E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression

Cell. 2002 Jul 12;110(1):19-32. doi: 10.1016/s0092-8674(02)00801-2.

Abstract

Smad3 is a direct mediator of transcriptional activation by the TGFbeta receptor. Its target genes in epithelial cells include cyclin-dependent kinase inhibitors that generate a cytostatic reponse. We defined how, in the same context, Smad3 can also mediate transcriptional repression of the growth-promoting gene c-myc. A complex containing Smad3, the transcription factors E2F4/5 and DP1, and the corepressor p107 preexists in the cytoplasm. In response to TGFbeta, this complex moves into the nucleus and associates with Smad4, recognizing a composite Smad-E2F site on c-myc for repression. Previously known as the ultimate recipients of cdk regulatory signals, E2F4/5 and p107 act here as transducers of TGFbeta receptor signals upstream of cdk. Smad proteins therefore mediate transcriptional activation or repression depending on their associated partners.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Binding Sites
  • COS Cells
  • Cell Cycle / physiology
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology
  • Chlorocebus aethiops
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • E2F4 Transcription Factor
  • E2F5 Transcription Factor
  • Gene Silencing*
  • Humans
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / genetics*
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Retinoblastoma-Like Protein p107
  • Smad3 Protein
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transcription Factor DP1
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcription, Genetic
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Tumor Cells, Cultured

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F4 Transcription Factor
  • E2F5 Transcription Factor
  • E2F5 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • RBL1 protein, human
  • Receptors, Transforming Growth Factor beta
  • Retinoblastoma-Like Protein p107
  • SMAD3 protein, human
  • Smad3 Protein
  • TFDP1 protein, human
  • TFDP2 protein, human
  • Trans-Activators
  • Transcription Factor DP1
  • Transcription Factors
  • Transforming Growth Factor beta