Abstract
Neddylation has an important role in ubiquitin-mediated protein degradation through modification of cullins, which are the main substrates for NEDD8 modification. Here, we show that breast cancer-associated protein 3 (BCA3) is a NEDD8 substrate. BCA3 suppressed NFkappaB-dependent transcription through its ability to bind to p65 and the cyclin D1 promoter in a neddylation-dependent manner. Transcriptional suppression mediated by BCA3 may be attributed to the ability of neddylated BCA3 to recruit SIRT1, a class III histone deacetylase. Silencing of endogenous BCA3 in DU145 and MCF7 cells enhanced NFkappaB transcription and inhibited tumour necrosis factor (TNF)alpha-induced apoptosis. Conversely, BCA3 silencing could be reversed by over-expression of wild-type BCA3 and SENP8, a NEDD8-specific protease, but not by neddylation-deficient BCA3 or a SENP8 mutant. These results provide a crucial link between neddylation and transcriptional regulation by SIRT1, a NAD-dependent histone deacetylase that prolongs life span in yeast and worms.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Apoptosis
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Breast Neoplasms
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COS Cells
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Chlorocebus aethiops
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Cyclin D
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Cyclins / genetics
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Cyclins / metabolism
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Endopeptidases / genetics
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Endopeptidases / metabolism
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Female
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Gene Silencing
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HeLa Cells
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Humans
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Male
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NEDD8 Protein
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Promoter Regions, Genetic
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Prostatic Neoplasms
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Sirtuin 1
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Sirtuins / genetics
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Sirtuins / metabolism*
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism*
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Transcription, Genetic
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Tumor Necrosis Factor-alpha / pharmacology
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Ubiquitins / genetics
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Ubiquitins / metabolism*
Substances
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AKIP1 protein, human
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Adaptor Proteins, Signal Transducing
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Cyclin D
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Cyclins
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NEDD8 Protein
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NEDD8 protein, human
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Neoplasm Proteins
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Nuclear Proteins
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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Ubiquitins
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Endopeptidases
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SENP8 protein, human
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SIRT1 protein, human
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Sirtuin 1
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Sirtuins