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Departments of Surgical Oncology [A. M. G., L. Z., W. W., D. B. E., P. J. C.], Tumor Biology [W. Z., P. J. C.], Gastrointestinal Medical Oncology and Digestive Diseases [J. L. A.], and Neuro-oncology [W. Z., S. R.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
The tumor suppressor gene deleted in pancreatic cancer locus 4 (DPC4) is inactivated in about 50% of pancreatic adenocarcinomas. DPC4 was found to be homologous to Smad4 and may function as a transcription factor in the transforming growth factor ß (TGF-ß) receptor-mediated signal transduction pathway. We have investigated the role of DPC4 in the TGF-ß receptor-mediated signal transduction cascade in five human pancreatic cancer cell lines (Panc-1, MDAPanc-28, HS766T, Capan-1, and MiaPaCa-2). Our results demonstrate that the loss of responsiveness to TGF-ß-induced growth inhibition correlates with the loss of expression of DPC4. We have shown that TGF-ß induces p21waf1 expression in Panc-1 cells, whereas no induction of p21waf1 expression by TGF-ß was detected in the other four cell lines lacking either DPC4 expression or the TGF-ß type II receptor. No increase in p21waf1 mRNA stability was observed after treatment with TGF-ß, which suggests that the induction of p21waf1 in Panc-1 cells is transcriptionally regulated by TGF-ß. Our data also demonstrate that the expression of DPC4 is directly involved in TGF-ß-mediated induction of the 3TP-lux reporter gene, which contains a known TGF-ß-inducible plasminogen activator inhibitor promoter. These data suggest that: (a) TGF-ß-mediated induction of p21waf1 and subsequent growth inhibition require the expression of DPC4; (b) p21waf1 is a down-stream target gene of DPC4; and (c) transfection of the DPC4 gene restores the TGF-ß-inducible gene expression. Inactivation of the tumor suppressor gene DPC4 and other components of the TGF-ß signal cascades may abolish one of the key negative controls of cell proliferation in pancreatic adenocarcinomas.
1 Supported in part by a grant from the University Cancer Foundation of the University of Texas M. D. Anderson Cancer Center.
2 Present address: Department of General Surgery, The University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724.
3 To whom requests for reprints should be address, 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: paul_chiao@surg.mdacc.tmc.edu.
Received 5/22/97. Accepted 7/31/97.
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