Specific androgen receptor activation by an artificial coactivator.
Transcription activation of steroid receptors, such as the androgen receptor (AR), is mediated by coactivators, which bridge the receptor to the preinitiation complex. To develop a tool for studying the role of the AR in normal development and disease, we constructed artificial coactivators consisting of the transcription activation domains of VP16 or p65/RelA and the AR hinge and ligand-binding domain (ARLBD), which has been shown to interact with the AR N-terminal domain. The artificial VP16-ARLBD and ARLBD-p65 coactivators interacted with the AR N terminus and wild-type AR in an androgen-dependent and androgen-specific manner. VP16-ARLBD and ARLBD-p65 enhanced the AR transactivity up to 4- and 13-fold, respectively, without affecting the expression of the AR protein. The coactivators did not enhance the transcription activity of the progesterone receptor (PR) or the glucocorticoid receptor (GR), showing their specificity for the AR. In addition, to construct PR- and GR-specific coactivators, the VP16 activation domain was fused to the PR and GR hinge/ligand-binding domain. Although VP16-PRLBD and VP16-GRLBD interacted with the C-terminal portion of steroid receptor coactivator-1, they did not enhance the transcription activity of their receptor. The presented strategy of directing activation domains or other protein activities into the DNA-bound AR complex provides a novel means of manipulating AR function in vitro and in vivo.
Sui
X
X
Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Bramlett
K S
KS
Jorge
M C
MC
Swanson
D A
DA
von Eschenbach
A C
AC
Jenster
G
G
D001665:Binding Sites; D006367:HeLa Cells; D017405:Herpes Simplex Virus Protein Vmw65 / Q000378:metabolism; D006801:Humans; D008024:Ligands; D016328:NF-kappa B / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015534:Trans-Activators / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D014162:Transfection
D017405:Herpes Simplex Virus Protein Vmw65; D008024:Ligands; D016328:NF-kappa B; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D015534:Trans-Activators; D051996:Transcription Factor RelA