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Interplay between Two Hormone-Independent Activation Domains in the Androgen Receptor

Molecular Endocrinology Laboratory, Faculty of Medicine, Campus Gasthuisberg, University of Leuven, Leuven, Belgium

Requests for reprints: Frank Claessens, Molecular Endocrinology Laboratory, Faculty of Medicine, Campus Gasthuisberg, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. Phone: 32-16-345770; Fax: 32-16-345995; E-mail: frank.claessens{at}med.kuleuven.ac.be.

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 -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. (Cancer Res 2006; 66(1): 543-53)

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