Targeted deletion of Smad4 shows it is required for transforming growth factor β and activin signaling in colorectal cancer cells

Smad4 (DPC4) is a candidate tumor suppressor gene that has been hypothesized to be critical for transmitting signals from transforming growth factor (TGF) β and related ligands. To directly test this hypothesis, the Smad4 gene was deleted through homologous recombination in human colorectal cancer cells. This deletion abrogated signaling from TGF-β, as well as from the TGF-β family member activin. These results provide unequivocal evidence that mutational inactivation of Smad4 causes TGF-β unresponsiveness and provide a basis for understanding the physiologic role of this gene in tumorigenesis.