The transcriptional co-activator P/CAF potentiates TGF-beta/Smad signaling

Nucleic Acids Res. 2000 Nov 1;28(21):4291-8. doi: 10.1093/nar/28.21.4291.

Abstract

Smads perform pivotal functions in the intracellular signaling of transforming growth factor-beta (TGF-beta). TGF-beta-mediated activation of TGF-beta type I receptor stimulates the phosphorylation of Smad2 and Smad3 and subsequent heteromeric complex formation with Smad4. The heteromeric Smad complexes translocate into the nucleus where they, in co-operation with co-activators and co-repressors, regulate transcriptional responses. Here we investigated the possible co-activator function of P/CAF in TGF-beta/Smad signaling. P/CAF was found to interact directly with Smad3 in vitro. Moreover, Smad2 and Smad3 interacted with P/CAF upon TGF-beta type I receptor activation in cultured mammalian cells. The interaction involves the MH2 domain of Smad3 and the N-terminal region of P/CAF. P/CAF potentiated the transcriptional activity of heterologous Gal4-Smad2 and Gal4-Smad3 fusion proteins. In addition, P/CAF potentiated the TGF-beta/Smad3-induced transcriptional responses, which could be further enhanced by co-activators p300 and Smad4. P/CAF may, therefore, activate Smad-mediated transcriptional responses independently or in co-operation with p300/CBP. Our results indicate a direct physical and functional interplay between two negative regulators of cell proliferation, Smad3 and P/CAF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / chemistry
  • Acetyltransferases / metabolism*
  • Activin Receptors, Type I*
  • Animals
  • Binding Sites
  • Blotting, Western
  • COS Cells
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Genes, Reporter / genetics
  • Histone Acetyltransferases
  • Humans
  • Nuclear Proteins / metabolism
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / drug effects*
  • Smad2 Protein
  • Smad3 Protein
  • Trans-Activators / chemistry
  • Trans-Activators / metabolism*
  • Transcription Factors
  • Transcriptional Activation
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Cells, Cultured
  • p300-CBP Transcription Factors

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Acetyltransferases
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I