Smad3/AP-1 interactions control transcriptional responses to TGF-beta in a promoter-specific manner.
Smad proteins transduce signals from TGF-beta 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-beta. 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-beta-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-beta-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-beta/Smad targets.
Verrecchia
F
F
INSERM, U532, Hôpital Saint-Louis, 75010 Paris, France.
Vindevoghel
L
L
Lechleider
R J
RJ
Uitto
J
J
Roberts
A B
AB
Mauviel
A
A
D030201:Activin Receptors, Type I; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016384:Consensus Sequence; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D009842:Oligopeptides; D010455:Peptides / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects* / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; D010455:Peptides; D016755:Proto-Oncogene Proteins c-jun; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D004247:DNA; C085706:FLAG peptide; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I