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BRCA1 regulates acetylation and ubiquitination of estrogen receptor-alpha.

Inherited mutations of the breast cancer susceptibility gene BRCA1 confer a high risk for breast cancer development. The (300)RXKK and (266)KXK motifs have been identified previously as sites for acetylation of the estrogen receptor-alpha (ER-alpha), and (302)K was also found to be a site for BRCA1-mediated mono-ubiquitination of ER-alpha in vitro. Here we show that ER-alpha proteins with single or double lysine mutations of these motifs (including K303R, a cancer-associated mutant) are resistant to inhibition by BRCA1, even though the mutant ER-alpha proteins retain the ability to bind to BRCA1. We also found that BRCA1 overexpression reduced and knockdown increased the level of acetylated wild-type ER-alpha, without changing the total ER-alpha protein level. Increased acetylation of ER-alpha due to BRCA1 small interfering RNA was dependent upon phosphatidylinositol 3-kinase/Akt signaling and on up-regulation of the coactivator p300. In addition, using an in vitro acetylation assay, we found that in vitro-translated wild-type BRCA1 but not a cancer-associated point mutant (C61G) inhibited p300-mediated acetylation of ER-alpha. Furthermore, BRCA1 overexpression increased the levels of mono-ubiquitinated ER-alpha protein, and a BRCA1 mutant that is defective for ubiquitin ligase activity but retains other BRCA1 functions (I26A) did not ubiquitinate ER-alpha or repress its activity in vivo. Finally, ER-alpha proteins with mutations of the (300)RXKK or (266)KXK motifs showed modest or no BRCA1-induced ubiquitination. We propose a model in which BRCA1 represses ER-alpha activity, in part, by regulating the relative degree of acetylation vs. ubiquitination of ER-alpha.

Pubmed ID: 19887647

Authors

  • Ma Y
  • Fan S
  • Hu C
  • Meng Q
  • Fuqua SA
  • Pestell RG
  • Tomita YA
  • Rosen EM

Journal

Molecular endocrinology (Baltimore, Md.)

Publication Data

January 29, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA072038
  • Agency: NCI NIH HHS, Id: R01-CA80000
  • Agency: NCI NIH HHS, Id: R01-CA82599

Mesh Terms

  • Acetylation
  • BRCA1 Protein
  • Breast Neoplasms
  • Cell Line, Tumor
  • Estradiol
  • Estrogen Receptor alpha
  • Female
  • Gene Knockdown Techniques
  • Genes, BRCA1
  • Genes, Reporter
  • Humans
  • Male
  • Mutation
  • Phosphatidylinositol 3-Kinases
  • Prostatic Neoplasms
  • Protein Binding
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt
  • RNA, Small Interfering
  • Transfection
  • Ubiquitination
  • p300-CBP Transcription Factors