Anabolic steroids, testosterone-precursors and virilizing androgens induce distinct activation profiles of androgen responsive promoter constructs.
Different androgens, e.g. virilizing androgens such as testosterone and its precursors as well as synthetic anabolic steroids, respectively, induce diverse biological effects. The molecular basis for this variety in biological actions, however, is not well understood. We hypothesized that this variability of actions may be due to steroid-specific target gene expression profiles following androgen receptor (AR)-activation. Therefore, we investigated androgen receptor dependent transactivation of three structurally different androgen responsive promoter constructs ((ARE)(2)TATA-luc, MMTV-luc, GRE-OCT-luc) in co-transfected Chinese hamster ovary (CHO)-cells as an artificial model simulating different natural target genes. Three virilizing androgens (dihydrotestosterone, testosterone, methyltrienolone), three anabolic steroids (oxandrolone, stanozolol, nandrolone) and two testosterone-precursors of gonadal and adrenal origin (dehydroepiandrosterone, androstenedione) were used as ligands (0.001-100 nM). All steroids proved to be potent activators of the AR. Remarkably, anabolic steroids and testosterone-precursors showed characteristic promoter activation profiles distinct from virilizing androgens with significantly lower (ARE)(2)TATA-luc activation. Hierarchical clustering based on similarity of activation profiles lead to a dendrogram with two major branches: first virilizing androgens, and second anabolics/testosterone-precursors. We conclude that steroid-specific differences in gene transcription profiles due to androgen receptor activation could contribute to differences in biological actions of androgens.
Holterhus
P M
PM
Department of Pediatrics, Medical University of Lübeck, Germany. holterhus@paedia.ukl.mu-luebeck.de
Piefke
S
S
Hiort
O
O
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D045930:Anabolic Agents / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology*; D000737:Androstenols / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D005786:Gene Expression Regulation; D008156:Luciferases; D008297:Male; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D016385:TATA Box / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection
D000276:Adjuvants, Immunologic; D045930:Anabolic Agents; D000728:Androgens; D000737:Androstenols; D011944:Receptors, Androgen; D008156:Luciferases