PROSTATIC ANDROGEN RECEPTORS--FORM AND FUNCTION

点击翻译按钮获取中文摘要

These studies are designed to examine the significance within prostatic tissue of androgen receptor species which, by virtue of differences in their avidity for androgenic ligands, may function as regulators of the responsiveness of androgen-sensitive cells. In pursuit of our observation that two such cytoplasmic forms of this receptor do co-exist, we propose to define various physicochemical properties of these forms, as well as any others which may occur, including especially nuclear and heat-transformed cytoplasmic moieties. The emphasis will be on comparative aspects of interaction with androgens, and susceptibility to interconversion by a cytoplasmic factor which has been discovered and which will be purified and characterized further. The relative levels of the different receptor forms will be assessed under a variety of experimentally-induced changes in endogenous hormonal milieu, including castration-replacement, aging, and administration of assorted types of steroid hormones and prolactin. We will exploit the ability to separate the cytoplasmic receptor forms by ammonium sulfate fractionation in experiments wherein the dynamics of nuclear uptake and mechanisms of nuclear retention of receptor will be explored. Patterned induction of specific protein synthesis in response to androgen will be investigated as a function of the relative receptor-dictated responsiveness of the cells; these analyses are an outgrowth of preliminary observations which suggest a potentially important correlation. While not within the scope of this initial stage of the project, the implications of these studies with respect to defining a relationship between functional androgen receptor concentration and prediction of responsiveness of human prostatic cancer to endocrine therapy will certainly constitute the next major phase of this work.