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

http://www.ncbi.nlm.nih.gov/pubmed/14988407

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 RIS Download

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

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Associated grants

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

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