Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highly specific binding of 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) by vitamin D receptor (VDR), a nuclear transcriptional factor, activates a genomic mechanism that is manifested in the multiple biologic properties of 1alpha,25(OH)(2)D(3). Numerous synthetic analogs of 1alpha,25(OH)(2)D(3) have been employed to study the interaction between 1alpha,25(OH)(2)D(3) and VDR, and to identify structural markers in 1alpha,25(OH)(2)D(3) that are important for VDR-binding. On the other hand the three-dimensional structure of VDR remained elusive till very recently. In the present study we employed affinity labeling (by 1alpha,25-dihydroxyvitamin D(3)-3-bromoacetate, 1alpha,25(OH)(2)D(3)-3-BE) of VDR to identify C(288) as the anchoring residue for the 3-hydroxyl group of 1alpha,25(OH)(2)D(3) inside the ligand-binding domain of VDR (VDR-LBD). In addition we carried out mutation/hormone-binding analyses to determine the importance of M(284) and W(286) toward hormone binding. We incorporated this information with the three-dimensional structure of the LBD of progesterone receptor to develop a homology-extension model of VDR-LBD. This model identified several amino acid residues as ligand-contact points inside the LBD. Mutational and hormone-binding analyses of these residues verified the structure-functional authenticity of this model, in comparison with the crystal structure of VDR, bound to 1alpha,25(OH)(2)D(3).
Steroids
PMID:Why do we need a three-dimensional architecture of the ligand-binding domain of the nuclear 1alpha,25-dihydroxyvitamin D(3) receptor? 1117 26

Estrogens have multiple effects on the growth and development of cells in their target tissues, including the uterus, ovary, breast, bone marrow and brain. The hormone regulates the transcription of diverse genes in these tissues via the estrogen receptor, a nuclear transcription factor. Naturally occurring estrogens and estrogen analogs including selective estrogen receptor modulators (SERMs), constitute important therapies for breast cancer and osteoporosis, and are major components of oral contraceptives. The in vitro biologic activities of pharmaceutical estrogen agonists and antagonists have frequently been monitored by cotransfection assay, where exogenous estrogen receptor and reporter genes are transiently inserted into a heterologous, non receptor-containing cell line, such as those derived from kidney cells. Here we describe an alternative to this method, where induction of an endogenous estrogen-responsive gene, the progesterone receptor gene, is monitored by branched DNA signal amplification. Assays are performed with cultured cells derived from estrogen-responsive tissues; namely, breast, uterine endothelium and bone. Hormonal induction occurs via the endogenous estrogen receptor of these cells. Our data show that SERMs, which are estrogen agonists on bone in vivo, antagonize estrogen-dependent target gene induction in conditionally immortalized osteoblast-like cells.
Steroids 2001 Sep
PMID:Induction of the progesterone receptor gene in estrogen target cells monitored by branched DNA signal amplification. 1154 54

Besides their binding to cognate intracellular receptors gonadal steroids may also act as functional antagonists at the 5-HT3 receptor. A structure-activity relationship for the actions of a variety of steroids at the 5-HT3 receptor was elaborated that differed considerably from that known for GABA(A) receptors. Steroids appear to interact allosterically with ligand-gated ion channels at the receptor membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders. Moreover, we could demonstrate that 3alpha-reduced neuroactive steroids concurrently modulate the GABA(A) receptor and regulate gene expression via the progesterone receptor after intracellular oxidation. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose dependent fashion in male Wister rats. Moreover, progesterone and 3alpha,5alpha-tetrahydroprogesterone produce a benzodiazepine-like sleep EEG profile in rats and humans. In addition, there is a dysequilibrium of such 3alpha-reduced neuroactive steroids during major depression which is corrected by successful treatment with antidepressants. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. First studies in patients with panic disorder suggest that neuroactive steroids may also play a pivotal role in human anxiety. The genomic and non-genomic effects of steroids in the brain contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may constitute a yet unexploited class of drugs.
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PMID:Neuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology. 1174 74

Steroids secreted by the ovary, specifically estrogen and progesterone, influence the expression of behaviors associated with reproduction by interacting with a specific binding protein, or receptor, located in target cells in certain hypothalamic nuclei. The present paper reviews the progesterone receptor studies in the vertebrates brain, the progesterone receptor fluctuations throughout the reproductive cycle and suggests a role for progesterone receptors in the regulation of hypothalamic functions in amphibians. Furthermore, we report here a combined biochemical and immunohistochemical analysis of the hypothalamic progesterone receptor during the reproductive cycle of a lower vertebrate, the female amphibian anura Rana esculenta. 3H-Progesterone binding activity was found in both cytosol and nuclear extract samples. The progesterone binding moiety showed typical characteristics of a true receptor, such as high affinity, low capacity and specificity for progesterone. Further characterization was performed by using monoclonal antiserum raised against both the subunits A and B of the chicken progesterone receptor. Immunostained neurons were located mainly in two specific regions of the hypothalamus: the preoptic area and the infundibular hypothalamus. An immunoreactive band of about 67 kDa was observed using Western blotting, both in the cytosol and in the nuclear extract. Progesterone receptor levels fluctuated throughout the cycle along with plasma steroids and vitellogenin synthesis.
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PMID:Progesterone receptor: some viewpoints on hypothalamic seasonal fluctuations in a lower vertebrate. 1174 85

Electrophoretic mobility shift assay was used to determine whether pregna-D'-pentaranes allow progesterone receptor (PR) from rat uterine cytosol to bind hormone response element (HRE)-containing oligonucleotide duplexes and to measure the affinity of this interaction. The formation of DNA-protein complexes in low salt medium was progesterone-related ligand-, temperature-, and PR-dependent, and specific for HRE. The highest affinity of PR to DNA (equilibrium K(a) = 0.420 +/- 0.185 nM(-1)) was found in the presence of the partial agonist/antagonist RU486, while the lowest affinity (K(a) = 0.074 +/- 0.013 nM(-1)) was demonstrated with the full agonist 6alpha-methyl-16alpha,17alpha-cyclohexanoprogesterone. With the exception of the strong full agonist R5020, there was a tendency toward correlation between the induced lower affinity of PR for DNA in the context of tyrosine aminotransferase HRE and the full agonistic activity of tested compounds.
Steroids 2002 Apr
PMID:Pregna-D'-pentarane structure influences progesterone receptor affinity for DNA. 1195 87

Rapid, nongenomic actions of steroid hormones have been characterized only recently. They may be mediated by interaction with a poorly characterized membrane receptor, by classic receptor located to the plasma membrane, or by interaction of the classic receptor with other signaling effectors. Among these, rapid effects of progesterone on human spermatozoa have been shown to be mediated by interaction with one or more membrane receptors. Two proteins, respectively of 57 and 28 kDa, representing the possible surface progesterone receptors in human spermatozoa, have been identified by our group employing an antibody (c-262) directed against the progesterone binding domain of the genomic receptor. The two proteins have been immunoprecipitated using c-262, isolated by 2D gel electrophoresis and analyzed by Maldi-Tof. Preliminary results of the analysis in data bank of the obtained masses suggest that the two proteins represent previously unidentified ones since they do not match with any protein in the database. We have also performed RT-PCR analysis with RNA extracted from human spermatozoa, utilizing various oligoprimers in different regions of the human progesterone genomic receptor. Results indicate the presence of transcripts for the complete genomic receptor. However, several previously published studies in the literature indicate the absence of expression of the genomic receptor in human spermatozoa. In this light posttranscriptional/posttraductional modifications of the receptor can be hypothesized. Interestingly, with primers amplifying in the DNA-binding domain of the progesterone receptor gene, we detected a higher molecular weight transcript when compared to the placenta. Further studies are needed to determine whether the sequences of the transcripts obtained by RT-PCR analysis of human sperm RNA match exactly with the human genomic receptor gene and to define the sequence of the higher molecular weight transcript detected in the DNA-binding region.
Steroids 2002 May
PMID:Characterization of membrane nongenomic receptors for progesterone in human spermatozoa. 1196 Jun 28

Monoclonal antibodies directed against human estrogen receptor (ER) and progesterone receptor (PR) have been used extensively for biochemical and immunohistochemical detection of receptors independent of hormone-binding assays. These antibodies have been valuable both for experimental work and for detection of receptors in clinical breast cancer specimens. The purpose of this study was to characterize the sensitivity and specificity of different antibodies for detection of PR by immunohistochemistry (IHC) of formalin-fixed paraffin breast carcinoma sections. The panel of twelve antibodies included two new ones (PgR636 and PgR1294) produced prospectively to be resistant to formalin fixation and paraffin embedding. Fifty-nine breast carcinomas, having known PR levels by biochemical ligand-binding assay, were used to prepare multitumor paraffin-embedded tissue blocks for characterization of the PR antibodies. Of all the antibodies tested, both PgR636 and PgR1294 stained the highest percentage of breast carcinomas known to be positive by the biochemical assay (95-98%) and they exhibited the highest concordance with the biochemical assay (88-90%). The PgR636 and PgR1294 antibodies, along with one other, PR 88, also gave the highest intensity of nuclear staining, while PgR636 and PgR1294 stained the highest mean percentage of tumor cell nuclei. Antigen retrieval was not necessary for PR immunostaining by PgR636 and PgR1294 in most tumors and other tissues examined, but did slightly increase the staining intensity. The majority of the other antibodies tested were highly dependent on antigen retrieval; only PR 88 and KD 68 antibodies approached the performance of PgR636 and PgR1294 without antigen retrieval. These results indicate that PgR636 and PgR1294 are optimal antibodies for IHC detection of PR in routine paraffin tissue blocks.
Steroids 2002 Aug
PMID:Comparison of different antibodies for detection of progesterone receptor in breast cancer. 1212 92

The receptor profiles and in vivo activity of tibolone, and its primary metabolites, Delta(4)-isomer, and 3alpha- and 3beta-hydroxytibolone, were studied and compared to those of structurally related compounds. The Delta(4)-isomer was the strongest binder and activator of the progesterone receptor (PR); tibolone was 10 times weaker in binding and half as potent in transactivation of PR; 3alpha- and 3beta-hydroxytibolone did not bind or activate PR. In rabbits oral tibolone produced a minor progestagenic effect in the endometrium, whereas co-administration of tibolone and the anti-estrogen ICI 164,384 unmasked tibolone's progestagenic effect. 3-Hydroxytibolones were the strongest binders and activators of the estrogen receptors (ERs), with greater affinity for ERalpha than for ERbeta. Tibolone showed weaker binding and activation of both ERs and the Delta(4)-isomer has a binding and activation activity of less than 0.1% of E2 for ERalpha or ERbeta. Tamoxifen and 4-hydroxytamoxifen showed partial ERalpha agonistic effects with a maximal response of 12% and raloxifene of 3-5%. Oral administration of 1mg tibolone to ovariectomized rats induced an estrogenic effect on vaginal epithelium. The Delta(4)-isomer was a stronger binder and activator of the androgen receptor (AR) than tibolone; both 3-hydroxytibolones did not bind or activate AR. Introducing a 7alpha-methyl group decreased progestagenic and increased androgenic activity. We conclude that the progestagenic and androgenic activities of tibolone are mediated by the Delta(4)-isomer, and the estrogenic activity, by the 3-hydroxytibolones. The estrogenic activity of the 3-hydroxytibolones masked the progestagenic activity of tibolone in rabbit endometrium. Full estrogenic response was observed in rat vaginal tissue after oral administration of tibolone.
Steroids 2003 Jan
PMID:Receptor profiling and endocrine interactions of tibolone. 1247 20

Steroids influence neuronal function through binding to cognate intracellular receptors which may act as transcription factors in the regulation of gene expression. In addition, certain so-called neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially distinct 3alpha-reduced metabolites of progesterone and deoxycorticosterone are potent positive allosteric modulators of gamma-aminobutyric acid type A (GABA(A)) receptors. However, also classical steroid hormones such as 17beta-estradiol, testosterone and progesterone are neuroactive steroids because they may act as functional antagonists at the 5-hydroxytryptamine type 3 (5-HT(3)) receptor, a ligand-gated ion channel or distinct glutamate receptors. A structure-activity relationship for the actions of a variety of steroids at the 5-HT(3) receptor was elaborated that differed considerably from that known for GABA(A) receptors. Although a bindings site for steroids at GABA(A) receptors is still a matter of debate, meanwhile there is also evidence that steroids interact allosterically with ligand-gated ion channels at the receptor membrane interface. On the other hand, also 3alpha-reduced neuroactive steroids may regulate gene expression via the progesterone receptor after intracellular oxidation into 5alpha-pregnane steroids. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose-dependent fashion in male Wistar rats. Moreover, progesterone and 3alpha-reduced neuroactive steroids produce a benzodiazepine-like sleep EEG profile in rats and humans. During major depression, there is a disequilibrium of such 3alpha-reduced neuroactive steroids which is corrected by successful treatment with antidepressant drugs. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. Studies in patients with panic disorder suggest that neuroactive steroids may also play a role in modulating human anxiety. Both the genomic and non-genomic effects of steroids in the brain may contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may represent a new treatment strategy for neuropsychiatric disorders.
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PMID:Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. 1251 9

Steroids and their nuclear receptors play crucial roles in the development and maintenance of normal functions of the human mammary gland (HMG). They have also been implicated in breast carcinogenesis. However, the study of steroid action in normal HMG has been hampered by experimental difficulties. By using a newly established in vitro long-term culture method, we successfully cultured normal HMG tissue for more than 2 months without detriment to its morphology or steroid receptor expression. Expression of the cellular structural and extracellular matrix proteins was similar to that prior to culture, and HMG tissue retained its properties of steroid receptor expression and regulation. Addition of 17-beta estrogen to mammary tissues markedly increased the expression of progesterone receptor (PR) but only slightly affected that of the estrogen receptor (ER). Medroxyprogesterone acetate down-regulated the expression of PR within 24-48 h and also increased the expression of androgen receptor. When HMG tissue was cultured in medium containing normal or dextran-coated charcoal-stripped fetal calf serum or normal human serum, the expression and regulation of steroid hormone receptors were similar, although different in extent. When serum was omitted, the morphology of HMG was normal after 1 week, but the expression and regulation of ER and PR were altered. Thus, as HMGs retain the capacity to express steroid receptors in culture, this long-term culture system is probably a good model for studying the regulation of the mammary gland by steroids.
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PMID:An in vitro long-term culture model for normal human mammary gland: expression and regulation of steroid receptors. 1259 41


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