A Self-Enabling TGFbeta Response Coupled to Stress Signaling: Smad Engages Stress Response Factor ATF3 for Id1 Repression in Epithelial Cells

Mol Cell. 2003 Apr;11(4):915-26. doi: 10.1016/s1097-2765(03)00109-6.

Abstract

Genome-wide transcriptional profiling of human epithelial cells revealed that repression of Id inhibitors of differentiation (Id1, Id2, and Id3) is a general feature of the TGFbeta cytostatic program. Opposite responses of Id1 to TGFbeta and the related factor BMP are dictated by the specific ability of the TGFbeta mediator, Smad3, to activate expression of stress response factor ATF3 and then recruit this factor to the Id1 promoter. Thus, a Smad3-mediated primary gene response, ATF3 induction, enables Smad3 to participate in an ATF3-mediated, secondary gene response. As a common target of TGFbeta/Smad signals and stress signals via p38 kinase, ATF3 additionally serves to channel synergy between these pathways in the response of epithelial cells to stress and injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3
  • Animals
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Epithelial Cells / metabolism*
  • Gene Expression Regulation / genetics
  • Genes, Regulator / genetics
  • Humans
  • Inhibitor of Differentiation Protein 1
  • Promoter Regions, Genetic / genetics
  • Protein Structure, Tertiary / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction / genetics*
  • Smad Proteins
  • Smad3 Protein
  • Smad4 Protein
  • Stress, Physiological / genetics
  • Stress, Physiological / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • Activating Transcription Factor 3
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • ID1 protein, human
  • Inhibitor of Differentiation Protein 1
  • Repressor Proteins
  • SMAD3 protein, human
  • SMAD4 protein, human
  • Smad Proteins
  • Smad3 Protein
  • Smad4 Protein
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta