In whole cells, the effects of several androgens and antiandrogens on the
in the induction of DNA binding for the human wild-type androgen receptor
(AR) and a mutant receptor ARL (LNCaP mutation; codon 868, Thr to Ala)
were examined and related to the transcription activation ability of these
receptors. To study DNA binding, an AR expression vector was cotransfected
in Chinese hamster ovary cells with a promoter interference plasmid
cytomegalovirus-(androgen-responsive element)3-luciferase, containing one
or more androgen-responsive elements between the TATA box of the
cytomegalovirus promoter and the start site of luciferase gene
transcription. Expression levels of the AR are up-regulated by some
agonists, but receptor expression levels are comparable for all
antiandrogens studied. In the presence of androgens, the wild-type AR is
able to reduce promoter activity of the
cytomegalovirus-(androgen-responsive element)3-luciferase plasmid,
indicating androgen-dependent DNA binding of the AR. The full antagonists
hydroxyflutamide, ICI 176.334, and RU 23908 block AR binding to DNA. The
antagonists cyproterone acetate and RU 38486 induce approximately 50% of
the DNA binding found for androgens. In a transcription activation assay,
the RU 38646-bound receptor was almost inactive, and the receptor
complexed with cyproterone acetate showed partial agonistic activity.
Interaction of the antagonists cyproterone acetate, hydroxyflutamide, and
RU 23908 with the mutant receptor ARL resulted in both DNA-bound and a
transcriptionally active receptor. In conclusion, transformation of the AR
to a DNA-binding state in whole cells is blocked by several antiandrogens.
Furthermore, studies with the antiandrogens cyproterone acetate and RU
38486 show that DNA binding alone is not sufficient to accomplish full
transcriptional activity. Full activity requires additional changes,
presumably in the protein structure of the receptor
