The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription
The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription
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DOI：
10.1038/sj.onc.1206688
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发表时间：
2003-08-07
期刊：
影响因子：
8
通讯作者：
Packham, G
中科院分区：
文献类型：
--
作者：
Cutress, RI;Townsend, PA;Packham, G
BAG-1是一种多功能蛋白质，与广泛的细胞靶点相互作用，包括热休克蛋白和一些核激素受体。BAG-1存在三种主要的同种型，BAG-1 L、BAG-1 M和BAG-1 S。BAG-1 L含有核定位信号，其不存在于其他同种型中，并且主要定位于细胞核中。在这里，我们研究了BAG-1对雌激素受体（ER）功能的影响，ER是乳腺癌激素治疗的关键生长控制分子和靶点。我们证明，BAG-1 L，而不是BAG-1 S或BAG-1 M增加乳腺癌细胞中的雌激素依赖性转录。BAG-1 L与ER α和ER β相互作用并刺激其活性。尽管BAG-1 L和ER共定位于细胞核，但将BAG-1 S融合到异源细胞核定位序列不足以刺激转录。与对受体功能的重要作用一致，乳腺癌中的核BAG-I表达与孕激素受体（ER α的转录靶点）的表达相关，并且与接受激素治疗的患者的存活率改善相关。这些数据表明，BAG-1 L是体外和人乳腺癌中ER功能的重要决定因素。
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.