SCFβ-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, Xu Cao

Research output: Contribution to journalArticlepeer-review

Abstract

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)-β-related ligands that regulate cell growth and differentiation. Mutations in Smad4/ DPC4 have been identified in ∼50% of pancreatic adenocarcinomas. Here we report that SCFβ-TrCP1, a ubiquitin (E3) ligase, is a critical determinant for Smad4 protein degradation in pancreatic cancer cells. We found that F-box protein β-TrCP1 in this E3 ligase interacted with Smad4 and that SCFβ-TrCP1 inhibited TGF-β 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 β-TrCP1 and significantly elevated protein ubiquitination by SCFβ-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 β-TrCp1. Both Smad4 levels and TGF-β signaling were elevated by retrovirus-delivered β-TrCP1 siRNA in pancreatic cancer cells. Therefore, inhibition of Smad4-specific E3 ligase might be a target for therapeutic intervention in pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1379-1392
Number of pages14
JournalAmerican Journal of Pathology
Volume166
Issue number5
DOIs
StatePublished - May 2005
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint

Dive into the research topics of 'SCF<sup>β-TrCP1</sup> controls Smad4 protein stability in pancreatic cancer cells'. Together they form a unique fingerprint.

Cite this