Callewaert Leen, Van Tilborgh Nora, Claessens Frank
Molecular Endocrinology Laboratory, Faculty of Medicine, Campus Gasthuisberg, University of Leuven, Leuven, Belgium.
Cancer Res. 2006 Jan 1;66(1):543-53. doi: 10.1158/0008-5472.CAN-05-2389.
The androgen receptor (AR) plays a key role in prostate cancer development, as well as its treatments, even for the hormone-refractory state. Here, we report that an earlier described lysine-to-arginine mutation at position 179 in AR leads to a more potent AR. We show that two activation domains (Tau-1 and Tau-5) are necessary and sufficient for the full activity of AR and the intrinsic activity of the AR-NTD. Two alpha-helices surrounding the Lys179 define the core of Tau-1, which can act as an autonomous activation function, independent of p160 coactivators. Furthermore, we show that although the recruitment of p160 coactivators is mediated through Tau-5, this event is attenuated by core Tau-1. This better definition of the mechanisms of action of both Tau-1 and Tau-5 is instrumental for the design of alternative therapeutic strategies against prostate cancer.
雄激素受体（AR）在前列腺癌的发展及其治疗中发挥着关键作用，即使是对于激素难治性状态也是如此。在此，我们报告先前描述的AR第179位赖氨酸到精氨酸的突变会导致产生更强效的AR。我们表明，两个激活域（Tau-1和Tau-5）对于AR的完全活性以及AR-NTD的内在活性是必需且充分的。围绕赖氨酸179的两个α螺旋定义了Tau-1的核心，其可作为自主激活功能，独立于p160共激活因子。此外，我们表明，尽管p160共激活因子的募集是通过Tau-5介导的，但这一事件会被核心Tau-1减弱。对Tau-1和Tau-5作用机制的这种更好定义有助于设计针对前列腺癌的替代治疗策略。
