The existence of extracellular proteins which bind androgens has been known for a number of decades, but their exact role in the reproductive biology remains an enigma. These proteins are thought by most to be carriers of hormones and serve to protect these compounds from rapid clearance. There are basically two classes of these proteins, one which arises from the liver and is principally found in blood is called sex hormone binding globulin (SHBG) while the other produced by the Sertoli cell and found both in the male reproductive tract and the blood is called Androgen Binding Protein (ABP). Interestingly, there is no well documented individual or species with a total lack of such a protein. This observation may reflect the great importance and absolute necessity of this protein in the developmental process. Recent studies from a number of laboratories have revealed a system for the receptor-mediated endocytosis of these proteins which appears to be present on androgen-responsive cells. The description of this system is still in its germinal stages and it is the goal of the application to more fully describe and characterize this process and to possibly shed light on its role in reproduction and development. It will do so by a detailed examination of the receptor-mediated uptake process in both primary cultures of testicular peritubular cells and two established human tumor cell lines, MCF-7, a breast cell line, and LNCaP, a prostatic cell line. This characterization will include the influence of steroids on SHBG uptake, the intracellular movement and ultimate fate of both the SHBG and the receptor. The proposal will also examine the consequences of SHBG binding and uptake in order to ascertain if these phenomena effect steroid transport or metabolism by cells and if there is any intrinsic signaling system associated with SHBG binding, which is capable of activating a second messenger system. In this context it will also examine the influence of SHBG uptake on androgen and estrogen responsiveness in these cells. In addition, it is proposed that a detailed investigation of the SHBG membrane receptor molecule will be undertaken. This will include a characterization of this receptor and ultimately its purification and cDNA isolation. Lastly, the proposal will examine the developmental biology of the SHBG receptor-mediated uptake by describing when and where it appears during development both during fetal and neonatal life. These studies will encompass a broad analysis of the receptor-mediated endocytosis of SHBG and examine its role in reproduction.
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