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

Nat Cell Biol. 2006 Oct;8(10):1171-7. doi: 10.1038/ncb1483. Epub 2006 Sep 24.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis
  • Breast Neoplasms
  • COS Cells
  • Chlorocebus aethiops
  • Cyclin D
  • Cyclins / genetics
  • Cyclins / metabolism
  • Endopeptidases / genetics
  • Endopeptidases / metabolism
  • Female
  • Gene Silencing
  • HeLa Cells
  • Humans
  • Male
  • NEDD8 Protein
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic
  • Prostatic Neoplasms
  • Sirtuin 1
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ubiquitins / genetics
  • Ubiquitins / metabolism*

Substances

  • AKIP1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Cyclin D
  • Cyclins
  • NEDD8 Protein
  • NEDD8 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Ubiquitins
  • Endopeptidases
  • SENP8 protein, human
  • SIRT1 protein, human
  • Sirtuin 1
  • Sirtuins