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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen is an important atheroprotective molecule that causes the rapid dilation of blood vessels by stimulating endothelial nitric oxide synthase (eNOS). There is also evidence that estrogen modulates airway epithelial NO production, thereby potentially affecting bronchial hyperresponsiveness. Studies in cultured endothelial and airway epithelial cells indicate that physiologic concentrations of estrogen cause rapid direct activation of eNOS that is unaffected by actinomycin D, but fully inhibited by estrogen receptor (ER) antagonism. Overexpression of ERalpha leads to marked enhancement of the acute response to estrogen, and this process is blocked by ER antagonism, it is specific to estrogen, and it requires the ERalpha hormone binding domain. In addition, the acute response of eNOS to estrogen can be reconstituted in COS-7 cells cotransfected with wild-type ERalpha and eNOS, but not by transfection with eNOS alone. Furthermore, the inhibition of calcium influx, or tyrosine kinases or MAP kinase prevents the stimulation of eNOS by estrogen, and estrogen causes rapid ER-dependent activation of MAP kinase. These findings indicate that the acute effects of estrogen on both endothelial and airway epithelial eNOS are mediated by ERalpha functioning in a novel, nongenomic manner to activate the enzyme via calcium-dependent, MAP kinase-dependent mechanisms.
Steroids
PMID:Rapid activation of endothelial nitric oxide synthase by estrogen. 1032 70

The purpose of this paper is to summarize recent advances in our understanding of the physiological role of 24(R),25(OH)(2)D(3) in bone and cartilage and its mechanism of action. With the identification of a target cell, the growth plate resting zone (RC) chondrocyte, we have been able to use cell biology methodology to investigate specific functions of 24(R),25(OH)(2)D(3) and to determine how 24(R),25(OH)(2)D(3) elicits its effects. These studies indicate that there are specific membrane-associated signal transduction pathways that mediate both rapid, nongenomic and genomic responses of RC cells to 24(R),25(OH)(2)D(3). 24(R),25(OH)(2)D(3) binds RC chondrocyte membranes with high specificity, resulting in an increase in protein kinase C (PKC) activity. The effect is stereospecific; 24R,25(OH)(2)D(3), but not 24S,25-(OH)(2)D(3), causes the increase, indicating a receptor-mediated response. Phospholipase D-2 (PLD2) activity is increased, resulting in increased production of diacylglycerol (DAG), which in turn activates PKC. 24(R),25(OH)(2)D(3) does not cause translocation of PKC to the plasma membrane, but activates existing PKCalpha. There is a rapid decrease in Ca(2+) efflux, and influx is stimulated. 24(R),25(OH)(2)D(3) also reduces arachidonic acid release by decreasing phospholipase A(2) (PLA(2)) activity, thereby decreasing available substrate for prostaglandin production via the action of cyclooxygenase-1. PGE(2) that is produced acts on the EP1 and EP2 receptors expressed by RC cells to downregulate PKC via protein kinase A, but the reduction in PGE(2) decreases this negative feedback mechanism. Both pathways converge on MAP kinase, leading to new gene expression. One consequence of this is production of new matrix vesicles containing PKCalpha and PKCzeta and an increase in PKC activity. The chondrocytes also produce 24(R),25(OH)(2)D(3), and the secreted metabolite acts directly on the matrix vesicle membrane. Only PKCzeta is directly affected by 24(R),25(OH)(2)D(3) in the matrix vesicles, and activity of this isoform is inhibited. This effect may be involved in the control of matrix maturation and turnover. 24(R),25(OH)(2)D(3) causes RC cells to mature along the endochondral developmental pathway, where they become responsive to 1alpha,25(OH)(2)D(3) and lose responsiveness to 24(R),25(OH)(2)D(3), a characteristic of more mature growth zone (GC) chondrocytes. 1alpha,25(OH)(2)D(3) elicits its effects on GC through different signal transduction pathways than those used by 24(R),25(OH)(2)D(3). These studies indicate that 24(R),25(OH)(2)D(3) plays an important role in endochondral ossification by regulating less mature chondrocytes and promoting their maturation in the endochondral lineage.
Steroids
PMID:24,25-(OH)(2)D(3) regulates cartilage and bone via autocrine and endocrine mechanisms. 1117 45

Estrogen has important atheroprotective and vasoactive properties related to its capacity to stimulate nitric oxide (NO) production by endothelial NO synthase. Previous work has shown that these effects are mediated by estrogen receptor (ER) alpha functioning in a nongenomic manner via calcium-dependent, MAP kinase-dependent mechanisms. Recent studies have demonstrated that estradiol (E(2)) activates eNOS in isolated endothelial plasma membranes in the absence of added calcium, calmodulin or eNOS cofactors. Studies of blockade by ICI 182,780 and by ER alpha antibody, and also immunoidentification experiments indicate that the process is mediated by a subpopulation of plasma membrane-associated ER alpha. Fractionation of endothelial cell plasma membranes has further revealed that ER alpha protein is localized to caveolae, and that E(2) causes stimulation of eNOS in isolated caveolae which is ER-dependent and calcium-dependent, whereas noncaveolae membranes are insensitive. Furthermore, in intact endothelial cells the activation of eNOS by E(2) is prevented by pertussis toxin, and exogenous GDP beta S inhibits the response in isolated plasma membranes. Coimmunoprecipitation studies have shown that E(2) exposure causes interaction between ER alpha and G(alpha i) on the plasma membrane, and eNOS activation by E(2) is enhanced by overexpression of G(alpha i) and attenuated by expression of a protein regulator of G protein signaling (RGS), RGS4. Thus, a subpopulation of ER alpha is localized to caveolae in endothelial cells, where they are coupled via G(alpha i) to eNOS in a functional signaling module. Emphasizing the dependence on cell surface-associated receptors, these observations provide evidence for the existence of a steroid receptor fast-action complex, or SRFC, in caveolae.
Steroids 2002 May
PMID:Rapid activation of endothelial NO synthase by estrogen: evidence for a steroid receptor fast-action complex (SRFC) in caveolae. 1196 Jun 16

Aromatase is the rate limiting enzyme that catalyzes the conversion of androgens to estrogens. Blockade of this step allows treatment of diseases that are dependent upon estrogen. Over the past two decades, highly potent and specific aromatase inhibitors have been developed which block total body aromatization by over 99%. An important recent question is whether aromatase inhibitors are superior to the antiestrogens for treatment of hormone-dependent breast cancer. The third generation aromatase inhibitors have been compared to tamoxifen for the treatment of breast cancer in the advanced, adjuvant, and neoadjuvant settings. All of these studies suggest the superiority of aromatase inhibitors over tamoxifen. The mechanism responsible for the superiority of the aromatase inhibitors relates to the estrogen agonistic effects of tamoxifen. During exposure to estrogen deprived conditions and to tamoxifen, breast cancer cells adapt and upregulate the MAP kinase and PI-3 kinase pathways. These growth factor signaling pathways potentiate the estrogen agonistic properties of tamoxifen. Data from a large adjuvant therapy trial (ATAC trial) provide evidence that the aromatase inhibitors may also be superior for breast cancer prevention. The mechanism for superiority in this setting probably relates to the genotoxic effects of estradiol metabolites. The aromatase inhibitors may be also useful for the treatment of endometriosis and for ovulation induction as evidenced by preliminary data. The recent advances in development of the aromatase inhibitors clearly demonstrate the utility of these agents for treatment of breast cancer and potentially for other indications.
Steroids 2003 Sep
PMID:Inhibition of aromatase: insights from recent studies. 1295 61

Breast cancer is one of the most common malignancies in the United States. Seventy percent of breast cancers are hormone-responsive due to the presence of estrogen receptors ERalpha and ERbeta, which are important diagnostic and therapeutic targets in cancer treatment. Estrogen acts through its receptors, which reside on the cell membrane as demonstrated recently and in the nucleus, leading to cancer cell proliferation and protection from cell death. The membrane ERalpha has been reported in MCF-7 human breast cancer cells and is believed to mediate estrogen effects to activate mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3-kinase). Activation of many growth factor receptors require adapter proteins to delivery the upstream signals to downstream kinases, such as MAP kinase. Both Shc and the p85alpha subunit of PI3-kinase are adapter proteins. In addition to their roles in transducing signals from membrane growth factor receptors, they have been demonstrated to interact with ERalpha in an estrogen dependent manner. In this review, the role of Shc in mediating estrogen effects on MAP Kinase regulation, cell growth and anti-apoptosis will be discussed. The possible role of PI3-kinase in estrogen rapid action is also reviewed in brief.
Steroids 2004 Aug
PMID:The role of adapter protein Shc in estrogen non-genomic action. 1528 64

Lung cancer is the most common cause of cancer mortality in male and female patients in the US. The etiology of non-small cell lung cancer (NSCLC) is not fully defined, but new data suggest that estrogens and growth factors promote tumor progression. In this work, we confirm that estrogen receptors (ER), both ERalpha and ERbeta, occur in significant proportions of archival NSCLC specimens from the clinic, with receptor expression in tumor cell nuclei and in extranuclear sites. Further, ERalpha in tumor nuclei was present in activated forms as assessed by detection of ER phosphorylation at serines-118 and -167, residues commonly modulated by growth factor receptor as well as steroid signaling. In experiments using small interfering RNA (siRNA) constructs, we find that suppressing expression of either ERalpha or ERbeta elicits a significant reduction in NSCLC cell proliferation in vitro. Estrogen signaling in NSCLC cells may also include steroid receptor coactivators (SRC), as SRC-3 and MNAR/PELP1 are both expressed in several lung cell lines, and both EGF and estradiol elicit serine phosphorylation of SRC-3 in vitro. EGFR and ER also cooperate in promoting early activation of p42/p44 MAP kinase in NSCLC cells. To assess new strategies to block NSCLC growth, we used Faslodex alone and with erlotinib, an EGFR kinase inhibitor. The drug tandem elicited enhanced blockade of the growth of NSCLC xenografts in vivo, and antitumor activity exceeded that of either agent given alone. The potential for use of antiestrogens alone and with growth factor receptor antagonists is now being pursued further in clinical trials.
Steroids 2007 Feb
PMID:Estrogen receptor signaling pathways in human non-small cell lung cancer. 1727 70

Progesterone is an ovarian steroid hormone that is essential for normal breast development. The actions of progesterone are largely mediated through binding to its cognate steroid hormone receptor, the progesterone receptor (PR). PR isoforms exist in the nucleus and transcriptionally activate genes necessary for proliferation and survival (classical role). Cytoplasmic or membrane-associated PR exists in the cytoplasm where it participates in protein complexes with signaling molecules and other steroid hormone receptors capable of rapid activation of cytoplasmic protein kinase cascades. This review details the extra nuclear scaffolding actions of PR with c-Src and MEK1, the upstream components of MAP kinase modules.
Steroids 2009 Jul
PMID:Scaffolding actions of membrane-associated progesterone receptors. 1913 65

Recent results showing that the binding characteristics of 33 steroids for human membrane progesterone receptor alpha (hu-mPRalpha) differ from those for the nuclear progesterone receptor (nPR) suggest that hu-mPRalpha-specific agonists can be identified for investigating its physiological functions. The binding affinities of an additional 21 steroids for hu-mPRalpha were determined to explore the structure-activity relationships in more detail and to identify potent, specific mPRalpha agonists. Four synthetic progesterone derivatives with methyl or methylene groups on positions 18 or 19, 18a-methylprogesterone (18-CH(3)P4, Org OE 64-0), 13-ethenyl-18-norprogesterone (18-CH(2)P4, Org 33663-0), 19a-methylprogesterone (19-CH(3)P4, Org OD 13-0) and 10-ethenyl-19-norprogesterone (19-CH(2)P4, Org OD 02-0), showed similar or higher affinities than progesterone for hu-mPRalpha and displayed mPRalpha agonist activities in G-protein and MAP kinase activation assays. All four steroids also bound to the nPR in cytosolic fractions of MCF-7 cells. However, two compounds, 19-CH(2)P4 and 19-CH(3)P4, showed no nPR agonist activity in a nPR reporter assay and therefore are selective mPRalpha agonists suitable for physiological investigations. The structure-binding relationships of the combined series of 54 steroids for hu-mPRalpha deviated strikingly from those of a published set of 60 3-keto or 3-desoxy steroids for nPR. Close correlations were observed between the receptor binding affinities of the steroids and their physicochemical properties calculated by comparative molecular field analysis (CoMFA) for both hu-mPRalpha and nPR. A comparison of the CoMFA field graphs for the two receptors revealed several differences in the structural features required for binding to hu-mPRalpha and nPR which could be exploited to develop additional mPR-specific ligands.
Steroids 2010 Apr
PMID:Comparison between steroid binding to membrane progesterone receptor alpha (mPRalpha) and to nuclear progesterone receptor: correlation with physicochemical properties assessed by comparative molecular field analysis and identification of mPRalpha-specific agonists. 2009 19