: 753–791.

  • Moran E, Grodzicker T, Roberts RJ, Mathews MB and Zerler B. . 1986 J. Virol. 57: 765–775.

  • Morozov A, Shiyanov P, Barr E, Leiden JM and Raychaudhuri P. . 1997 J. Virol. 71: 3451–3457.

  • Muraoka M, Konishi M, Kikuchi-Yanoshita R, Tanaka K, Shitara N, Chong J-M, Iwama T and Miyaki M. . 1996 Oncogene 12: 1565–1569.

  • Myers JC, Chu ML, Faro SH, Clark WJ, Prockop DJ and Ramirez F. . 1981 Proc. Natl. Acad. Sci. USA 78: 3516–3520.

  • Nakajima T, Uchida C, Anderson SF, Lee CG, Hurwitz J, Parvin JD and Montminy M. . 1997 Cell 90: 1107–1112.

  • Nishihara A, Hanai J, Imamura T, Miyazono K and Kawabata M. . 1999 J. Biol. Chem. 274: 28716–28723.

  • Ogryzko VV, Schiltz RL, Russanova V, Howard BH and Nakatani Y. . 1996 Cell 87: 953–959.

  • Padgett RW, Das P and Krishna S. . 1998 BioEssays 20: 382–390.

  • Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RCM, Masuno M, Tommerup N, van Ommen G-JB, Goodman RH, Peters DJM and Breuning MH. . 1995 Nature 376: 348–351.

  • Pouponnot C, Jayaraman L and Massague J. . 1998 J. Biol. Chem. 273: 22865–22868.

  • Raychaudhuri P, Bagchi S, Devoto SH, Kraus VB, Moran E and Nevins JR. . 1991 Genes Dev. 5: 1200–1211.

  • Roberts AB and Sporn MB. . 1990 Peptide growth factors and their receptors. Sporn MB and Roberts AB (eds) Springer-Verlag, Heidelberg, Germany pp419–472.

  • Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero RA, Meltzer PS, Hahn SA and Kern SE. . 1996 Cancer Res. 56: 2527–2530.

  • Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A, Schlegelberger B, Housman D, Doggett NA, Rowley JD and Zeleznik LN. . 1997 Proc. Natl. Acad. Sci. USA. 94: 10215–10220.

  • Struhl K. . 1998 Genes Dev. 12: 599–606.

  • Tamaki T, Ohnishi K, Hartl C, LeRoy EC and Trojanowska M. . 1995 J. Biol. Chem. 270: 4299–4304.

  • Topper JM, DiChiara MR, Brown JD, Williams AJ, Falb D, Collins T and Gimbrone Jr MA. . 1998 Proc. Natl. Acad. Sci. USA 95: 9506–9511.

  • Varga J, Rosenbloom J and Jimenez SA. . 1987 Biochem. J. 247: 597–604.

  • Vindevoghel L, Kon A, Lechleider R, Uitto J, Roberts AB and Mauviel A. . 1998 J. Biol. Chem. 273: 13053–13057.

  • Waltzer L and Bienz M. . 1999 EMBO J. 18: 1630–1641.

  • Yang XJ, Ogryzko VV, Nighikawa J, Howard BH and Nakatani Y. . 1996 Nature 382: 319–324.

  • Yao T-P, Oh SP, Fuchs M, Zhou N-D, Ch'ng L-E, Newsome D, Bronson RT, Li E, Livingston DM and Eckner R. . 1998 Cell 93: 361–372.

  • Zhang W and Beiker JJ. . 1998 Proc. Natl. Acad. Sci. USA 95: 9855–9860.

  • Zhang Y, Feng X, Wu R and Derynck R. . 1996 Nature 383: 168–171.

  • Zhou S, Zawel L, Lengauer C, Kinzler KW and Vogelstein B. . 1998 Mol. Cell. 2: 121–127.

Download references

Acknowledgements

We are grateful to J Boyes, M Trojanowska, DM Livingston, R Janknecht, P Raychaudhuri, R Derynck, HF Lodish and E Moran for providing plasmids and recombinant adenovirus, and K Westcott and DR Olsen for human recombinant TGF-β1 and TGF-β2. We are especially indebted to P Raychaudhuri and L Platanias for helpful discussion. Supported by grants from the National Institute of Health (AR-42309 and AR-46390).

Author information

Authors and Affiliations

  1. Section of Rheumatology, University of Illinois at Chicago College of Medicine, Chicago, 60607, Illinois, IL, USA

    Asish K Ghosh, Weihua Yuan, Yasuji Mori & John Varga

Authors
  1. Asish K Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weihua Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasuji Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John Varga
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ghosh, A., Yuan, W., Mori, Y. et al. Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-β involves functional cooperation with p300/CBP transcriptional coactivators. Oncogene 19, 3546–3555 (2000). https://doi.org/10.1038/sj.onc.1203693

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203693

Keywords

Search

Advanced search

Quick links