Cutress, Ramsey I., Townsend, Paul A., Sharp, Adam, Maison, Anna, Wood, Lynn, Lee, Ron, Brimmell, Matthew, Mullee, Mark A., Johnson, Peter W.M., Royle, Gavin T., Bateman, Adrian C. and Packham, Graham (2003) The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription. Oncogene, 22 (32), 4973-4982. (doi:10.1038/sj.onc.1206688). (PMID:12902980)
Abstract
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 ? and ?. 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-1 expression in breast cancers was associated with expression of the progesterone receptor, a transcriptional target of ER?, 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.
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