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

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          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.

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          Author and article information

          Journal
          Nat Cell Biol
          Nature cell biology
          Springer Science and Business Media LLC
          1465-7392
          1465-7392
          Oct 2006
          : 8
          : 10
          Affiliations
          [1 ] Department of Cardiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 449, Houston, TX 77030, USA.
          Article
          ncb1483
          10.1038/ncb1483
          16998474
          9e85a776-4c23-4361-8bdf-2fcb4639d0a9
          History

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