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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
15
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pubmed:dateCreated |
2004-4-6
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/SKP Cullin F-Box Protein Ligases,
http://linkedlifedata.com/resource/pubmed/chemical/SMAD2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/SMAD3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/SMAD4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Smad2 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Smad3 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Smad4 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
9
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pubmed:volume |
279
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
14484-7
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:14988407-Blotting, Western,
pubmed-meshheading:14988407-Cell Line,
pubmed-meshheading:14988407-DNA, Complementary,
pubmed-meshheading:14988407-DNA-Binding Proteins,
pubmed-meshheading:14988407-Down-Regulation,
pubmed-meshheading:14988407-Gene Silencing,
pubmed-meshheading:14988407-Humans,
pubmed-meshheading:14988407-Phosphorylation,
pubmed-meshheading:14988407-Precipitin Tests,
pubmed-meshheading:14988407-Protein Binding,
pubmed-meshheading:14988407-Protein Structure, Tertiary,
pubmed-meshheading:14988407-RNA, Small Interfering,
pubmed-meshheading:14988407-SKP Cullin F-Box Protein Ligases,
pubmed-meshheading:14988407-Signal Transduction,
pubmed-meshheading:14988407-Smad2 Protein,
pubmed-meshheading:14988407-Smad3 Protein,
pubmed-meshheading:14988407-Smad4 Protein,
pubmed-meshheading:14988407-Time Factors,
pubmed-meshheading:14988407-Trans-Activators,
pubmed-meshheading:14988407-Transcription, Genetic,
pubmed-meshheading:14988407-Transcriptional Activation,
pubmed-meshheading:14988407-Ubiquitin
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pubmed:year |
2004
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pubmed:articleTitle |
Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1.
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pubmed:affiliation |
Department of Pathology, University of Alabama at Birmingham, School of Medicine, Birmingham, Alabama 35294, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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