Negative regulation of parathyroid hormone-related protein expression by steroid hormones

Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here we studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor α, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.     

Transcription regulation by steroid hormones: a computer simulation study.

Three-dimensional structures of complexes of 66 amino acid-DNA binding domains of human progesterone (hPR), estrogen (hER) and glucocorticoid (hGR) receptors (proteins), with ten base pair DNA duplexes: d(AGGTCATGCT).d(AGCATGACCT) and d(AGAACATGCT).d(AGCATGTTCT) were obtained using computer modeling and molecular mechanics techniques. Cartesian coordinates for the proteins were obtained from: 1) structural data of hER and hGR by NMR spectroscopy; 2) steric constraints imposed by tetrahedral coordination of the zinc ion to Cys residues, and 3) energy minimization in torsional and cartesian space. The proteins were made to interact with DNA (in B-form) in major groove through alpha-helical linker between the two zinc fingers. The geometry of the complexes was obtained by allowing them to slide, glide, penetrate in to and out of the groove, and to rotate about the helical axis. The complexes were energy minimized. Also maximized was the number of H-bonds between proteins and DNA. The complex structures were refined by molecular mechanics using AMBER 3.0. Structural parameters of DNA were analyzed in each complex and compared with those of native DNA optimized separately. The stereochemical differences of the complexes are discussed.     

Excitatory amino acid regulation of gonadotropin secretion: modulation by steroid hormones

Excitatory amino acids (EAAs) can potently modulate gonadotropin secretion in the male rat and monkey. In the present study we examined of EAAs on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the female rat under low estrogen (ovariectomized) and high estrogen (proestrus) backgrounds. In ovariectomized immature female rats (NMDA) inhibited LH but not FSH secretion at 30 min post-injection. In contrast, NMDA potently stimulated LH but not FSH secretion when administered on proestrus to adult female rats. Both glutamate and kainate were also found to stimulate LH but not FSH secretion in estrogen-treated ovariectomized immature rats. This study suggests that EAA neurotransmission may be an important component in the expression of gonadotropin surges and that EAA effects appear to be subject to gonadal steroid regulation.     

Regulation of apoptosis by steroid hormones

Steroid hormones play major roles in regulation of growth, development, homeostasis, and cell death. Together with other hormones and growth factors, steroids regulate both the function and cellular composition of organs throughout the body. In this article we will discuss the mechanisms of steroid hormone regulated apoptosis. Emphasis will be placed on the effect of glucocorticoids on lymphoid cells.     

Paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system

In males, androgens are essential in maintaining the integrity of the prostate. Androgen-ablation induces apoptosis of the prostatic epithelium. In females, ovariectomy induces apoptosis in uterine epithelium while progesterone inhibits this process. The objective of this study was to determine whether androgen and progesterone inhibit apoptosis, respectively, in mouse prostatic and uterine epithelia via steroid receptors in the epithelium or in the stroma. To address this question, prostatic tissue recombinants were prepared with rat urogenital sinus mesenchyme plus bladder epithelium from wild-type or testicular feminization mutant (Tfm) mice. Thus, prostatic tissue was generated having androgen receptor (AR) in both epithelium and stroma or in the stroma only. Castration of hosts induced apoptosis in the AR-negative Tfm prostatic epithelium with an epithelial apoptotic index virtually identical to prostatic tissue recombinants containing wild-type epithelium. Moreover, this castration-induced prostatic epithelial apoptosis was blocked by testosterone and dihydrotestosterone in both wild-type and Tfm prostatic tissue recombinants. Likewise, uterine tissue recombinants were prepared in which epithelium and/or stroma was devoid of progesterone receptor (PR) by using uterine epithelium and stroma of wild-type and PR knockout mice. Progesterone inhibited uterine epithelial apoptosis only in tissue recombinants prepared with PR-positive stroma. The PR status of the epithelium did not affect epithelial apoptotic index. Therefore, the apoptosis in prostatic and uterine epithelia is regulated by androgen and progesterone via stromal AR and PR, respectively. In both cases, epithelial AR or PR is not required for hormonal regulation of epithelial apoptosis in prostatic and uterine epithelium.     

Modulation of appetite by gonadal steroid hormones

Several sex differences in eating, their control by gonadal steroid hormones and their peripheral and central mediating mechanisms are reviewed. Adult female rats and mice as well as women eat less during the peri-ovulatory phase of the ovarian cycle (estrus in rats and mice) than other phases, an effect under the control of cyclic changes in estradiol secretion. Women also appear to eat more sweets during the luteal phase of the cycle than other phases, possibly due to simultaneous increases in estradiol and progesterone. In rats and mice, gonadectomy reveals further sex differences: orchiectomy decreases food intake by decreasing meal frequency and ovariectomy increases food intake by increasing meal size. These changes are reversed by testosterone and estradiol treatment, respectively. A variety of peripheral feedback controls of eating, including ghrelin, cholecystokinin (CCK), glucagon, hepatic fatty acid oxidation, insulin and leptin, has been shown to be estradiol-sensitive under at least some conditions and may mediate the estrogenic inhibition of eating. Of these, most progress has been made in the case of CCK. Neurons expressing estrogen receptor-alpha in the nucleus tractus solitarius of the brainstem appear to increase their sensitivity to CCK-induced vagal afferent input so as to lead to an increase in the satiating potency of CCK, and consequently decreased food intake, during the peri-ovulatory period in rats. Central serotonergic mechanisms also appear to be part of the effect of estradiol on eating. The physiological roles of other peripheral feedback controls of eating and their central mediators remain to be established.     

Demonstration of adrenergic catecholamine receptors in rat myometrium and their regulation by sex steroid hormones.

The molecular basis of sex steroid hormone-modulation of catecholamine-regulated smooth muscle cell contraction in the uterus was investigated at the level of the catecholamine receptor in rat myometrium. Myometrial membrane binding sites for ³H)-dihydroergocryptine bound α-but not β-adrenergic antagonists and stereospecifically bound the α-agonists (?)-norepinephrine > (?)-epinephrine > phenylephrine. Binding sites for (?) (³H)-dihydroalprenolol were specific for β-adrenergic antagonists and stereospecifically bound (?)-isoproterenol > epinephrine ? norepinephrine. These results were consistent with the expected properties of the myometrial α- and β-adrenergic catecholamine receptors. Myometrial content of β- but not α-adrenergic catecholamine receptors was significantly elevated during proestrus and estrus, suggesting a role for sex steroid hormones in the regulation of these receptors. This posibility was substantiated in ovariectomized rats where castration resulted in a reduction in myometrial β-receptor content which was restored in a dose-dependent manner by estrodiol administration. We conclude: 1) rat uterus contains a substantial concentration of α- and β-adrenergic catecholamine receptors, 2) sex steroid hormones may modulated uterine contractility by regulation of these cell surface receptors; 3) modulation of cell responses to surface active hormones and agents by regulation of their cell surface receptors may be a major way in which sex steroids regulate target organ function.     

The regulation of expression of mouse mammary tumor virus DNA by steroid hormones and growth factors

Mouse mammary tumor virus (MMTV) expression is associated with hyperplastic alveolar growth and subsequent development of mammary cancers in the mouse. The expression of this virus is also controlled by factors involved in the normal proliferation and differentiation of the mammary epithelium. During pregnancy when the mammary gland undergoes massive proliferation, MMTV expression is increased. Steroid hormones and growth factors that play an important role in the proliferation of mammary gland cells are responsible for the increased MMTV expression. In sarcomatous transformation of mouse mammary epithelial cells, MMTV expression is repressed. This repression is due to negative control of MMTV expression by transforming growth factor-beta (TGF beta). This growth factor is produced in high amounts when mammary epithelial cells progress into the transformed state. The expression of MMTV is therefore under multiple control by steroid hormones and growth factors.