Atif M. Nakhla

Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane.

Sex hormone-binding globulin is a plasma glycoprotein that binds certain estrogens and androgens with high affinity. Over the past several years it has been shown that, in addition to functioning as a regulator of the free concentration of a number of steroid hormones, SHBG plays a central role in permitting certain steroid hormones to act without entering the cell. The system is complex. SHBG interacts with a specific, high affinity receptor (R(SHBG)) on cell membranes that appears to transduce its signal via a G protein. The SHBG-R(SHBG) complex causes the activation of adenylyl cyclase and the generation of cAMP within a matter of minutes after exposure to an appropriate steroid. Only steroids that bind to SHBG can activate SHBG-R(SHBG), but not all steroids that bind have this function, e.g. are agonists. All steroids that bind to SHBG but do not activate adenylyl cyclase are antagonists. The signals generated by the steroid-SHBG-R(SHBG) complex generate messages that have effects on the transcriptional activity of classic, intracellular receptors for steroid hormones. These and other downstream effects of this system are reviewed.

Androgen and estrogen signaling at the cell membrane via G-proteins and cyclic adenosine monophosphate

Androgens and estrogens are well-known to initiate their actions by binding to specific intracellular receptors. The steroid-receptor interaction, the receptors, and the details of transcriptional activation consequent to the binding of these steroids with their respective receptors have been, and continue to be, intensively studied. More recently, it has become increasingly apparent that steroids may interact with cells by other than this classic pathway. This communication will deal with activation by sex hormones of a signal transduction pathway that originates at the cell membrane and utilizes cyclic adenosine monophosphate (cAMP) as a second messenger. The system consists of three components, an agonist steroid, sex hormone-binding globulin (SHBG), and a membrane receptor (R(SHBG)) for SHBG. SHBG is a well-characterized plasma protein that has two binding sites, one binds certain estrogens and androgens, and the other binds to R(SHBG). The characteristics of this novel signal transduction system, from the interaction of SHBG with R(SHBG), to the intermediacy of G-proteins, to cAMP generation, to downstream effects of the second messenger will be reviewed.

Interactions of sex hormone-binding globulin with target cells

Sex hormone-binding globulin (SHBG) was initially described as a plasma protein synthesized in, and secreted by, the liver. It was discovered by its ability to bind certain androgens and estrogens and, for many years, was believed to serve as a transporter/reservoir for the steroids which it bound. Subsequently, it became clear that the cell membranes of selected tissues contained a receptor for SHBG (R(SHBG)). This review deals with what is known of that receptor - its anatomy, physiology and biochemistry.

Estradiol Activates the Prostate Androgen Receptor and Prostate-specific Antigen Secretion through the Intermediacy of Sex Hormone-binding Globulin

These experiments were designed to examine the relationship between the effects of steroid hormones mediated by classic intracellular steroid hormone receptors and those mediated by a signaling system subserved at the plasma membrane by a receptor for sex hormone-binding globulin. It is known that unliganded sex hormone-binding globulin (SHBG) binds to a receptor (RSHBG) on prostate membranes. The RSHBG·SHBG complex is rapidly activated by estradiol to stimulate adenylate cyclase, with a resultant increase in intracellular cAMP. In this paper we examine the effect of this system on a prostate gene product known to be activated by androgens, prostate-specific antigen. In serum-free organ culture of human prostates, dihydrotestosterone caused an increase in prostate specific antigen secretion. This event was blocked by the anti-androgens cyproterone acetate and hydroxyflutamide. In the absence of androgens, estradiol added to prostate tissue, whose RSHBG was occupied by SHBG, reproduced the results seen with dihydrotestosterone. Neither estradiol alone nor SHBG alone duplicated these effects. The estradiol·SHBG-induced increase in prostate-specific antigen was not blocked by anti-estrogens, but was blocked both by anti-androgens and a steroid (2-methoxyestradiol) that prevents the binding of estradiol to SHBG. Furthermore, an inhibitor of protein kinase A prevented the estradiol·SHBG-induced increase in prostate-specific antigen but not that which followed dihydrotestosterone. These data indicate that there is a signaling system that amalgamates steroid-initiated intracellular events with steroid-dependent occurrences generated at the cell membrane and that the latter signaling system proceeds by a pathway that involves protein kinase A.

Induction of adenylate cyclase in a mammary carcinoma cell line by human corticosteroid-binding globulin

Corticosteroid-Binding globulin (CBG) is a plasma protein that binds certain steroid hormones, mainly cortisol and progesterone. It has been demonstrated recently that specific binding sites for this protein exist on cell membranes. In this communication we establish that binding to these sites results in the induction of adenylate cyclase activity and the accumulation of cAMP in MCF-7 cells. These events are critically dependent upon a steroid being bound to CBG. These data are consistent with the hypothesis that CBG is a prohormone which is activated when cortisol is bound to it.

Characterization of ALVA-41 cells, a new human prostatic cancer cell line

The ALVA-41 cell line was derived from a bony metastasis from a human prostatic carcinoma. The line has a number of distinct, advantageous properties that should make it useful as a tool for the study of prostate cancer. It grows rapidly and is easy to work with. It has receptors for androgens and glucocorticoids but not for estrogens. Its growth is enhanced by physiological concentrations of dihydrotestosterone. It does not secrete prostate specific antigen, but does secrete prostatic acid phosphatase. Further, the secretion of prostatic acid phosphatase is enhanced by dihydrotestosterone.

Estradiol causes a dose‐dependent stimulation of prostate growth in castrated beagle dogs

Previous studies have shown that chronic treatment of castrate dogs with androgen and estrogen results in significant prostate growth. Estrogen treatment of castrate dogs in the absence of androgen has resulted in conflicting data as reported by several authors. The purpose of this experiment was to evaluate the effect of a physiological dose of estradiol on prostate growth in dogs, using ultrasound to study size changes over time.

Calcitonin induces ornithine decarboxylase in various rat tissues

A single dose of synthetic salmon calcitonin administered to rats (20 MRC U/kg body weight) stimulated the activity of ornithine decarboxylase in the brain, liver, kidney, testis and ovaries by 3-, 15-, 5-, 2- and 2-fold respectively after 4 h of the treatment. The increase in the enzyme activity in the brain, testis and ovaries was accompanied by a comparable increase in the enzyme protein content. Hepatic and renal ornithine decarboxylase concentration increased only by 2-fold. These results suggest that calcitonin influences polyamine biosynthesis through a tissue-specific regulation of the activity and/or the number of ornithine decarboxylase molecules.