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Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1.

Smad4 is a key intracellular mediator for the transforming growth factor-beta (TGF-beta) superfamily of growth factors and is also an important tumor suppressor. The receptor-regulated Smad (R-Smad) proteins are regulated by ubiquitin-mediated degradation, yet the precise control of Smad4 protein stability is unclear. We have identified SCF(beta-TrCP1), a ubiquitin (E3) ligase, as a critical determinant for the protein degradation of Smad4 protein. F-box protein beta-TrCP1 in this E3 ligase interacts with Smad4 both in yeast and in mammalian cells, but has no interaction with Smad2 and has weak interaction with Smad3. The beta-TrCP1/Smad3 interaction was abolished by Smad4 gene silencing, indicating the interaction is indirect and is through Smad4. Ectopic expression of SCF complex containing beta-TrCP1 is sufficient to induce the ubiquitination and degradation of Smad4. Furthermore, small interfering RNA-triggered endogenous beta-TrCP1 suppression increases the expression of Smad4 protein. Consistent with these results, cells that overexpress the SCF complex display an inhibited TGF-beta-dependent transcriptional activity and an impaired cell cycle arrest function. Thus, SCF(beta-TrCP1) abrogates TGF-beta function in vivo by decreasing Smad4 stability.

Pubmed ID: 14988407

Authors

  • Wan M
  • Tang Y
  • Tytler EM
  • Lu C
  • Jin B
  • Vickers SM
  • Yang L
  • Shi X
  • Cao X

Journal

The Journal of biological chemistry

Publication Data

April 9, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA101955-01
  • Agency: NIDDK NIH HHS, Id: DK53757
  • Agency: NIDDK NIH HHS, Id: DK57501

Mesh Terms

  • Blotting, Western
  • Cell Line
  • DNA, Complementary
  • DNA-Binding Proteins
  • Down-Regulation
  • Gene Silencing
  • Humans
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA, Small Interfering
  • SKP Cullin F-Box Protein Ligases
  • Signal Transduction
  • Smad2 Protein
  • Smad3 Protein
  • Smad4 Protein
  • Time Factors
  • Trans-Activators
  • Transcription, Genetic
  • Transcriptional Activation
  • Ubiquitin