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)

To study the role of glucocorticoid receptor (GR) at different stages of mammary gland development, mammary anlage were rescued from GR-/- mice by transplantation into the cleared fat pad of wild-type mice. In virgin mice, GR-/- outgrowths displayed abnormal ductal morphogenesis characterized by distended lumena, multiple layers of luminal epithelial cells in some regions along the ducts, and increased periductal stroma. In contrast, the loss of GR did not result in overt phenotypic changes in mammary gland development during pregnancy, lactation, and involution. Surprisingly, despite the known synergism between glucocorticoids and prolactin in the regulation of milk protein gene expression, whey acidic protein and beta-casein mRNA levels were unaffected in GR-/- transplants as compared with wild-type transplants. That mineralocorticoid receptor (MR) might compensate for the loss of GR was suggested by the detection of MR in the mammary gland at d 1 of lactation. This hypothesis was tested using explant cultures derived from the GR-/- transplants in which the mineralocorticoid fludrocortisone was able to synergistically induce beta-casein gene expression in the presence of prolactin and insulin. These studies suggest that MR may compensate for the absence of GR at some, but not at all stages of mammary gland development.
Mol Endocrinol 2002 Sep
PMID:The mineralocorticoid receptor may compensate for the loss of the glucocorticoid receptor at specific stages of mammary gland development. 1219 39

In clinical trials of heart failure, spironolactone, an antagonist of the mineralocorticoid receptor (MR), reduced mortality rates by unknown mechanisms. We hypothesized that spironolactone functions by upregulating expression of certain cardiovascular genes. An RNA differential display technique was used to identify genes whose expression was increased by spironolactone in an Xenopus kidney epithelial cell line (A6), a known target of aldosterone. We found that integrin beta3 gene expression was increased by spironolactone, and reversed by aldosterone or dexamethasone in a dose dependent manner. Competition binding studies and RT-PCR indicate the presence of MR in A6 cells, suggesting that regulation of expression occurred primarily through MR. Spironolactone also increased integrin beta3 expression in rat neonatal cardiomyocytes. In summary, spironolactone increases integrin beta3 gene expression in kidney epithelial cells and cardiomyocytes. The findings suggest new mechanisms for spironolactone actions with possible relevance to treatment of heart disease.
Mol Cell Endocrinol 2002 Aug 30
PMID:Spironolactone increases integrin beta3 gene expression in kidney and heart muscle cells. 1224 40

The binding of mineralocorticoid hormones to the mineralocorticoid receptor is the first step in a cascade of events leading to the stimulation of Na(+) reabsorption by renal cortical collecting duct (CCD) principal cells. The agonist properties of mineralocorticoid hormones are linked to contacts between their 21-hydroxyl group and Asn770, a residue of the ligand-binding domain of the human mineralocorticoid receptor (hMR). Here, we investigate whether the presence of a hydroxyl group at position 11, 17, or 20 could also alter the activity of progesterone (P), a mineralocorticoid antagonist without the 21-hydroxyl group. Both 17 alpha-hydroxyprogesterone (17OHP) and 20 alpha-hydroxyprogesterone (20OHP) antagonized the aldosterone-induced trans-activation activity (IC(50): 17OHP, 10(-7) M; 20OHP, 10(-8) M) of the hMR transiently expressed in COS-7 cells lacking steroid receptors. In cultured mouse mpkCCD(cl4) principal cells, 17OHP and 20OHP also prevented the aldosterone-stimulated amiloride-sensitive component of the short-circuit current (Ams I(sc)), reflecting Na(+) absorption mediated by the epithelial Na(+) channel (ENaC). In contrast, 11 beta-hydroxyprogesterone (11OHP) activated the transiently expressed hMR in COS-7 cells in a dose-dependent manner (ED(50): 10(-8) M) and, like aldosterone, stimulated Ams I(sc) in mpkCCD(cl4) cells. Docking 11OHP within the hMR-ligand-binding domain homology model revealed that the agonist activity of 11OHP is caused by contacts between its 11 beta-hydroxyl group and Asn770. Furthermore, 11OHP was unable to activate the mutant hMR/N770A, in which Ala is substituted for Asn at position 770. These findings demonstrate that in the absence of the 21-hydroxyl group, the 11 beta-hydroxyl group can produce the contact with the hMR-Asn770 required for the hMR activation leading to stimulated Na(+) absorption.
Mol Pharmacol 2002 Dec
PMID:11beta-hydroxyprogesterone acts as a mineralocorticoid agonist in stimulating Na+ absorption in mammalian principal cortical collecting duct cells. 1243 97

Cardiac remodeling, CR, is a complex and rather controversial issue and results from the, sometimes opposite, trophic effects of pure mechanical overload, and susceptibility factors, as senescence, aetiologies, as ischemia, and the neurohormonal reaction. The molecular mechanisms of CR are heritable and had, in the past, increased fitness, as such CR belongs to evolutionary medicine. Aldosterone production plays an important role in the remodeling of the heart. (i) There are numerous evidences that aldosterone induces fibrosis in all the cardiovascular system in the presence of high sodium diet. The aldosterone receptor is a transcriptional factor and the pathways that lead to aldosterone-induced fibrosis are multiple. Aldosterone induces the expression of the angiotensin II receptors subtype I and that of the glucocorticoid receptors. The RALES trial have recently evidenced a significant beneficial effect of spironolactone on both mortality and morbidity in heart failure, and a substudy has shown that these effects are linked to a reduction is fibrosis. (ii) An intracardiac production of aldosterone and corticosterone have been evidenced in the rat. Aldosterone production is regulated by low sodium/high potassium diets and by angiotensin II and is predominant in atria, cardiac production is low as compared to the adrenal production, nevertheless it results in high local concentrations, just like angiotensin II. In rats, myocardial infarction activates aldosterone production and this activation is prevented by losartan. Heart failure, in human, activates aldosterone production and is accompanied by a significant increase of the arteriovenous difference in aldosterone by the myocardium. To conclude (i) after a myocardial infarction local production of aldosterone and angiotensin II are likely to play a major role in regulating collagen turnover and fibrous tissue formation; (ii) during heart failure, the activation of adrenal and cardiovascular production of aldosterone belongs to the neurohormonal reaction and would play a detrimental role in producing reactive fibrosis.
J Mol Cell Cardiol 2002 Dec
PMID:Molecular mechanisms of myocardial remodeling. The role of aldosterone. 1250 56

Despite previous observations on isolated ventricular myocytes, there are still few evidences that angiotensin II induces cardiomyocyte apoptosis in vivo. The possibility that aldosterone, the final hormone of the renin-angiotensin-aldosterone system under Ang II control, can stimulate cardiac apoptosis has not yet been explored. Angiotensin II or aldosterone (1mg/kg each) were infused in adult normotensive rats for different times, and the number of apoptotic ventricular myocyte nuclei was quantified by the TUNEL method, along with caspase-3 activation. The role of angiotensin II type 1 receptor in vivo was assessed by selective blockade with valsartan and ex vivo by binding experiments. In addition, myocytes in primary culture were incubated with Ang II or aldosterone in presence of spironolactone. Continuous infusion of Ang II induced a rapid, AT(1)-mediated increase of apoptotic cardiomyocyte nuclei (from 14+/-9 to 188+/-35 TdT-labeled nuclei/10(6) after 3h, P<0.005) and of activated caspase-3, that normalized after 24h. The normalization was associated with a down-regulation of myocardial AT(1) receptors. Aldosterone stimulated cardiomyocyte apoptosis both in vivo and in isolated cells, to a similar extent as Ang II. The maximal apoptotic rate reported here ( approximately 0.02%) and the transient effect of Ang II suggest that myocyte loss by apoptosis is limited in the present model. The data on aldosterone-induced ventricular myocyte apoptosis deserve further attention to delineate the role of aldosterone in cell death and offer possible mechanistic explanations on the benefits afforded by aldosterone receptor antagonists in heart failure.
J Mol Cell Cardiol 2002 Dec
PMID:Appraisal of the role of angiotensin II and aldosterone in ventricular myocyte apoptosis in adult normotensive rat. 1250 63

The potential for interaction between the N-terminal domain and the C-terminal region (hinge and ligand-binding domain) of the mineralocorticoid receptor (MR) was examined using the mammalian-2-hybrid assay. The MR C-terminal region was fused to the GAL4 DNA-binding domain (GAL4-MRC). To examine if the AF-2 is involved in the interaction, as has been reported for other steroid hormone receptors, it was inactivated by point mutation (E962A). The N-terminal domain was fused to the VP16 transactivation domain (VP16-MRNT). In the mammalian-2-hybrid assay both GAL4-MRC and GAL4-MRC(E962A) interact with VP16-MRNT in an aldosterone-dependent manner. The GAL4-MRC(E962A) construct was used in subsequent experiments to examine the AF-2-independent N/C-interaction. The MR antagonist spironolactone inhibits the aldosterone-mediated association of the two domains. GAL4-MRC(E962A) interacts weakly with the GR or AR N-terminal domains in the presence of aldosterone. No dimerization between GAL4-MRC(E962A) and VP16-MRC is observed. Interestingly, cortisol produces a much weaker N/C-interaction than aldosterone, and it is possible that the N/C-interaction may contribute to observed functional differences in the MR bound to the two ligands.
Mol Cell Endocrinol 2003 Feb 28
PMID:Interdomain interactions in the mineralocorticoid receptor. 1264 98

The mineralocorticoid receptor (MR) binds aldosterone, but also glucocorticoid hormones (corticosterone in rodents, cortisol in humans), which largely prevail in the plasma. To prevent permanent and maximal occupancy of MR by glucocorticoid hormones in aldosterone-target cells, specific effects of aldosterone require metabolism of glucocorticoid hormones into 11-dehydroderivatives by 11-beta hydroxysteroid dehydrogenase (11-HSD2). We analyzed the effect of corticosterone or 11-dehydrocorticosterone (11-DHC) on the transactivation activity of the MR, transiently expressed in a new renal cell line expressing 11-HSD2. We show that, because of its metabolism by 11-HSD2, corticosterone is a poor activator of MR transactivation, except at micromolar concentrations, where the enzyme is saturated. We also show that high micromolar concentrations of 11 DHC are required to activate the MR. The weak antagonist property of 11-DHC on aldosterone-induced hMR transactivations is also documented. Such partial agonist activity of 11-DHC is discussed in the light of its positioning in a three-dimensional model of the MR ligand-binding domain.
J Steroid Biochem Mol Biol 2003 Feb
PMID:Glucocorticoid metabolism by 11-beta hydroxysteroid dehydrogenase type 2 modulates human mineralocorticoid receptor transactivation activity. 1271 Oct 9

In earlier studies, we reported reduced human insulin receptor (hIR) mRNA levels, insulin binding and insulin responsiveness in U-937 human promonocytic cells treated with aldosterone. The mechanism for this inhibition could be diminished IR gene transcription, since aldosterone did not affect hIR mRNA stability. All the effects were mediated by a downregulation of the mineralocorticoid receptor (MR, NR3C2) expressed at both the RNA and protein levels, suggesting that MR could act as a transcription factor that binds to hormone response elements in the hIR gene promoter. Indeed, MR has been shown to bind glucocorticoid response elements (GREs) in target genes. Given that five GREs have been characterized in the hIR promoter, we decided to test whether these elements could mediate the aldosterone-elicited inhibition of hIR expression detected by us in U-937 cells. In the present report, we demonstrate that aldosterone inhibits the activity of the hIR wild-type promoter by 23%, and causes 23 and 31% reductions in the activity of progressive deletions of this promoter comprised of fragments up to -1473 and -876bp, respectively. This indicates that the -876 to -271bp region of the hIR promoter may be sufficient for this transcriptional inhibition by aldosterone. We also provide evidence for direct MR interaction with some of the GREs of this promoter region, specifically with the cGRE1 and cGRE3, presumably as MR-MR homodimers, and with pGRE as a MR-GR heterodimer. This heterodimer may play the most relevant role and participate in the cross-talk between mineralocorticoids, glucocorticoids and insulin signalling in U-937 cells.
J Steroid Biochem Mol Biol 2003 Apr
PMID:Transcriptional inhibition of the human insulin receptor gene by aldosterone. 1276 79

Glucocorticoid hormones bind both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) exerting a broad spectrum of actions in various tissues. The concentrations of glucocorticoid hormones in the target cells are regulated by 11 beta-hydroxysteroid dehydrogenases, type 1 (11 beta-HSD1) and type 2 (11 beta-HSD2). 11 beta-HSD2 is a unidirectional dehydrogenase, which inactivates biologically active glucocorticoid into inert metabolite, while 11 beta-HSD1 is a bi-directional oxidoreductase, which either inactivates biologically active glucocorticoid or activates inert metabolite into active forms. GRs and MRs are present in various tissues and mediate a broad spectrum of physiological actions. The co-existence of 11 beta-HSD1 with these two types of receptors plays an important role in regulation of glucocorticoid actions. This review examines the roles of 11 beta-HSD1 in vascular tissues, testis, brain and other tissues such as placental, retinal and adipose tissues.
Mol Cell Endocrinol 2003 May 30
PMID:The functional roles of 11 beta-HSD1: vascular tissue, testis and brain. 1278 98

Nongenomic actions of aldosterone have been described in a number of cell culture and in vivo systems. They occur, in contrast to the classical genomic effects on gene transcription, rapidly within seconds to minutes after aldosterone administration. The primary effector is still unknown. Whether it is a so far unidentified membrane bound aldosterone receptor or the classical mineralocorticoid receptor or both is under debate. The downstream signaling cascade involved in such rapid actions begins to be elucidated. In this work, we discuss the nature of the putative membrane receptor for aldosterone and summarize observed rapid aldosterone effects in different in vitro and in vivo systems.
J Steroid Biochem Mol Biol 2003 Jun
PMID:Rapid aldosterone actions: from the membrane to signaling cascades to gene transcription and physiological effects. 1294 25


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