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Overexpression of the Tumor Suppressor Gene Smad4/DPC4 Induces p21^waf1 Expression and Growth Inhibition in Human Carcinoma Cells¹

Department of Surgical Oncology, The University of Texas M. D. Anderson Cencer Center, Houston, Texas 77030

The Smad4/DPC4 protein functions as a key transcription factor in transforming growth factor ß (TGF-ß) 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-ß-induced p21^waf1 expression and growth inhibition correlates with inactivation of the Smad4/DPC4 gene. Now we show that transient overexpression of Smad4/DPC4 can induce p21^waf1 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-ß. Taken together, these data show that p21^waf1 is one of the Smad4/DPC4-regulated downstream target genes and suggest that overexpression of the Smad4/DPC4 gene can bypass TGF-ß receptor activation and reestablish one of the key regulatory controls of cell proliferation.

¹ Supported in part by a grant from the University Cancer Foundation at M. D. Anderson Cancer Center and the Advanced Technology/Research Program of the Texas Higher Education Coordinating Board.

² To whom requests for reprints should be addressed, at Department of Surgical Oncology, Box 107, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 794-1030; Fax: (713) 794-4830; E-mail: pjchiao@notes.mdacc.tmc.edu.

Received 8/27/98. Accepted 10/26/98.

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