Smad3/AP-1 interactions control transcriptional responses to TGF-beta in a promoter-specific manner

Oncogene. 2001 Jun 7;20(26):3332-40. doi: 10.1038/sj.onc.1204448.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activin Receptors, Type I*
  • Animals
  • Base Sequence
  • COS Cells
  • Cells, Cultured
  • Chlorocebus aethiops
  • Consensus Sequence
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Fibroblasts / cytology
  • Humans
  • Macromolecular Substances
  • Molecular Sequence Data
  • Oligodeoxyribonucleotides / metabolism
  • Oligopeptides
  • Peptides / immunology
  • Promoter Regions, Genetic / drug effects*
  • Protein-Serine-Threonine Kinases / drug effects*
  • Protein-Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins c-jun / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / drug effects*
  • Receptors, Transforming Growth Factor beta / physiology
  • Regulatory Sequences, Nucleic Acid
  • Signal Transduction / drug effects
  • Smad3 Protein
  • Substrate Specificity
  • Trans-Activators / metabolism*
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic / drug effects*
  • Transcriptional Activation
  • Transfection
  • Transforming Growth Factor beta / pharmacology*

Substances

  • DNA-Binding Proteins
  • Macromolecular Substances
  • Oligodeoxyribonucleotides
  • Oligopeptides
  • Peptides
  • Proto-Oncogene Proteins c-jun
  • Receptors, Transforming Growth Factor beta
  • SMAD3 protein, human
  • Smad3 Protein
  • Trans-Activators
  • Transcription Factor AP-1
  • Transforming Growth Factor beta
  • DNA
  • FLAG peptide
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I