Abstract
Activation of NF-kappaB transcription factors requires phosphorylation and ubiquitin-proteasome-dependent degradation of IkappaB proteins. We provide evidence that a human F-box protein, h-betaTrCP, a component of Skp1-Cullin-F-box protein (SCF) complexes, a new class of E3 ubiquitin ligases, is essential for inducible degradation of IkappaBalpha. betaTrCP associates with Ser32-Ser36 phosphorylated, but not with unmodified IkappaBalpha or Ser32-Ser36 phosphorylation-deficient mutants. Expression of a F-box-deleted betaTrCP inhibits IkappaBalpha degradation, promotes accumulation of phosphorylated Ser32-Ser36 IkappaBalpha, and prevents NF-kappaB-dependent transcription. Our findings indicate that betaTrCP is the adaptor protein required for IkappaBalpha recognition by the SCFbetaTrCP E3 complex that ubiquitinates IkappaBalpha and makes it a substrate for the proteasome.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle Proteins / metabolism*
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Cysteine Endopeptidases / metabolism*
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DNA-Binding Proteins / metabolism*
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GTP-Binding Proteins / metabolism*
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HeLa Cells
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Humans
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I-kappa B Proteins*
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Models, Chemical
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Multienzyme Complexes / metabolism*
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NF-KappaB Inhibitor alpha
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NF-kappa B / biosynthesis
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NF-kappa B / genetics
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Peptide Synthases / metabolism*
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Phosphorylation
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Proteasome Endopeptidase Complex
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S-Phase Kinase-Associated Proteins
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SKP Cullin F-Box Protein Ligases
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Serine / metabolism
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Transcription, Genetic
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beta-Transducin Repeat-Containing Proteins
Substances
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BTRC protein, human
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Cell Cycle Proteins
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DNA-Binding Proteins
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I-kappa B Proteins
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Multienzyme Complexes
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NF-kappa B
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NFKBIA protein, human
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S-Phase Kinase-Associated Proteins
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beta-Transducin Repeat-Containing Proteins
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NF-KappaB Inhibitor alpha
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Serine
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SKP Cullin F-Box Protein Ligases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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GTP-Binding Proteins
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Peptide Synthases