Mineralocorticoid receptor splice variants in different human tissues

Wickert, Lucia; Watzka, Matthias; Bolkenius, Ursula; Bidlingmaier, F.; Ludwig, Michael

doi:10.1530/eje.0.1380702

Cited by 30 publications

(24 citation statements)

References 14 publications

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“…However, heterodimerization of steroid receptors (GR, MR, progesterone, androgen and estrogen receptors) has been more rarely described, and their functional consequences are still poorly understood. The first clue for understanding the physiological significance of such heterodimerization came from co-localization of the two receptors in the same cells: both receptors have been co-localized in various tissues and cells including the brain, the heart, vascular smooth muscle and leukocytes in mammals (van Steensel et al 1996, Zennaro et al 1997, Wickert et al 1998. A similar situation was also recently observed in trout, where the GR and the MR co-localized in the same cells in the gill, intestine and kidneys (Kiilerich et al 2011a).…”

Section: Figurementioning

confidence: 99%

Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro

Kiilerich¹,

Triqueneaux²,

Christensen³

et al. 2015

Journal of Molecular Endocrinology

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The salmonid corticosteroid receptors (CRs), glucocorticoid receptors 1 and 2 (GR1 and GR2) and the mineralocorticoid receptor (MR) share a high degree of homology with regard to structure, ligand-and DNA response element-binding, and cellular co-localization. Typically, these nuclear hormone receptors homodimerize to confer transcriptional activation of target genes, but a few studies using mammalian receptors suggest some degree of heterodimerization. We observed that the trout MR confers a several fold lower transcriptional activity compared to the trout GRs. This made us question the functional relevance of the MR when this receptor is located in the same cells as the GRs and activated by cortisol. A series of co-transfection experiments using different glucocorticoid response elements (GREs) containing promoter-reporter constructs were carried out to investigate any possible interaction between the piscine CRs. Co-transfection of the GRs with the MR significantly reduced the total transcriptional activity even at low MR levels, suggesting interaction between these receptors. Co-transfection of GR1 or GR2 with the MR did not affect the subcellular localization of the GRs, and the MR-mediated inhibition seemed to be independent of specific activation or inhibition of the MR. Site-directed mutagenesis of the DNA-binding domain and dimerization interface of the MR showed that the inhibition was dependent on DNA binding but not necessarily on dimerization ability. Thus, we suggest that the interaction between MR and the GRs may regulate the cortisol response in cell types where the receptors co-localize and propose a dominant-negative role for the MR in cortisolmediated transcriptional activity.

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Section: Figurementioning

confidence: 99%

Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro

Kiilerich¹,

Triqueneaux²,

Christensen³

et al. 2015

Journal of Molecular Endocrinology

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“…Although the functional consequences of MR/GR heterodimerization are not well understood, the possible physiological significance stems from the observed co-localization of the receptors in various tissues and cells including the brain, heart, vascular smooth muscle, and leukocytes (21)(22)(23)(24). For example, in the brain, the MR is involved in the excitability of neurons, whereas the GR opposes these effects.…”

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confidence: 99%

Inhibition of Glucocorticoid-induced Apoptosis in 697 Pre-B Lymphocytes by the Mineralocorticoid Receptor N-terminal Domain

Planey¹,

Derfoul²,

Steplewski

et al. 2002

Journal of Biological Chemistry

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The glucocorticoid and mineralocorticoid receptors (GR and MR) share considerable structural and functional homology and bind as homodimers to hormoneresponse elements. We have shown previously that MR and GR can form heterodimers that inhibit transcription from a glucocorticoid (GC)-responsive gene and that this inhibition was mediated by the N-terminal domain (NTD) of MR. In this report, we examined the effect of NTD-MR on GC-induced apoptosis in the GC-sensitive pre-B lymphoma cell line, 697. In GC-treated 697 cells, we demonstrated that stable expression of NTD-MR blocks apoptosis and inhibits proteolytic processing of pro-caspases-3, -8, and -9 and poly(ADP-ribose) polymerase. Importantly, gel shift and immunoprecipitation analyses revealed a direct association between the GR and amino acids 203-603 of NTD-MR. We observed down-regulation of c-Myc and of the anti-apoptotic proteins Bcl-2 and Bfl-1 as well as high levels of the proapoptotic proteins Bax and Bid. Conversely, cells stably expressing NTD-MR exhibited increased expression of Bcl-2 and Bfl-1 and diminished levels of Bid and Bax. These data provide a potential mechanism for the observed inhibition of cytochrome c and Smac release from the mitochondria of NTD-MR cells and resultant resistance to GC-induced apoptosis. Thus, NTD-MR may mediate GC effects through heterodimerization with GR and ensuing inhibition of GC-regulated gene transcription.The glucocorticoid and the mineralocorticoid receptors (GR 1 and MR) are closely related members of the steroid receptor superfamily, with high sequence homology within the DNA binding and ligand binding domains (1). These receptors function as ligand-activated transcription factors that control various aspects of metabolic homeostasis, embryonic development, and physiological stress by binding to specific hormone-response elements in the regulatory regions of target genes

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“…The GR is ubiquitously expressed, and has considerable structural and functional homology with the MR [31]. On the other hand, recent reports have shown the MR to be expressed in several tissues, including non-epithelial cells of the brain, heart, and skin, as well as leukocytes and brown adipocytes [32,33]. In fact, we also detected MR expression in hepatocytes by RT-PCR (data not shown), raising the possibility that MR may play a role in the regulation of gluconeogenic gene expression.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Stimulates Gene Expression of Hepatic Gluconeogenic Enzymes through the Glucocorticoid Receptor in a Manner Independent of the Protein Kinase B Cascade

et al. 2004

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Abstract. Primary aldosteronism is associated with glucose intolerance and diabetes, which is due in part to impaired insulin release caused by reduction of potassium, although other possibilities remain to be elucidated. To evaluate the in vivo effects of aldosterone on glucose metabolism, a single dose of aldosterone was administered to mice, which resulted in elevation of the blood glucose level. In primary cultured mouse hepatocytes, the gene expression of gluconeogenic enzymes such as glucose-6-phosphatase (G6Pase), fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase increased in response to aldosterone in a dose-dependent manner even at a concentration similar to a physiological condition (10 -9 M). The inhibitory effect of insulin on G6Pase gene expression was partially suppressed by aldosterone. Furthermore, aldosterone enhanced G6Pase promoter activity in human hepatoma cell line HepG2, which was prevented by co-treatment with a glucocorticoid antagonist RU-486, but not a mineralocorticoid antagonist spironolactone. In contrast, aldosterone had no effects on major insulin signaling pathways including insulin receptor substrate-1, protein kinase B, and forkhead transcription factor. These results suggest that aldosterone may affect the inhibitory effect of insulin on hepatic gluconeogenesis through the glucocorticoid receptor, which may be one of the causes of impaired glucose metabolism in primary aldosteronism.

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Mineralocorticoid receptor splice variants in different human tissues

Cited by 30 publications

References 14 publications

Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro

Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro

Inhibition of Glucocorticoid-induced Apoptosis in 697 Pre-B Lymphocytes by the Mineralocorticoid Receptor N-terminal Domain

Aldosterone Stimulates Gene Expression of Hepatic Gluconeogenic Enzymes through the Glucocorticoid Receptor in a Manner Independent of the Protein Kinase B Cascade

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