The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription

被引:65
作者
Cutress, RI
Townsend, PA
Sharp, A
Maison, A
Wood, L
Lee, R
Brimmell, M
Mullee, MA
Johnson, PWM
Royle, GT
Bateman, AC
Packham, G
机构
[1] Univ Southampton, Canc Res UK,Southampton Gen Hosp, Oncol Unit, Canc Sci Div,Sch Med, Southampton SO16 6YD, Hants, England
[2] Univ Southampton, Southampton Gen Hosp, Hlth Care Res Unit, Southampton SO16 6YD, Hants, England
[3] Royal S Hants Hosp, Southampton Breast Unit, Southampton SO14 0YG, Hants, England
[4] Southampton Gen Hosp, Dept Pathol, Southampton SO16 6YD, Hants, England
关键词
BAG-1; breast cancer; oestrogen; receptor; hormone therapy; survival;
D O I
10.1038/sj.onc.1206688
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
BAG-1 is a multifunctional protein that interacts with a wide range of cellular targets including heat-shock proteins and some nuclear hormone receptors. BAG-1 exists as three major isoforms, BAG-1L, BAG-1M and BAG-1S. BAG-1L contains a nuclear localization signal, which is not present in the other isoforms, and is predominantly localized in the cell nucleus. Here we have investigated the effects of BAG-1 on function of the oestrogen receptor (ER), a key growth control molecule and target for hormonal therapy in breast cancer. We demonstrate that BAG-1L, but not BAG-1S or BAG-1M increased oestrogen-dependent transcription in breast cancer cells. BAG-1L interacted with and stimulated the activity of both ER alpha and beta. Although BAG-1L and ERs colocalize to the nucleus, fusing BAG-1S to an heterologous nuclear localization sequence was not sufficient to stimulate transcription. Consistent with an important effect on receptor function, nuclear BAG-I expression in breast cancers was associated with expression of the progesterone receptor, a transcriptional target of ER(x, and was associated with improved survival in patients treated with hormonal therapy. These data suggest that BAG-1L is an important determinant of ER function in vitro and in human breast cancer.
引用
收藏
页码:4973 / 4982
页数:10
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