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:

Retinoic acid receptors interfere with the TGF-β/Smad signaling pathway in a ligand-specific manner

Oncogene volume 22, pages 8212–8220 (2003)Cite this article

Abstract

Transforming growth factor-β (TGF-β) and retinoic acid (RA) are important regulators of cell growth and differentiation. The TGF-β receptors utilize Smad proteins to transduce signals intracellularly and regulate transcription of target genes, either directly or in combination with other sequence-specific transcription factors. Two classes of nuclear receptors, the retinoic acid receptors (RARs) and the retinoic X receptors, are involved in mediating transcriptional responses to RA. Given the known interactions between the TGF-β and RAR pathways, we have investigated the role played by RAR ligands in modulating functional interactions between Smad3 and RARs. Using transient cell transfection experiments with an artificial Smad3/Smad4-dependent reporter construct, we demonstrate that RAR overexpression enhances Smad-driven transactivation, an effect that requires both Smad3 and Smad4. We provide evidence that RAR effect on Smad3/Smad4-driven transcription is prevented by natural and synthetic RAR agonists, and potentiated by synthetic RAR antagonists. The activity of two TGF-β-responsive human gene promoter constructs was regulated in a parallel fashion. Using both mammalian two-hybrid and immunoprecipitation/Western methods, we demonstrate a direct interaction between the region DEF of RARγ and the MH2 domain of Smad3, inhibited by RAR agonists and enhanced by their antagonists. We propose that RARs may function as coactivators of the Smad pathway in the absence of RAR agonists or in the presence of their antagonists, a phenomenon that contrasts with their known role as agonist-activated transcriptional regulators of RA-dependent genes.

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
Figure 5
Figure 6

Similar content being viewed by others

Abbreviations

ATRA:

all-trans retinoic acid

FCS:

fetal calf serum

RA:

retinoic acid

RAR:

retinoic acid receptor

TGF-β:

transforming growth factor-β

References

  • Allenby G . (1995). Hum. Exp. Toxicol., 14, 226–230.

  • Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF Chambon P and Levin AA . (1993). Proc. Natl. Acad. Sci. USA, 90, 30–34.

  • Attisano L and Wrana JL . (2002). Science, 296, 1646–1647.

  • Borger DR, Mi Y, Geslani G, Zyzak LL, Batova A, Engin TS, Pirisi L and Creek KE . (2000). Virology, 270, 397–407.

  • Cao Z, Flanders KC, Bertolette D, Lyakh LA, Wurthner JU, Parks WT, Letterio JJ, Ruscetti FW and Roberts AB . (2003). Blood, 101, 498–507.

  • Chambon P . (1996). FASEB J., 10, 940–954.

  • Chen JY, Penco S, Ostrowski J, Balaguer P, Pons M, Starrett JE, Reczek P, Chambon P and Gronemeyer H . (1995). EMBO J., 14, 1187–1197.

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

  • Chipuk JE, Cornelius SS, Pultz NJ, Jorgenson JS, Bonham MJ, Kim SJ and Danielpour D . (2001). J. Biol. Chem., 13, 13.

  • Datto MB and Wang XF . (2000). Cytokine Growth Factor Rev., 11, 37–48.

  • Datto MB, Yu Y and Wang XF . (1995). J. Biol. Chem., 270, 28623–28628.

  • de Caestecker MP, Piek E and Roberts AB . (2000). J. Natl. Cancer Inst., 92, 1388–1402.

  • Defacque H, Sevilla C, Piquemal D, Rochette-Egly C, Marti J and Commes T . (1997). Leukemia, 11, 221–227.

  • Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S and Gauthier JM . (1998). EMBO J., 17, 3091–3100.

  • Derynck R and Feng XH . (1997). Biochim. Biophys. Acta, 1333, F105–F150.

  • Feng XH, Lin X and Derynck R . (2000). EMBO J., 19, 5178–5793.

  • Fink SP, Mikkola D, Willson JK and Markowitz S . (2003). Oncogene, 22, 1317–1323.

  • Fu M, Zhang J, Zhu X, Myles DE, Willson TM, Liu X and Chen YE . (2001). J. Biol. Chem., 276, 45888–45894.

  • Germain S, Howell M, Esslemont GM and Hill CS . (2000). Genes Dev., 14, 435–451.

  • Gold LI . (1999). Crit. Rev. Oncogen., 10, 303–360.

  • Jacob K, Wach F, Holzapfel U, Hein R, Lengyel E, Buettner R and Bosserhoff AK . (1998). Melanoma Res., 8, 211–219.

  • Jetten AM, Kurebayashi S and Ueda E . (2001). Prog. Nucleic Acid Res. Mol. Biol., 69, 205–247.

  • Kumar R and Thompson EB . (1999). Steroids, 64, 310–319.

  • La P, Morgan TA, Sykes SM, Mao H, Schnepp RW, Petersen CD and Hua X . (2003). Oncogene, 22, 198–210.

  • Liberati NT, Datto MB, Frederick JP, Shen X, Wong C, Rougier-Chapman EM and Wang XF . (1999). Proc. Natl. Acad. Sci. USA, 96, 4844–4849.

  • Massagué J and Wotton D . (2000). EMBO J., 19, 1745–1754.

  • Matsuda T, Yamamoto T, Muraguchi A and Saatcioglu F . (2001). J. Biol. Chem., 276, 42908–42914.

  • Moustakas A and Kardassis D . (1998). Proc. Natl. Acad. Sci. USA, 95, 6733–6738.

  • Nagarajan RP, Liu J and Chen Y . (1999). J. Biol. Chem., 274, 31229–31235.

  • Nunes I, Kojima S and Rifkin DB . (1996). Cancer Res., 56, 495–499.

  • Pemrick SM, Lucas DA and Grippo JF . (1994). Leukemia, 8, 1797–1806.

  • Reiss M . (1999). Microbes Infect., 1, 1327–1347.

  • Roberts AB and Sporn MB . (1992). Cancer Surv., 14, 205–220.

  • Rodeck U, Nishiyama T and Mauviel A . (1999). Cancer Res., 59, 547–550.

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

  • Seoane J, Pouponnot C, Staller P, Schader M, Eilers M and Massagué J . (2001). Nat. Cell Biol., 3, 400–408.

  • Shi Y . (2001). BioEssays, 23, 223–232.

  • Toma S, Isnardi L, Raffo P, Riccardi L, Dastoli G, Apfel C, LeMotte P and Bollag W . (1998). Int. J. Cancer, 78, 86–94.

  • Verrecchia F, Chu ML and Mauviel A . (2001a). J. Biol. Chem., 276, 17058–17062.

  • Verrecchia F, Vindevoghel L, Lechleider RJ, Uitto J, Roberts AB and Mauviel A . (2001b). Oncogene, 20, 3332–3340.

  • Vindevoghel L, Lechleider RJ, Kon A, de Caestecker MP, Uitto J, Roberts AB and Mauviel A . (1998). Proc. Natl. Acad. Sci. USA, 95, 14769–14774.

  • Yanagisawa J, Yanagi Y, Masuhiro Y, Suzawa M, Watanabe M, Kashiwagi K, Toriyabe T, Kawabata M, Miyazono K and Kato S . (1999). Science, 283, 1317–1321.

Download references

Acknowledgements

We are indebted to Drs A Atfi (INSERM U482, Paris, France), P Chambon, and C Rochette-Egly (IGBMC, Strasbourg, France), S Dennler and J-M Gauthier (Glaxo-Wellcome, Les Ulis, France), and CS Hill (Imperial Cancer Research Fund, London, UK) for providing us with reagents essential for these studies. This work was supported by INSERM and a research grant from Galderma R&D (Sophia-Antipolis, France) to AM. This work is dedicated to the memory of our colleague and friend Serge.

Author information

Author notes

  1. Serge Michel: Deceased

Authors and Affiliations

  1. INSERM U532, Université Paris VII, Institut de Recherche sur la Peau, Pavillon Bazin, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, Paris, Cedex 10, F-75475, France

    Valérie Pendaries, Franck Verrecchia & Alain Mauviel

  2. Galderma R&D, Sophia-Antipolis, F-06902, France

    Serge Michel

Authors
  1. Valérie Pendaries
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Franck Verrecchia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Serge Michel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alain Mauviel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alain Mauviel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pendaries, V., Verrecchia, F., Michel, S. et al. Retinoic acid receptors interfere with the TGF-β/Smad signaling pathway in a ligand-specific manner. Oncogene 22, 8212–8220 (2003). https://doi.org/10.1038/sj.onc.1206913

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206913

Keywords

This article is cited by

Search

Advanced search

Quick links