Human prostatic membranes have been shown to contain what appears to be a classic membrane receptor for the plasma protein, sex hormone-binding globulin (SHBG, testosterone-estradiol-binding globulin). Further, the membrane-bound adenylate cyclase is activated when a small fraction of these receptors are occupied. Since the discovery of this receptor is so new, relatively little is known about it, or the consequences of its interactions with SHBG. The receptor will be purified to homogeneity from human prostatic membranes obtained at the time of transurethral prostatectomy for benign prostatic hypertrophy. The isolated receptor will be characterized as to its mol wt and subunit structure, and the kinetics of its interaction with SHBG will be examined. The binding domain of the receptor will be isolated by cross-linking it to [125-I]SHBG, submitting the cross-linked complex to tryptic digestion, and then isolating the complex by HPLC. The purified receptor also will be used as an antigen to obtain monoclonal and polyclonal antibodies. An estrogen responsive cell line (MCF-7) and an androgen responsive one (LNCaP), will be used as models to probe the biologic effects of SHBG, which has been prebound either to estradiol or testosterone. In these models, growth, overall protein secretion, the synthesis of specific proteins, the induction of adenylate cyclase activity, and receptor internalization will be evaluated. Finally, these cell lines will be used to establish whether the internalization of SHBG results in the concomitant internalization of steroids which are bound to it. SHBG binds estrogens and androgens with high affinity. The demonstration that receptors for the complex exist, and that important events occur after binding, opens new avenues to our understanding of both the normal physiology and the pathophysiology of the sex hormones.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Endocrinology Study Section (END)
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St. Luke's-Roosevelt Institute for Health Sciences
New York
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Rosner, W; Hryb, D J; Khan, M S et al. (1999) Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane. J Steroid Biochem Mol Biol 69:481-5
Nakhla, A M; Leonard, J; Hryb, D J et al. (1999) Sex hormone-binding globulin receptor signal transduction proceeds via a G protein. Steroids 64:213-6
Rosner, W; Hryb, D J; Khan, M S et al. (1998) Androgens, estrogens, and second messengers. Steroids 63:278-81
Nakhla, A M; Romas, N A; Rosner, W (1997) Estradiol activates the prostate androgen receptor and prostate-specific antigen secretion through the intermediacy of sex hormone-binding globulin. J Biol Chem 272:6838-41
Nakhla, A M; Rosner, W (1996) Stimulation of prostate cancer growth by androgens and estrogens through the intermediacy of sex hormone-binding globulin. Endocrinology 137:4126-9
Blithe, D L; Khan, M S; Rosner, W (1992) Comparison of the carbohydrate composition of rat and human corticosteroid-binding globulin: species specific glycosylation. J Steroid Biochem Mol Biol 42:475-8
Rosner, W; Hryb, D J; Khan, M S et al. (1992) Sex hormone-binding globulin. Binding to cell membranes and generation of a second messenger. J Androl 13:101-6
Rosner, W; Hryb, D J; Khan, M S et al. (1991) Sex hormone-binding globulin: anatomy and physiology of a new regulatory system. J Steroid Biochem Mol Biol 40:813-20
Khan, M S; Hryb, D J; Hashim, G A et al. (1990) Delineation and synthesis of the membrane receptor-binding domain of sex hormone-binding globulin. J Biol Chem 265:18362-5
Rosner, W (1990) The functions of corticosteroid-binding globulin and sex hormone-binding globulin: recent advances. Endocr Rev 11:80-91

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