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Tenascin-C upregulation by transforming growth factor-β in human dermal fibroblasts involves Smad3, Sp1, and Ets1

Oncogene volume 23, pages 1656–1667 (2004)Cite this article

Abstract

In cultured human dermal fibroblasts, transforming growth factor (TGF)-β induced the mRNA expression of tenascin-C (TN-C). The molecular mechanism(s) underlying this process is not presently understood. In this study, we performed serial 5′ deletion and a transient transfection analysis to define a region in the TN-C promoter mediating the inducible responsiveness to TGF-β. This region contains an atypical nucleotide recognition element for the Smad family of transcriptional regulators. A DNA affinity precipitation assay revealed that Smad2/Smad3 bound to this site in a transient and specific manner. Overexpression of Smad3 or Smad4 activated the TN-C promoter activity and superinduced the TN-C promoter activity stimulated by TGF-β. Moreover, simultaneous cotransfection of Smad3 and Smad4 activated the TN-C promoter activity in a synergistic manner. Mutation of the Smad-binding sites, the Ets-binding sites, or Sp1/3-binding sites in the TN-C promoter abrogated the TGF-β/Smad-inducible promoter activity. Immunoprecipitation analysis revealed that Smad3, Sp1, and Ets1 form a transcriptionally active complex. Furthermore, the interaction between Smads and CBP/p300 in TGF-β signaling was confirmed. These findings demonstrate the existence of a novel, functional binding element in the proximal region of the TN-C promoter mediating responsiveness to TGF-β involving Smad3/4, Sp1, Ets1, and CBP/p300.

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Acknowledgements

We thank Dr Wolfgang Rettig, Dr Mario Bourdon, Dr Harvey F Lodish, Dr Rik Derynck, Dr Joan Boyes, Dr Ralf Janknecht, and Dr Roberto Gherzi for kindly providing NEC1b, human TN-C 1431-bp fragment, expression vector for Smad3, expression vector for Smad4, p300 constructs, CBP constructs, and PTN-I-CAT construct, respectively. This study was supported in part by a grant for scientific research from the Japanese Ministry of Education, and by the project research for progressive systemic sclerosis from the Japanese Ministry of Health and Welfare.

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Authors and Affiliations

  1. Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Masatoshi Jinnin, Hironobu Ihn, Yoshihide Asano, Kenichi Yamane & Kunihiko Tamaki

  2. Division of Rheumatology and Immunology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, 29425-2229, SC, USA

    Maria Trojanowska

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Correspondence to Hironobu Ihn.

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Jinnin, M., Ihn, H., Asano, Y. et al. Tenascin-C upregulation by transforming growth factor-β in human dermal fibroblasts involves Smad3, Sp1, and Ets1. Oncogene 23, 1656–1667 (2004). https://doi.org/10.1038/sj.onc.1207064

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