Neddylation of a breast cancer-associated protein recruits a class III histone deacetylase that represses NFkappaB-dependent transcription.

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.
Mesh Terms:
Animals, Apoptosis, Breast Neoplasms, COS Cells, Cercopithecus aethiops, Cyclin D, Cyclins, Endopeptidases, Female, Gene Silencing, Hela Cells, Humans, Male, Neoplasm Proteins, Nuclear Proteins, Promoter Regions, Genetic, Prostatic Neoplasms, Sirtuin 1, Sirtuins, Transcription Factor RelA, Transcription, Genetic, Tumor Necrosis Factor-alpha, Ubiquitins
Nat. Cell Biol.
Date: Oct. 01, 2006
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