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.
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
J. Biol. Chem.
Date: Apr. 09, 2004
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