DPC4 (SMAD4) mediates transforming growth factor-beta1 (TGF-beta1) induced growth inhibition and transcriptional response in breast tumour cells

Oncogene. 1997 Apr 24;14(16):1891-9. doi: 10.1038/sj.onc.1201017.


A family of structurally related proteins homologous to the Drosophila mothers against dpp (MAD) gene product have been implicated in signal transduction by members of the TGF-beta superfamily. One of these MAD related proteins (DPC4) has been cloned as a candidate tumour suppressor in pancreas carcinomas, suggesting a role for DPC4 in growth regulation by TGF-beta related proteins. The involvement of DPC4 in TGF-beta1 induced growth inhibition and transcriptional response is demonstrated here, by the introduction of DPC4 in the TGF-beta and activin insensitive breast tumour cell line MDA-MB-468, from which the DPC4 gene is deleted. Transfection of DPC4 in this cell line restores both growth inhibition and the induction of a TGF-beta sensitive reporter construct (3TPlux) by TGF-beta1. In contrast, a DPC4 splice variant lacking amino acid residues 223-301 and cloned from another TGF-beta and activin resistant breast tumour cell line (MDA-MB-231), does not restore the induction of the 3TPlux reporter by TGF-beta1. We also show that in this latter cell line activin resistance is partly due to the absence of a functional activin type IB receptor. These results indicate that DPC4 is part of the TGF-beta signalling cascade and mediates TGF-beta induced growth inhibition. Together with the deletion of DPC4 from pancreas carcinomas these results suggest a role for DPC4 as a tumour suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins
  • Alternative Splicing
  • Amino Acid Sequence
  • Base Sequence
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Breast Neoplasms
  • Cell Division / drug effects
  • DNA Primers
  • DNA-Binding Proteins / chemistry
  • Drug Resistance, Neoplasm
  • Female
  • Gene Deletion
  • Genes, Tumor Suppressor*
  • Humans
  • Inhibins / pharmacology
  • Luciferases / biosynthesis
  • Molecular Sequence Data
  • Pancreatic Neoplasms / genetics
  • Polymerase Chain Reaction
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins*
  • Sequence Deletion
  • Sequence Homology, Amino Acid
  • Smad4 Protein
  • Trans-Activators / biosynthesis*
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Transcription, Genetic / drug effects*
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Cells, Cultured


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA Primers
  • DNA-Binding Proteins
  • MXD1 protein, human
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • SMAD4 protein, human
  • Smad4 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Activins
  • Inhibins
  • Luciferases