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| Original Paper |
Smad3/AP-1 interactions control transcriptional responses to TGF- in a promoter-specific manner |
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| Franck Verrecchia1, Laurence Vindevoghel2, Robert J Lechleider3, Jouni Uitto2, Anita B Roberts3 and Alain Mauviel1,2 |
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1INSERM, U532, Hôpital Saint-Louis, 75010 Paris, France
2Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, PA 19107, USA
3Laboratory of Cell Regulation and Carcinogenesis, NCI, NIH, Bethesda, Maryland, MD 20892, USA
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Correspondence to: A Mauviel, INSERM U532, Institut de Recherche sur la Peau, Pavillon Bazin, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75010 Paris, France
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| Abstract |
| Smad proteins transduce signals from TGF- receptors and regulate transcription of target genes either directly or in combination with other sequence-specific transcription factors. AP-1 sites and their cognate transcription factors also play important roles in the gene regulatory activities of TGF-. In this report, we have investigated the functional interactions of the Smad and AP-1 transcription factors. We demonstrate that Smad and AP-1 complexes specifically bind to their cognate cis-elements and do not interact with each other on-DNA, whereas off-DNA interactions occur between Smad3 and both c-Jun and JunB. Using both artificial constructs specific for either the Smad or AP-1 signaling pathways or natural promoters known to be TGF--responsive, we have determined that Jun family members downregulate Smad3-mediated gene transactivation whereas AP-1-dependent promoters are synergistically activated by Smad3 and Jun proteins. We propose a model where the presence of Smad- and/or AP-1-specific cis-elements within TGF--responsive genes allows dynamic modulation of gene expression, in contrast to the existing model where interactions between Smad and AP-1 proteins are merely an on/off mechanism to regulate TGF-/Smad targets. Oncogene (2001) 20, 3332-3340. |
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| Keywords |
| TGF- ; AP-1; Smad; gene regulation; Jun |
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| Abbreviations |
| CAT, chloramphenicol acetyl-transferase; EMSA, electrophoretic mobility shift assay; PAI-1, plasminogen activator inhibitor-1; SBE, Smad binding element; SBS, Smad binding sequence (from COL7A1 promoter); TGF-, transforming growth factor-; TRE, TGF- response element |
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| Received 17 January 2001; revised 1 March 2001; accepted 7 March 2001 |
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| 7 June 2001, Volume 20, Number 26, Pages 3332-3340 |
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