The androgenic regulation of the activities of enzymes engaged in the synthesis of deoxyribonucleic acid in rat ventral prostate gland

Abstract

1. The restoration of mitosis and growth of the prostate gland of castrated animals by androgens provides a favourable experimental system for studying the hormonal regulation of enzymes engaged in DNA replication. 2. Many DNA polymerase activities were identified in the prostate gland, but only a 9 S form with a particular preference for denatured DNA as template was conspicuously enhanced by androgenic stimulation. 3. Thymidine kinase also provided a sensitive indicator of the hormonal regulation of DNA replication, and on electrophoretic criteria, one discrete form of the enzyme appeared precisely with the onset of mitosis. 4. Evidence is presented to support the view that DNA ligase activity is intimately associated in the process of DNA replication in the prostate gland. 5. A spectrum of deoxyribonuclease activities is present in the prostate gland, but only one form (pI7.0) can safely be said to be implicated in the process of DNA replication. 6. Androgenic stimulation of the prostate gland leads to the appearance of a component capable of denaturing or unwinding prostate DNA. This component is seemingly distinct from RNA or DNA polymerase activities on the basis of several distinct physicochemical characteristics. 7. The conspicuous feature of all the changes in enzyme activities evoked by androgens in the prostate gland is their acute tissue-and steroid-specificity. Such changes could not be mimicked in liver or spleen and the regulatory role ofandrogens could not be simulated by other classes of steroid hormones. Particularly on the basis of studies with the anti-androgen cyproterone acetate, it is concluded that the changes are initially mediated by the androgen-receptor system and the high-affinity binding of 5cr-dihydrotestosterone in the prostate gland. 8. The results are discussed in the context of the mechanism of action of androgens.

Radioimmunoassay measurements of nuclear dihydrotestosterone in rat prostate. Relationship to androgen receptors and androgen-regulated responses

“…is well documented (Coffey et al, 1968;Lesser & Bruchovsky, 1973;Rennie et al, 1975), the precise intracellular concentration of dihydrotestosterone necessary to obtain this and other androgen-dependent responses is not known. To determine the relationship between dose and intracellular concentration of androgen, groups of rats that hact been castrated 7 days previously were given daily injections of dihydrotestosterone over a period of 4 days.…”

“…2000 androgen receptors were present in the prostatic nuclei; higher concentrations of nuclear androgen receptors were associated with decreased amounts of this enzyme. Hence the results imply, first, that the total amount of dihydrotestosterone accumulated by nuclei is not a direct consequence of carrier-mediated transport by androgen receptors, and, secondly, that, whereas acid phosphatase may be differentially controlled by androgens in the regenerating prostate, increases in the amount of cell proliferation and 5a-reductase activity directly parallel increases in the nuclear concentration of androgen receptors.In the prostate, androgenic regulation of physiological functions and cellular growth is attributed largely to the formation, and subsequent binding to chromatin, of androgen-receptor complexes (King & Mainwaring, 1974 (Coffey, 1974;Rennie et al, 1975;Van Doorn et al, 1976). Although it has been postulated that androgen receptors are involved in the uptake and retention of dihydrotestosterone by target-cell * To whom correspondence should be addressed.…”

“…In the prostate, androgenic regulation of physiological functions and cellular growth is attributed largely to the formation, and subsequent binding to chromatin, of androgen-receptor complexes (King & Mainwaring, 1974 (Coffey, 1974;Rennie et al, 1975;Van Doorn et al, 1976). Although it has been postulated that androgen receptors are involved in the uptake and retention of dihydrotestosterone by target-cell * To whom correspondence should be addressed.…”

“…Results from experiments performed in vitro by several groups (Davies & Griffiths, 1973;Mainwaring & Jones, 1975;Hu et al, 1975) have indicated that androgen-receptor complexes directly modulate the transcription of chromatin by RNA polymerase. Androgen receptors have also been implicated in the regulation of DNA synthesis and cell proliferation in the regenerating prostate (Coffey, 1974;Rennie et al, 1975;Van Doorn et al, 1976). Although it has been postulated that androgen receptors are involved in the uptake and retention of dihydrotestosterone by target-cell nuclei (Rennie & Bruchovsky, 1973;Bruchovsky et al, 1975a), a direct stoicheiometric relationship has not been demonstrated.…”

Analysis by DNA polymerase α activity of human breast tumour proliferation and the effect of endocrine therapy

“…DNA polymerase a is associated with proliferating tissues (Lynch et al, 1976) and tumours (DePhilip et al, 1977), and is elevated during the late G, to mid S phase of the cell cycle, whereas the activity of DNA polymerase P remains unchanged (Chiu & Baril, 1975;Barr et al, 1975). In vivo, the activity of DNA polymerase a has been correlated with cellular proliferation in a variety of steroid hormone target tissues including the rat ventral prostate gland (Rennie et al, 1975) and the rat uterus (Harris & Gorski, 1978). DNA polymerase is tightly bound to the nucleus whereas DNA polymerase a is lightly bound and extracted under aqueous conditions (Foster & Gurney, 1976;Edwards et al, 1980).…”