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(American Journal of Pathology. 2005;166:1379-1392.)
© 2005 American Society for Investigative Pathology

SCF^ß-TrCP1 Controls Smad4 Protein Stability in Pancreatic Cancer Cells

Mei Wan^*, Jin Huang^*, Nirag C. Jhala^*, Ewan M. Tytler, Lei Yang^*, Selwyn M. Vickers, Yi Tang^*, Chongyuan Lu^*, Ning Wang^* and Xu Cao^*

From the Departments of Pathology^* and Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

Smad4, also known as deleted in pancreatic carcinoma locus 4 (DPC4), is a critical co-factor in signal transduction pathways activated by transforming growth factor (TGF)-ß-related ligands that regulate cell growth and differentiation. Mutations in Smad4/DPC4 have been identified in 50% of pancreatic adenocarcinomas. Here we report that SCF^ß-TrCP1, a ubiquitin (E3) ligase, is a critical determinant for Smad4 protein degradation in pancreatic cancer cells. We found that F-box protein ß-TrCP1 in this E3 ligase interacted with Smad4 and that SCF^ß-TrCP1 inhibited TGF-ß biological activity in pancreatic cancer cells by decreasing Smad4 stability. Very low Smad4 protein levels in human pancreatic ductal adenocarcinoma cells were observed by immunohistochemistry. By analyzing pancreatic tumor-derived Smad4 mutants, we found that most point-mutated Smad4 proteins, except those within or very close to a mutation cluster region, exhibited higher interaction affinity with ß-TrCP1 and significantly elevated protein ubiquitination by SCF^ß-TrCP1. Furthermore, AsPC-1 and Caco-2, two cancer cell lines harboring Smad4 point mutations, exhibited rapid Smad4 protein degradation due to the effect of SCF^ß-TrCP1. Both Smad4 levels and TGF-ß signaling were elevated by retrovirus-delivered ß-TrCP1 siRNA in pancreatic cancer cells. Therefore, inhibition of Smad4-specific E3 ligase might be a target for therapeutic intervention in pancreatic cancer.

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