Smad4 Protein Stability Is Regulated by Ubiquitin Ligase SCF β-TrCP1

Mei Wan, Yi Tang, Ewan M. Tytler, Chongyuan Lu, Bingwen Jin, Selwyn M. Vickers, Lei Yang, Xingming Shi, Xu Cao

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)14484-14487
Number of pages4
JournalJournal of Biological Chemistry
Volume279
Issue number15
DOIs
StatePublished - Apr 9 2004
Externally publishedYes

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Smad4 Protein
SKP Cullin F-Box Protein Ligases
Protein Stability
Transforming Growth Factors
Ubiquitin-Protein Ligases
Receptor-Regulated Smad Proteins
Degradation
Cells
F-Box Proteins
Ubiquitination
Gene Silencing
Ubiquitin
Cell Cycle Checkpoints
Yeast
Small Interfering RNA
Proteolysis
Tumors
Intercellular Signaling Peptides and Proteins
Genes
Yeasts

ASJC Scopus subject areas

  • Biochemistry

Cite this

Smad4 Protein Stability Is Regulated by Ubiquitin Ligase SCF β-TrCP1 . / Wan, Mei; Tang, Yi; Tytler, Ewan M.; Lu, Chongyuan; Jin, Bingwen; Vickers, Selwyn M.; Yang, Lei; Shi, Xingming; Cao, Xu.

In: Journal of Biological Chemistry, Vol. 279, No. 15, 09.04.2004, p. 14484-14487.

Research output: Contribution to journalArticle

Wan, M, Tang, Y, Tytler, EM, Lu, C, Jin, B, Vickers, SM, Yang, L, Shi, X & Cao, X 2004, 'Smad4 Protein Stability Is Regulated by Ubiquitin Ligase SCF β-TrCP1 ', Journal of Biological Chemistry, vol. 279, no. 15, pp. 14484-14487. https://doi.org/10.1074/jbc.C400005200
Wan, Mei ; Tang, Yi ; Tytler, Ewan M. ; Lu, Chongyuan ; Jin, Bingwen ; Vickers, Selwyn M. ; Yang, Lei ; Shi, Xingming ; Cao, Xu. / Smad4 Protein Stability Is Regulated by Ubiquitin Ligase SCF β-TrCP1 In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 15. pp. 14484-14487.
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