Targeted deletion of Smad4 shows it is required for transforming growth factor beta 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) beta 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-beta, as well as from the TGF-beta family member activin. These results provide unequivocal evidence that mutational inactivation of Smad4 causes TGF-beta unresponsiveness and provide a basis for understanding the physiologic role of this gene in tumorigenesis.
Zhou
S
S
The Howard Hughes Medical Institute at Johns Hopkins University, Baltimore, MD 21231, USA.
Buckhaults
P
P
Zawel
L
L
Bunz
F
F
Riggins
G
G
Dai
J L
JL
Kern
S E
SE
Kinzler
K W
KW
Vogelstein
B
B
D028341:Activins; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology; D051858:Forkhead Transcription Factors; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D007265:Inhibins / Q000502:physiology*; D009414:Nerve Growth Factors; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic; D015183:Restriction Mapping; D015398:Signal Transduction; D051785:Smad Proteins; D051901:Smad4 Protein; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D029867:Xenopus Proteins
D017931:DNA Primers; D004268:DNA-Binding Proteins; C510350:FOXH1 protein, human; D051858:Forkhead Transcription Factors; C491117:Foxh1 protein, mouse; D009414:Nerve Growth Factors; C497796:SMAD4 protein, human; D051785:Smad Proteins; D051901:Smad4 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C490808:smad4.1 protein, Xenopus; C117263:smad4.2 protein, Xenopus; D028341:Activins; D007265:Inhibins