Overexpression of the tumor suppressor gene Smad4/DPC4 induces p21waf1 expression and growth inhibition in human carcinoma cells.
The Smad4/DPC4 protein functions as a key transcription factor in transforming growth factor beta (TGF-beta) signaling pathways. However, the downstream target genes regulated by Smad4/DPC4 have not been identified until now. We previously demonstrated that the loss of TGF-beta-induced p21waf1 expression and growth inhibition correlates with inactivation of the Smad4/DPC4 gene. Now we show that transient overexpression of Smad4/DPC4 can induce p21waf1 expression, specific Smad4 DNA binding activity, SBE4-luc reporter gene activity, and subsequent growth inhibition in Smad4/DPC4-null cells and other carcinoma cells in the presence or absence of TGF-beta. Taken together, these data show that p21waf1 is one of the Smad4/DPC4-regulated downstream target genes and suggest that overexpression of the Smad4/DPC4 gene can bypass TGF-beta receptor activation and reestablish one of the key regulatory controls of cell proliferation.
Hunt
K K
KK
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Fleming
J B
JB
Abramian
A
A
Zhang
L
L
Evans
D B
DB
Chiao
P J
PJ
D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D015398:Signal Transduction; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta