Smad4 Protein Stability Is Regulated by Ubiquitin Ligase SCFβ-TrCP1*

By M. Wan, Yi Tang, E. Tytler, Chongyuan Lu, Bingwen Jin, S. Vickers, Lei Yang, Xingming Shi, Xu Cao. Journal of Biological Chemistry, 2004

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Smad4 is a key intracellular mediator for the transforming growth factor-β (TGF-β) 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 SCFβ-TrCP1, a ubiquitin (E3) ligase, as a critical determinant for the protein degradation of Smad4 protein. F-box protein β-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 β-TrCP1/Smad3 interaction was abolished by Smad4 gene silencing, indicating the interaction is indirect and is through Smad4. Ectopic expression of SCF complex containing β-TrCP1 is sufficient to induce the ubiquitination and degradation of Smad4. Furthermore, small interfering RNA-triggered endogenous β-TrCP1 suppression increases the expression of Smad4 protein. Consistent with these results, cells that overexpress the SCF complex display an inhibited TGF-β-dependent transcriptional activity and an impaired cell cycle arrest function. Thus, SCFβ-TrCP1 abrogates TGF-β function in vivo by decreasing Smad4 stability.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b73a234e29a47729ed4e222729946aee7bb35549

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