DPC4 (SMAD4) mediates transforming growth factor-beta1 (TGF-beta1) induced growth inhibition and transcriptional response in breast tumour cells.
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.
de Winter
J P
JP
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht.
Roelen
B A
BA
ten Dijke
P
P
van der Burg
B
B
van den Eijnden-van Raaij
A J
AJ
D028341:Activins; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D005260:Female; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D007265:Inhibins / Q000494:pharmacology; D008156:Luciferases / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000235:genetics; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D051901:Smad4 Protein; D015534:Trans-Activators / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017931:DNA Primers; D004268:DNA-Binding Proteins; C079439:MXD1 protein, human; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D028341:Activins; D007265:Inhibins; D008156:Luciferases