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Articles by Q Meng
Total Records ( 1 ) for Q Meng
  Y Ma , S Fan , C Hu , Q Meng , S. A Fuqua , R. G Pestell , Y. A Tomita and E. M. Rosen

Inherited mutations of the breast cancer susceptibility gene BRCA1 confer a high risk for breast cancer development. The 300RXKK and 266KXK motifs have been identified previously as sites for acetylation of the estrogen receptor- (ER-), and 302K was also found to be a site for BRCA1-mediated mono-ubiquitination of ER- in vitro. Here we show that ER- 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- 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-, without changing the total ER- protein level. Increased acetylation of ER- 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-. Furthermore, BRCA1 overexpression increased the levels of mono-ubiquitinated ER- protein, and a BRCA1 mutant that is defective for ubiquitin ligase activity but retains other BRCA1 functions (I26A) did not ubiquitinate ER- or repress its activity in vivo. Finally, ER- proteins with mutations of the 300RXKK or 266KXK motifs showed modest or no BRCA1-induced ubiquitination. We propose a model in which BRCA1 represses ER- activity, in part, by regulating the relative degree of acetylation vs. ubiquitination of ER-.

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