Specific androgen receptor activation by an artificial coactivator

Transcription activation of steroid receptors, such as the androgen recepto r (AR), is mediated by coactivators, which bridge the receptor to the prein itiation complex. To develop a tool for studying the role of the AR in norm al development and disease, we constructed artificial coactivators consisti ng of the transcription activation domains of VP16 or p65/RelA and the AR h inge and ligand-binding domain (AR(LBD)), which has been shown to interact with the AR N-terminal domain. The artificial VP16-AR(LBD), and AR(LBD)-p65 coactivators interacted with the AR N terminus and wild-type AR in an andr ogen-dependent and androgen-specific manner. VP16-AR(LBD) and AR(LBD)-p65 e nhanced the AR transactivity up to 4- and 13-fold, respectively, without af fecting the expression of the AR protein. The coactivators did not enhance the transcription activity of the progesterone receptor (PR) or the glucoco rticoid receptor (GR), showing their specificity for the AR. In addition, t o construct PR- and GR-specific coactivators, the VP16 activation domain wa s fused to the PR and GR hinge/ligand-binding domain. Although VP16-PRLBD, and VP16-GR(LBD), interacted with the C-terminal portion of steroid recepto r coactivator-l, they did not enhance the transcription activity of their r eceptor. The presented strategy of directing activation domains or other pr otein activities into the RNA-hound AR complex provides a novel means of ma nipulating AR function in vitro and in vivo.