Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

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


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


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