Transforming growth factor-β responsiveness in DPC4/SMAD4-null cancer cells

✍ Scribed by Jia Le Dai; Mieke Schutte; Ravi K. Bansal; Robb E. Wilentz; Avrahom Y. Sugar; Scott E. Kern

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 135 KB
• Volume: 26
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/(sici)1098-2744(199909)26:1<37::aid-mc5>3.0.co;2-6

✦ Synopsis

DPC4/SMAD4 is a candidate tumor suppressor gene with a strikingly high frequency of gene alterations in pancreatic cancer that suggests a discrete role for DPC4 in these tumors. DPC4 tumor-suppressive function has been implicated to mediate the transforming growth factor-b (TGFb)±suppressive pathway; however, in a DPC4-null pancreatic cancer cell line, TGFb growth-inhibitory and transcriptional responses were found to be DPC4-independent. This was observed within native cells having a natural homozygous deletion and in clones engineered for stable expression of wild-type DPC4 integrated into the genome. This observation contrasted with the absolute DPC4 dependence of TGFb responses in a breast cancer cell line studied in parallel. This growth-inhibitory response to TGFb in DPC4-null cells relied on an intact ras effector pathway. These data further suggest a major categorization of TGFb responses into DPC4-dependent and -independent signaling pathways and specifically suggest that disruption of the TGFb-independent signal might be a basis of selection for the emergence of DPC4 alterations during tumorigenesis in the pancreas and other sites. Mol.