Abstract
Smad proteins transduce signals from TGF-β 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-β. 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-β-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-β-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-β/Smad targets.
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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-β:
-
transforming growth factor-β
- TβRE:
-
TGF-β response element
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Acknowledgements
Charlotte Tacheau provided invaluable technical help. The authors also wish to express their gratitude to Drs A Atfi, SM Frisch, M Karin, S Kern, DJ Loskutoff, and K Miyazono, who kindly provided reagents. Supported in part by grants from Association pour la Recherche contre le Cancer (ARC), INSERM, Electricité de France (Service de Radioprotection), and the Dermatology Foundation (Leon M. Ariyan Research Grant) to A Mauviel; a research fellowship from the Fondation René Touraine to L Vindevoghel; and by NIH, USPS RO1 AR41439 to J Uitto.
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Verrecchia, F., Vindevoghel, L., Lechleider, R. et al. Smad3/AP-1 interactions control transcriptional responses to TGF-β in a promoter-specific manner. Oncogene 20, 3332–3340 (2001). https://doi.org/10.1038/sj.onc.1204448
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DOI: https://doi.org/10.1038/sj.onc.1204448
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