SCF(beta-TrCP1) controls Smad4 protein stability in pancreatic cancer cells.

Academic Article

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

    Keywords

  • Adenocarcinoma, Aged, Aged, 80 and over, Carcinoma, Ductal, Breast, DNA-Binding Proteins, Drug Stability, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms, Point Mutation, Proteasome Endopeptidase Complex, SKP Cullin F-Box Protein Ligases, Smad4 Protein, Trans-Activators, Transforming Growth Factor beta, Ubiquitin
  • Digital Object Identifier (doi)

    Pubmed Id

  • 19931899
  • Author List

  • Wan M; Huang J; Jhala NC; Tytler EM; Yang L; Vickers SM; Tang Y; Lu C; Wang N; Cao X
  • Start Page

  • 1379
  • End Page

  • 1392
  • Volume

  • 166
  • Issue

  • 5