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Androgens control a broad range of physiological functions by binding and modulating the activity of the androgen receptor (AR), a member of the nuclear hormone receptor superfamily. The AR is a ligand-dependent transcription factor that is widely distributed among reproductive and non-reproductive tissues. It is predicted that, as in the case of the estrogen receptor, different AR ligands will promote distinct pharmacological activities in different cell types depending on the specific transcriptional environment, that is the presence or the absence of specific co-activators and co-repressors. In order to test this prediction in vivo, we generated a transgenic mouse line (ARLUC) that expresses the luciferase cDNA downstream of an androgen-responsive promoter containing two copies of the 11-base pair DR-1 (5'-GAACG-GAACA-3') oriented as an overlapping direct repeat. This arrangement demonstrated a strong preference for AR binding and transactivation when compared with the glucocorticoid receptor [1]. Tissues with an active AR emit light when tested for luciferase activity that is detected by the use of a cooled charged-coupled device camera or by direct measurements of enzymatic activity in tissue extracts. Experiments through biochemical analysis of tissue extracts showed expression of luciferase in the testis, seminal vesicles, quadriceps, brain and bone marrow. The luciferase expression was observed to be androgen-dependent since it was dramatically diminished in castrated animals and in animals treated with the anti-androgen bicalutamide compared with intact animals. The use of such a model in the evaluation of AR modulators will be discussed.

Development of a transgenic mouse line for the evaluation of the androgen receptor activity in vivo