Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mineralocorticoids have been implicated in promoting fibrous tissue formation in various organs. In the present study, we sought to address the potential contribution of mineralocorticoids to fibrous tissue formation using a skin pouch model which has proved valuable for the analysis of inflammatory and wound healing responses. Skin pouches were induced in rats by administration of a phorbol ester, croton oil (0.5 ml of a 1% solution). After 2 weeks, rats were killed and intact pouch tissue collected. Pouch weights of control and aldosterone-treated (0.75 microg/h via osmotic minipump) rats were similar (3.33 +/- 0.44 g vs. 3.70 +/- 0.28 g respectively). However, pouch weights were reduced by more than 50% in spironolactone-treated (25 mg/day powdered in food) animals (1.62 +/- 0.22 g and 1.27 +/- 0.23 g respectively in aldosterone and spironolactone alone groups). To ascertain the effects of different treatments on collagen accumulation, hydroxyproline concentration was measured. Compared with controls, hydroxyproline concentration was significantly reduced following spironolactone treatment (17.1 +/- 0.08 vs. 7.5 +/- 2.0 microg/mg dry wt, respectively, p < 0.01). This response to spironolactone was negated by coadministration of aldosterone (hydroxyproline concentration was 18.6 +/- 2.1 microg/mg dry wt). Following bilateral adrenalectomy, spironolactone reduced pouch weight and hydroxyproline concentration, which was not the case for adrenalectomy alone. Two week aldosterone administration in uninephrectomized rats on high salt diet was deemed ineffective in modulating pouch development (pouch wet wts were 3.48 +/- 0.4 g vs. 3.00 +/- 0.19 g in controls and aldosterone-treated rats, respectively). Mineralocorticoid receptor expression in pouch tissue was demonstrated by RT/PCR. Furthermore, NADP+-dependent 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) activity was detected in pouch tissue, together with lower levels of NAD+-dependent 11beta-HSD2. Spironolactone (p < 0.05) significantly reduced 11beta-HSD1 activity compared with controls. Thus, fibrous tissue possesses requisite components of MC action, and antagonism of mineralocorticoid receptors by spironolactone attenuates its formation. Pouch formation is under the influence of circulating MC and, we would like to propose, is also mediated through corticosteroids generated de novo at the site of tissue repair.
Mol Cell Biochem 1998 Dec
PMID:Inhibition of tissue repair by spironolactone: role of mineralocorticoids in fibrous tissue formation. 987 53

The mineralocorticoid receptor (MR) acts as a ligand-dependent transcription factor modulating specific gene expression in sodium-transporting epithelia. Physiological evidence suggest a cross-talk between the cAMP- and aldosterone-signaling pathways. We provide evidence that protein kinase A (PKA), a major mediator of signal transduction pathways, modulates transcriptional activity of the human MR (hMR). Using transient transfection assays in HepG2 cells, we show that 8-bromo-cAMP, a protein kinase A activator, stimulates glucocorticoid response element (GRE)-containing promoters in a ligand-independent manner. This effect was strictly MR dependent since no activation of the reporter gene was observed in the absence of cotransfected hMR expression plasmid. Furthermore, a synergistic activation was achieved when cells were treated with both aldosterone and cAMP. This synergistic effect was also observed in the CV1 and the stable hMR-expressing M cells but was dependent on the promoter used. In particular, synergism was less pronounced in promoters containing several GREs. We show that (protein kinase-inhibiting peptide (PKI), the peptide inhibitor of PKA, prevented both cAMP and aldosterone induction, which indicates that a functional cAMP pathway is required for stimulation of transcription by aldosterone. Using MR-enriched baculovirus extracts in gel shift assays, we have shown that the binding of the MR to a GRE-containing oligonucleotide was enhanced by PKA. Increased DNA binding of hMR is likely to reflect an increase in the number of active receptors, as measured by Scatchard analysis. Using a truncated MR, we show that the N-terminal domain is required for the effect. Finally, the N-terminal truncated MR was not directly phosphorylated by PKA in vitro. We conclude that PKA acts indirectly, probably by relieving the effect of an MR repressor.
Mol Endocrinol 1999 Jan
PMID:Modulation of human mineralocorticoid receptor function by protein kinase A. 989 12

Targeted disruption of mineralocorticoid receptor (MR) gene results in pseudohypoaldosteronism type I with failure to thrive, severe dehydration, hyperkalemia, hyponatremia, and high plasma levels of renin, angiotensin II, and aldosterone. In this study, mRNA expression of the different components of the renin-angiotensin system (RAS) were evaluated in liver, lung, heart, kidney and adrenal gland to assess their response to a state of extreme sodium depletion. Angiotensinogen, renin, angiotensin-I converting enzyme, and angiotensin II receptor (AT1 and AT2) mRNA expressions were determined by Northern blot and RT-PCR analysis. Furthermore, in situ hybridization and immunohistochemistry allowed us to identify the cell types involved in the variation of the RAS component expression. In the heterozygous mice (MR+/-), compared with wild-type mice (MR+/+), there was no significant variation of any mRNA of the RAS components. In MR knockout mice (MR-/-), compared with wild-type mice, there were significant increases in the expression level of several RAS components. In the liver, angiotensinogen and AT1 receptor mRNA expressions were moderately stimulated. In the kidney, renin mRNA was increased up to 10-fold and in situ hybridization showed a marked recruitment of renin-producing cells; however, the levels of angiotensin-I converting enzyme mRNA and AT1 mRNA were not changed. Interestingly, in adrenal gland, renin expression was also strongly up-regulated in a thickened zona glomerulosa, whereas AT1 mRNA expression remained unchanged. Altogether, these results demonstrate that in the MR knockout mice model, RAS component expressions are differentially altered, renin being the most stimulated component. Angiotensinogen and AT1 in the liver are also increased, but the other elements of the RAS are not affected.
Mol Endocrinol 1999 Feb
PMID:Effects of mineralocorticoid receptor gene disruption on the components of the renin-angiotensin system in 8-day-old mice. 997 59

The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) belong to the steroid/thyroid hormone superfamily of ligand-induced transcription factors. Both activate the human Na/K ATPase alpha1 and beta1 genes transcriptionally. To assess the role of the transcription factor Sp1 and the nuclear factor I (NF-I), in MR- and GR-mediated gene expression using the human Na/K ATPase beta1 full-length promoter, we have examined the functions of Sp-I and NF-I functions in two different cell lines, COS-1 and T-84. By transient transfections we have shown that Sp-I significantly enhances MR and GR expression, whereas NF-I had negligible effect. We propose that the transcriptional enhancement could be through a direct interaction physically between MR or GR with Sp1 that allows other factors to bind the responsive element resulting in synergistic upregulation of transcription.
Mol Cell Biol Res Commun 1999 Apr
PMID:Upregulation of mineralocorticoid- and glucocorticoid-receptor gene expression by Sp-I. 1032 76

In experimental models where chronic inappropriate (relative to sodium intake and intravascular volume) elevations in circulating mineralocorticoids (aldosterone or deoxycorticosterone) are created, a reactive fibrosis with vascular remodeling is observed in systemic organs and the heart. Until recently, it was assumed that aldosterone was derived solely from adrenal glands via the circulation; however, there is now convincing evidence that cells of the heart and vasculature express genes responsible for the formation of both aldosterone and corticosterone and are capable of producing these steroids. Vascular endothelial and smooth muscle cells express CYP11B1 and CYP11B2, genes responsible for 11 beta -hydroxylase and aldosterone synthase, respectively. Furthermore, smooth muscle cells elaborate aldosterone. There is evidence that similar regulatory mechanisms operate in vascular cells as in adrenal cortex, since aldosterone synthase and 11 beta -hydroxylase expression are differentially modulated by low sodium/high potassium, angiotensin II and ACTH. It is likely that such localized corticosteroid production also occurs at sites of tissue repair, where populations of collagen-producing myofibroblasts, nourished by a neovasculature, predominate. Using a subcutaneous pouch model of granulation tissue we have obtained compelling data which would support such a notion. The mineralocorticoid receptor antagonist, spironolactone, severely attenuates pouch formation over a 2-week period and significantly reduces pouch wall hydroxyproline concentration. This effect is apparent even following adrenalectomy, when circulating corticosteroids are undetectable; however, with adrenalectomy alone, pouch formation is barely affected. This we took to be a possible indication of an effect of local, non-adrenal steroids in maintaining pouch tissue. Spironolactone inhibits angiogenesis. A recent clinical study demonstrates the efficacy of low-dose spironolactone in enhancing survival in patients with advanced chronic cardiac failure. Although it is not known how spironolactone brings about such an improvement in survival, we would propose that inhibition of fibrous tissue formation and/or angiogenesis might be important contributory factors. Further studies are required to address the relative contributions of circulating vs local aldosterone in promoting normal vs pathologic connective tissue formation.
J Mol Cell Cardiol 1999 Jun
PMID:Extra-adrenal mineralocorticoids and cardiovascular tissue. 1037 93

The natural steroid 11beta-hydroxyprogesterone is not only a modulator of 11beta-hydroxy-steroid dehydrogenase activity, but also an efficient inducer of tyrosine aminotransferase activity in hepatocytes. In contrast with the low affinity for the mineralocorticoid receptor. 11beta-hydroxyprogesterone binds well to both the glucocorticoid receptor and the carrier protein transcortin. It is accepted that the introduction of a 1:ene double bond into 3-keto 4:ene steroids increases the glucocorticoid potency, so that 3-keto-1,4:diene steroids show improved chemical stability and are more potent glucocorticoids than their respective 4:ene analogs. The steroid pregna-1,4-diene-11beta-ol-3,20-dione (deltaHOP) had previously been described as an anti-inflamatory compound and an inhibitor of macromolecular biosynthesis in thymocytes and lymphocytes. In such studies, deltaHOP also exhibited some particular glucocorticoid properties which made it attractive as a tool for the study of the mechanism of action of glucocorticoids. In the present paper we show that deltaHOP possesses some classical biological actions of glucocorticoids such as deposition of glycogen in rat liver, induction of TAT activity in hepatocytes, and inhibition of the uptake of leucine and thymidine by thymocytes. It also exhibits minimal sodium-retaining properties. Consistent with these biological effects, deltaHOP shows a 70 times lower relative binding affinity for the mineralocortioid receptor than aldosterone, but a reasonable affinity for the glucocorticoid receptor, and is as efficient as dexamethasone in dissociating the 90 kDa heat shock protein from the glucocorticoid receptor heterocomplex. However, the inhibition of the uptake of amino acids and nucleotides observed in the presence of deltaHOP is not efficiently blocked when thymocytes are coincubated in the presence of steroids with known antiglucocorticoid activity. deltaHOP is similarly inefficient in inducing chloramphenicol-acetyl transferase activity in cells transfected with a plasmid that possesses two canonical glucocorticoid-responsive elements. Unlike most glucocorticoids, deltaHOP does not induce the fragmentation of DNA in a regular pattern characteristic of apoptosis and it does not reduce thymus weight. This unusual dissociation of glucocorticoid parameters makes deltaHOP a useful tool to discriminate between mechanisms of action by which steroids can exert their biological effects.
Mol Cell Endocrinol 1999 Mar 25
PMID:The glucocorticoid properties of the synthetic steroid pregna-1,4-diene-11beta-ol-3,20-dione (deltaHOP) are not entirely correlated with the steroid binding to the glucocorticoid receptor. 1037 32

The estrogen receptor (ER) regulates the expression of target genes in a ligand-dependent manner. The ligand-dependent activation function AF-2 of the ER is located in the ligand binding domain (LBD), while the N-terminal A/B domain (AF-1) functions in a ligand-independent manner when isolated from the LBD. AF-1 and AF-2 exhibit cell type and promoter context specificity. Furthermore, the AF-1 activity of the human ERalpha (hERalpha) is enhanced through phosphorylation of the Ser(118) residue by mitogen-activated protein kinase (MAPK). From MCF-7 cells, we purified and cloned a 68-kDa protein (p68) which interacted with the A/B domain but not with the LBD of hERalpha. Phosphorylation of hERalpha Ser(118) potentiated the interaction with p68. We demonstrate that p68 enhanced the activity of AF-1 but not AF-2 and the estrogen-induced as well as the anti-estrogen-induced transcriptional activity of the full-length ERalpha in a cell-type-specific manner. However, it did not potentiate AF-1 or AF-2 of ERbeta, androgen receptor, retinoic acid receptor alpha, or mineralocorticoid receptor. We also show that the RNA helicase activity previously ascribed to p68 is dispensable for the ERalpha AF-1 coactivator activity and that p68 binds to CBP in vitro. Furthermore, the interaction region for p68 in the ERalpha A/B domain was essential for the full activity of hERalpha AF-1. Taken together, these findings show that p68 acts as a coactivator specific for the ERalpha AF-1 and strongly suggest that the interaction between p68 and the hERalpha A/B domain is regulated by MAPK-induced phosphorylation of Ser(118).
Mol Cell Biol 1999 Aug
PMID:Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor alpha. 2450 60

The 11beta-hydroxysteroid dehydrogenase enzymes (11beta-HSD) interconvert cortisol and cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. Two distantly related congeners have been isolated and conserved domains identified by multiple alignment and hydrophobic cluster analysis. 11Beta-HSD1 in the liver acts mainly as an oxoreductase maintaining circulating glucocorticoid levels. Gene deletion studies suggest it plays an important role in providing elevated local concentrations of hormone. In contrast, 11beta-HSD2 inactivates glucocorticoids and is pivotal in the distal tubule where it protects the mineralocorticoid receptor from occupation, thus endowing specificity on a non-selective receptor. Mutations in 11beta-HSD2 result in sodium retention and severe hypertension, account for the syndrome of apparent mineralocorticoid excess and may be responsible for other forms of hypertension. 11Beta-HSD2 is also present in the placenta where it protects the fetus from high circulating levels of maternal glucocorticoids. Attenuated placental 11beta-HSD2 activity has recently been shown to be associated with intrauterine growth retardation. 11Beta-HSD2 may also play important roles in pulmonary physiology and breast cancer. This review focuses on recent developments.
Mol Cell Endocrinol 1999 May 25
PMID:The 11beta-hydroxysteroid dehydrogenases: functions and physiological effects. 1041 26

The pathways which connect extracellular signals with the regulation of the activity of transcription factors are being investigated in molecular detail. Extensive progress has been made in the description of the mode of action of steroid hormones and of cytokines. Steroid hormones associate intracellularly with latent receptor molecules, cause the dissociation of masking proteins, the dimerization of receptors, and their binding to specific hormone response elements in the promoters of target genes. Cytokines also activate latent transcription factors (Stats--signal transducers and activators of transcription), but act through an enzymatic mechanism. Tyrosine kinases associated with the transmembrane cytokine receptors phosphorylate Stat molecules. The phosphorylated monomers dimerize and assume specific DNA binding ability. Both classes of transcription factors bind to different response elements and regulate different target genes and both signals, cytokines and steroid hormones, can affect growth differentiation and homeostasis of different cell types. Here, we describe that Stat5, a molecule activated by several essential cytokines, functionally interacts with members of the steroid receptor family. We find that glucocorticoid receptor, mineralocorticoid receptor and progesterone receptor synergize with Stat5 in the induction of the transcription from the beta-casein gene promoter. The estrogen receptor diminishes Stat5 mediated induction and the androgen receptor has no effect. Conversely, Stat5 negatively interferes with glucocorticoid receptor, mineralocorticoid receptor and progesterone receptor induced transcription from the MMTV LTR and the estrogen receptor induced transcription from an ERE-containing promoter.
J Steroid Biochem Mol Biol
PMID:Interactions in the transcriptional regulation exerted by Stat5 and by members of the steroid hormone receptor family. 1041 93

Local tissue concentrations of glucocorticoids are modulated by the enzyme 11beta-hydroxysteroid dehydrogenase which interconverts cortisol and the inactive glucocorticoid cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. The type I isoform (11beta-HSD1) is a bidirectional enzyme but acts predominantly as a oxidoreductase to form the active glucocorticoids cortisol or corticosterone, while the type II enzyme (11beta-HSD2) acts unidirectionally producing inactive 11-keto metabolites. There are no known clinical conditions associated with 11beta-HSD1 deficiency, but gene deletion experiments in the mouse indicate that this enzyme is important both for the maintenance of normal serum glucocorticoid levels, and in the activation of key hepatic gluconeogenic enzymes. Other important sites of action include omental fat, the ovary, brain and vasculature. Congenital defects in the 11beta-HSD2 enzyme have been shown to account for the syndrome of apparent mineralocorticoid excess (AME), a low renin severe form of hypertension resulting from the overstimulation of the non-selective mineralocorticoid receptor by cortisol in the distal tubule of the kidney. Inactivation of the 11beta-HSD2 gene in mice results in a phenotype with similar features to AME. In addition, these mice show high neonatal mortality associated with marked colonic distention, and remarkable hypertrophy and hyperplasia of the distal tubule epithelia. 11Beta-HSD2 also plays an important role in decreasing the exposure of the fetus to the high levels of maternal glucocorticoids. Recent work suggests a role for 11beta-HSD2 in non-mineralocorticoid target tissues where it would modulate glucocorticoid access to the glucocorticoid receptor, in invasive breast cancer and as a mechanism providing ligand for the putative 11-dehydrocorticosterone receptor. While previous homologies between members of the SCAD superfamily have been of the order of 20-30% phylogenetic analysis of a new branch of retinol dehydrogenases indicates identities of > 60% and overlapping substrate specificities. The availability of crystal structures of family members has allowed the mapping of conserved 11beta-HSD domains A-D to a cleft in the protein structure (cofactor binding domain), two parallel beta-sheets, and an alpha-helix (active site), respectively.
J Steroid Biochem Mol Biol
PMID:The type I and type II 11beta-hydroxysteroid dehydrogenase enzymes. 1041 17


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