Brassinosteroids signal through two receptor-like kinases

Both animals and plants use steroids to regulate their growth and development, but their mechanisms for steroid perception are different. Animal steroids are mainly recognized by intracellular steroid receptors, whereas plant steroids are perceived by cell-surface receptors that contain a transmembrane receptor serine/threonine kinase. Recent studies suggest that heterodimerization between two receptor kinases might be a key step in steroid perception and signaling in plants.     

Estradiol restores diabetes-induced reductions in sex steroid receptor expression and distribution in the vagina of db/db mouse model

Sex steroid hormones and receptors play an important role in maintaining vaginal physiology. Disruptions in steroid receptor signaling adversely impact vaginal function. Limited studies are available investigating the effects of diabetic complications on steroid receptor expression and distribution in the vagina. The goals of this study were to investigate type 2 diabetes-induced changes in expression, localization and distribution of estrogen (ER), progesterone (PR) and androgen receptors (AR) in the vagina and to determine if estradiol treatment ameliorates these changes. Eight-week-old female diabetic (db/db) mice (strain BKS.Cg-m+/+ Lepr^db/J) were divided into two subgroups: untreated diabetic and diabetic animals treated with pellets containing estradiol. Control normoglycemic littermates were subcutaneously implanted with pellets devoid of estradiol. At 16 weeks of age, animals were sacrificed, vaginal tissues excised and analyzed by Western blot and immunohistochemical methods. Diabetes produced marked reductions in protein expression of ER, PR, and AR. Diabetes also resulted in marked differences in the distribution, staining intensity and proportion of immunoreactive cells containing these steroid receptors in the epithelium, lamina propria and muscularis. Treatment of diabetic animals with estradiol restored receptor protein expression and distribution similar to those levels observed in control animals. This study demonstrates that type 2 diabetes markedly reduces steroid receptor protein expression and distribution in the vagina. Estradiol treatment of diabetic animals ameliorates these diabetes-induced changes.     

The environmental pollutant aromatic hydrocarbon, benzpyrene has deleterious effect on hormone receptor development

In this review, works to clear the effect of perinatal and pubertal benzpyrene imprinting to the steroid hormone receptors of adult animals are summarized. There is a comparison between the perinatal and adolescent effects and between the effects on the receptors of males and females. On the basis of the experiments benzpyrene is a general and dangerous imprinter which can influence durably the development of different steroid receptors given directly to the animals studied (perinatally) of given to the nursing mothers or influencing the offspring generations of the perinatally treated parents or grandparents. The results call attention to the outstanding deleterious effects of benzpyrene pollution.     

Novel approaches for the study of vertebrate steroid hormone receptors

Steroid hormones are essential for the normal function of most organ systems in vertebrates. Reproductive activities in females and males, such as the differentiation, growth and maintenance of the reproductive system, require signaling by sex steroid hormones. Although extensively studied in mammals and a few fish and bird species, the evolution and molecular mechanisms associated with the nuclear steroid hormone receptors are still poorly understood in amphibians and reptiles. Given our interest in environmental signaling of sex determination as well as a major interest in environmental contaminants that can mimic steroid hormone signaling, we have established an approach to study the molecular function (ligand binding and trans-activation) of steroid hormone receptors cloned from reptiles. This approach involves molecular cloning and sequencing of steroid hormone receptors, phylogenic analysis and in vitro trans-activation assays using endogenous or exogenous ligands. Comparing the in vitro trans-activation induced by different ligands with receptors cloned from different species would develop additional functional relationships (classification) among steroid hormone receptors. This approach can provide insight into understanding why each species could have different responses to exogenous ligands. Further, we have developed a novel and less invasive approach to obtaining mRNA for molecular cloning and sequencing of steroid hormone receptors in reptiles and other non-mammalian species, using blood cells as a source of genetic material. For example, white blood cells (WBCs) and red blood cells (RBCs) of the American alligator both express steroid hormone receptors and have adequate amounts of mRNA for molecular cloning. This approach would allow us to analyze components of endocrine function of steroid hormones without sacrificing animals. Especially in endangered species, this approach could provide an understanding of endocrine functions, elucidate the phylogenic relationships of various receptors in vitro, such as the steroid hormone receptors, and determine possible effects of environmental contaminants in a minimally invasive manner.     

Sex steroid receptors in human lung diseases

Several epidemiological studies have reported that gender differences exist in clinical and biological manifestations of human lung diseases. In particular, women are far more likely to develop both neoplastic and non-neoplastic lung diseases than men. This gender difference above suggests that sex steroid may be involved in the pathogenesis of various lung diseases. These sex steroids mediate their effects through sex steroid receptors including estrogen receptors (ER) i.e. ERα and ERβ progesterone receptors (PR) i.e. PR-A and PR-B and androgen receptors (ARs), all of which have been reported to be expressed in lung tissue. Therefore it becomes important to clarify the potential roles of sex steroid receptor in both neoplastic and non-neoplastic lung diseases toward improved treatment options for the patients. In this review, we summarized a number of studies in humans and experimental animals that have identified possible roles of sex steroids in respiratory physiology and pathology.     

Plant immunity: the origami of receptor activation

Mutations in plant cytosolic HSP90 genes have been found to impair the immune responses triggered by host pathogen receptors. HSP90 links the plant receptors to other components essential for receptor function. The new findings suggest mechanistic parallels with steroid receptor regulation in animals.     

Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain

The effects of social isolation on behavior, neuroactive steroid concentrations, and GABA(A) receptor function were investigated in rats. Animals isolated for 30 days immediately after weaning exhibited an anxiety-like behavioral profile in the elevated plus-maze and Vogel conflict tests. This behavior was associated with marked decreases in the cerebrocortical, hippocampal, and plasma concentrations of pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone compared with those apparent for group-housed rats; in contrast, the plasma concentration of corticosterone was increased in the isolated animals. Acute footshock stress induced greater percentage increases in the cortical concentrations of neuroactive steroids in isolated rats than in group-housed rats. Social isolation also reduced brain GABA(A) receptor function, as evaluated by measuring both GABA-evoked Cl(-) currents in XENOPUS: oocytes expressing the rat receptors and tert-[(35)S]butylbicyclophosphorothionate ([(35)S]TBPS) binding to rat brain membranes. Whereas the amplitude of GABA-induced Cl(-) currents did not differ significantly between group-housed and isolated animals, the potentiation of these currents by diazepam was reduced at cortical or hippocampal GABA(A) receptors from isolated rats compared with that apparent at receptors from group-housed animals. Moreover, the inhibitory effect of ethyl-beta-carboline-3-carboxylate, a negative allosteric modulator of GABA(A) receptors, on these currents was greater at cortical GABA(A) receptors from socially isolated animals than at those from group-housed rats. Finally, social isolation increased the extent of [(35)S]TBPS binding to both cortical and hippocampal membranes. The results further suggest a psychological role for neurosteroids and GABA(A) receptors in the modulation of emotional behavior and mood.     

Steroid hormone receptors in MCCLX, a transplantable lactogen-dependent mammary tumor of the rat

MCCLX is a transplantable rat mammary tumor which, for sustained growth, requires the elevated levels of circulating lactogen provided by pregnancy or the implantation of an estrogen pellet. High affinity receptors for estradiol, as well as for the glucocorticoids, dexamethasone and triamcinolone acetonide and the progestin R5020 were measured in the cytosols of these tumors. Estrogen binding capacities were significantly lower in the cytosols of tumors from estrogen pellet treated animals compared with tumors from pregnant animals. Ligand exchange assays demonstrated that nuclei of tumors from estrogen-treated rats contained 3-4 times the estrogen receptors but that there was a definite decrease in total estrogen binding capacity compared with tumors from pregnant rats. It was concluded that this lactogen-dependent tumor contains steroid receptors with molecular properties similar to those of normal target tissues, including estrogen receptors capable of nuclear translocation, the levels of which are modulated by the specific growth conditions.     

Proteins of multiple classes may participate in nongenomic steroid actions

Responses to steroids initiated from non-nuclear receptors impinge on a wide variety of cellular responses and utilize nearly all known signal transduction webs. While the mechanisms by which steroid receptors localize in the membrane are still unclear, it is apparent that this alternative localization allows steroid receptors to participate in a wide range of complex functions influencing cell proliferation, death, and differentiation. The central debate still remains the identity of the protein class or classes that mediate membrane-initiated (nongenomic) responses. The data thus far have supported several possibilities, including: nuclear steroid receptor-like forms in non-nuclear locations; other known (nonsteroid) membrane receptors or channels with additional steroid-binding sites; enzymes; transporters; receptors for serum steroid-binding proteins; unique and previously undescribed proteins; or chimeras of typical steroid receptor domains with other unique or known protein domains. Categorizing membrane steroid receptor proteins based exclusively on the actions of antagonists and agonists, without considering cell context and protein partnering issues, may mislead us into predicting more receptor subtypes than really exist. However, the plethora of signaling and functional outcomes may indicate the participation of more than one kind of steroid-binding protein. Resolving such unanswered questions will require future investigative focus on this alternative arm of steroid action, which is likely to yield as many therapeutic opportunities as have nuclear steroid mechanisms.     

Influence of anabolic combinations of an androgen plus an estrogen on biochemical pathways in bovine uterine endometrium and ovary

The application of anabolic steroids in food producing animals is forbidden in the EU since 1988, but the abuse of such drugs is a potential problem. The existing test systems are based on known compounds and can be eluded by newly emerging substances. The examination of physiological effects of anabolic hormones on different tissues to indirectly detect misuse might overcome this problem. Two studies were conducted with post-pubertal 24-months old Nguni heifers and pre-pubertal female 2-4 weeks old Holstein Friesian calves, respectively. The animals of the accordant treatment groups were administered combinations of estrogenic and androgenic compounds. The measurement of the gene expression pattern was undertaken with RT-qPCR. Target genes of different functional groups (receptors, angiogenesis, steroid synthesis, proliferation, apoptosis, nutrient metabolism and others) have been quantified. Several biochemical pathways were shown to be influenced by anabolic treatment. Both studies identified significant regulations in steroid and growth factor receptors (AR, ERβ, LHR, FSHR, Flt-1, PR, IGF-1R, Alk-6), angiogenic and tissue remodeling factors (VEGFs, FGFs, BMPs, ANGPT-2, MMPs, TIMP-2, CTSB), steroid synthesis (S5A1, HSD17, CYP19A1), proliferation (TNFα, IGF-1, IGFBPs, p53, c-fos; CEBPD, c-kit), apoptosis (CASP3, FasL, p53) and others (C7, INHA, STAR). Several genes were regulated to opposite directions in post-pubertal compared to pre-pubertal animals. PCA for Nguni heifers demonstrated a distinct separation between the control and the treatment group. In conclusion, anabolics modify hormone sensitivity and steroid synthesis, and they induce proliferative effects in the whole reproductive tract (uterus and ovary) as well as anti-angiogenic effects in the ovary. However, the extent will depend on the developmental stage of the animals.     

Gonadal Steroid Hormone Receptors and Sex Differences in the Hypothalamo-Pituitary-Adrenal Axis

The rapid activation of stress-responsive neuroendocrine systems is a basic reaction of animals to perturbations in their environment. One well-established response is that of the hypothalamo-pituitary-adrenal (HPA) axis. In rats, corticosterone is the major adrenal steroid secreted and is released in direct response to adrenocorticotropin (ACTH) secreted from the anterior pituitary gland. ACTH in turn is regulated by the hypothalamic factor, corticotropin-releasing hormone. A sex difference exists in the response of the HPA axis to stress, with females reacting more robustly than males. It has been demonstrated that in both sexes, products of the HPA axis inhibit reproductive function. Conversely, the sex differences in HPA function are in part due to differences in the circulating gonadal steroid hormone milieu. It appears that testosterone can act to inhibit HPA function, whereas estrogen can enhance HPA function. One mechanism by which androgens and estrogens modulate stress responses is through the binding to their cognate receptors in the central nervous system. The distribution and regulation of androgen and estrogen receptors within the CNS suggest possible sites and mechanisms by which gonadal steroid hormones can influence stress responses. In the case of androgens, data suggest that the control of the hypothalamic paraventricular nucleus is mediated trans-synaptically. For estrogen, modulation of the HPA axis may be due to changes in glucocorticoid receptor-mediated negative feedback mechanisms. The results of a variety of studies suggest that gonadal steroid hormones, particularly testosterone, modulate HPA activity in an attempt to prevent the deleterious effects of HPA activation on reproductive function.     

Ouabain binding of the rat's heart muscle cells after neonatal glucocorticoid (triamcinolone) treatment

In adult rats the ouabain-sensitive ATP-ase activity of the heart muscle as well as the amount of specifically bound 3H-ouabain decreased by 1/3 as a result of a single triamcinolone treatment undertaken in the neonatal period. Neonatal ouabain treatment did not alter the triamcinolone binding of the thymus of adult animals. The experiments again call attention to the phenomenon that the steroid hormones, even though specific for their target cells, are able to induce "alien" imprinting when administered in the neonatal period. They are also able to bind to steroid receptors of other cells altering, thereby, the responsiveness of these cells in adulthood.     

Estrogen, progesterone receptors and proliferating activity evaluated by immunocytochemistry in breast cancer.

The correlation of the most important prognostic indicators was evaluated in 75 breast cancer cases. Estrogen-progesterone receptors and proliferating activity were analyzed by immunocytochemical methods (ER-ICA, PR-ICA, Ki-67). Both steroid receptors were inversely correlated with the proliferating activity (ER-ICA vs Ki-67, p less than 0.003; PR-ICA vs. Ki-67, p less than 0.0001). No correlation was found between steroid receptors or cell kinetics and tumor size or lymph node status. These findings confirm the relevance of biochemical and kinetic parameters as independent markers in breast cancer and suggest a routine use of the simple immunocytochemical methods in assessing the biological behavior of tumors.