The Influence of Androgen-Receptor Complexes on Transcription by Rat and Human Prostatic Ribonucleic Acid Polymerases

s of Communications Meeting of the Biochemical Society Steroid Group held at Imperial College, London, 1 July 1975 HORMONAL. REGULATION OF MACROMOLECULAR SYNTHESES : a Colloquium organized by W. I. P. Mainwaring (London) The Influence of Androgen-Receptor Complexes on Transcription by Rat and Human Prostatic Ribonucleic Acid Polymerases PETER DAVIES Tenovus Institute for Cancer Research, Welsh National School of Medicine, Heath Park, Cardifs CF4 4XX, U.K. The many changes in cellular components that occur in a sensitive tissue in response to hormonal stimulation are largely secondary to the key molecular step at the genomic or transcriptional level, resulting in an enhancement of RNA synthesis (Williams-Ashman & Reddi, 1971 ; Jensen & DeSombre, 1972). The eukaryotic transcriptional machinery involves acomplexity of functional, structural and regulatory macromolecules, and RNA synthesis may be controlled at the level of chromatin template activity and activity, RNA polymerase activity, biosynthesis and pool size of RNA precursors or RNA processing and maturation. Androgenic influences in the rat ventral prostate gland are mediated by the metabolism of testosterone to 5a-dihydrotestosterone, the binding of this latter compound to proteins of selective high affinity and the transfer of the complex thus formed to nuclear acceptor sites with steroid and tissue specificity [see review by Minguell & Sierralta (1975)l. Previous investigations using reconstituted cell-free systems based on nuclei or on chromatin transcribed by purified prostatic RNA polymerases have shown that 5a-dihydrotestosterone-receptor complexes prepared from subcellular fractions of rat ventral prostate have significant stimulatory effects on the activities of discrete RNA polymerases from the same source (Davies & Griffiths, 1973a,b; 1974a,b). Studies on transcription of chromatin by solubilized RNA polymerases have shown that for stimulation to occur the steroid-receptor complex, rather than the steroid or receptor protein alone, must be present together with prostatic chromatin rather than chromatin from non-target tissues or naked DNA, the chromatin specificity depending on the presence of a small proportion of non-histone proteins tightly bound to the DNA (Davies & Griffiths, 1973a,b). The abilities of the specific cytoplasmic and nuclear steroid-receptor complexes to stimulate RNA polymerase activity to equivalent extents have been attributed to the ‘activation’ of the cytoplasmic form in the assay medium, causing it to undergo a temperature-dependent conversion into a form similar to that of the complex extractable from nuclear preparations (Davies & Griffiths, 1974b). Recent studies have indicated that the macromolecules specifically binding 5adihydrotestosterone in rat ventral prostate and human benign hypertrophic prostate have similar properties and that the cytoplasmic receptor complexes in each case may transfer the steroid to homologous or heterologous nuclear fractions of androgenVOl. 3