A Serine/Threonine-rich Motif Is One of Three Nuclear Localization Signals That Determine Unidirectional Transport of the Mineralocorticoid Receptor to the Nucleus

Walther, Rhian F.; Atlas, Ella; Carrigan, Amanda; Rouleau, Y; Edgecombe, Allison; Visentin, Laura; Lamprecht, Claudia; Addicks, Gregory C.; Haché, Robert J.G.; Lefebvre, Yvonne A.

doi:10.1074/jbc.m501548200

Cited by 64 publications

(71 citation statements)

References 64 publications

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“…Furthermore, after ligand binding, mammalian MR is translocated into nucleus in response to NLS (59). There are three known NLS in human MR (60), Sequence comparison between chicken and human MR revealed that there is 84.6%, 93%, and 100% homology between human and chicken NLS1, NLS2, and NLS3, respectively.…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of chicken glucocorticoid and mineralocorticoid receptors

Proszkowiec‐Weglarz

Porter

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Glucocorticoid (GR) and mineralocorticoid (MR) receptors are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Little is known about the function of GR and MR in avian species. Recently, the chicken homologue of the GR (cGR) gene was cloned, and its tissue-specific expression was characterized, whereas the full-length sequence of the chicken MR (cMR) gene remains unknown. Therefore, the aims of this project were to clone the full-length cMR and to functionally characterize both chicken receptors. Cos-7 cells were transiently transfected with cGR or cMR expression vectors along with a glucocorticoid response element-luciferase (GRE-Luc) reporter construct. Transfected cells were then treated with increasing doses of corticosterone (CORT) or aldosterone (ALDO) alone and with GR or MR antagonists (ZK98299 and spironolactone, respectively). Transactivation of cGR or cMR was evaluated by luciferase assay. CORT and ALDO induced cGR- and cMR-driven transcriptional activity in a dose-dependent manner. Each receptor responded to both steroids, but cMR transcriptional activity was induced by lower levels of CORT and ALDO than cGR. Coexpression of both chicken corticosteroid receptors in Cos-7 cells had no synergistic or additive effect on CORT- or ALDO-induced transcriptional activity. Corticosteroid-dependent transactivation of cGR and cMR was partially blocked by antagonists. ZK98299 showed high specificity to cGR, while spironolactone had agonist properties toward both receptors. Immunocytochemistry was used to assess the cellular localization of both receptors. Corticosteroids induced translocation of both receptors into the nucleus. The functional properties of cGR and cMR determined in this study will be helpful in defining the physiological roles of GR and MR in avian species.

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Section: Discussionmentioning

confidence: 99%

Functional characterization of chicken glucocorticoid and mineralocorticoid receptors

Proszkowiec‐Weglarz

Porter

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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“…5). Ligand-bound MR is transported into the nucleus, where it binds to specific hormone response elements (Drouin et al, 1992; Walther et al, 2005), which are located up to 10 kb upstream or downstream from the transcriptional start site of target genes and regulates transcriptional activity (Wang et al, 2004;van der Laan et al, 2008). Taken together, these results suggest that HDAC increases the transcriptional activity by deacetylation of MR in SHRs, whereas HDACi prevents action of MR by acetylation of MR in SHRs.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibition Attenuates Cardiac Hypertrophy and Fibrosis through Acetylation of Mineralocorticoid Receptor in Spontaneously Hypertensive Rats

et al. 2015

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Inhibition of histone deacetylases (HDACs) by valproic acid (VPA) attenuates inflammatory, hypertrophic, and fibrotic responses in the hearts of spontaneously hypertensive rats (SHRs); however, the molecular mechanism is still unclear. We hypothesized that HDAC inhibition (HDACi) attenuates cardiac hypertrophy and fibrosis through acetylation of mineralocorticoid receptor (MR) in SHRs. Seven-week-old SHRs and Wistar-Kyoto rats were treated with an HDAC class I inhibitor (0.71% w/v in drinking water; VPA) for 11 weeks. Sections of heart were visualized after trichrome stain as well as H&E stain. Histone modifications, such as acetylation (H3Ac [acetylated histone 3]) and fourth lysine trimethylation (H3K4me3) of histone 3, and recruitment of MR and RNA polymerase II (Pol II) into promoters of target genes were measured by quantitative real-time polymerase chain reaction after chromatin immunoprecipitation assay. MR acetylation was determined by Western blot with anti-acetyl-lysine antibody after immunoprecipitation with anti-MR antibody. Treatment with VPA attenuated cardiac hypertrophy and fibrosis. Although treatment with VPA increased H3Ac and H3K4me3 on promoter regions of MR target genes, expression of MR target genes as well as recruitment of MR and Pol II on promoters of target genes were decreased. Although HDACi did not affect MR expression, it increased MR acetylation. These results indicate that HDACi attenuates cardiac hypertrophy and fibrosis through acetylation of MR in spontaneously hypertensive rats.

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“…In the absence of ligand the vast majority of cells showed a predominantly cytosolic MR localization (Fig. 2, A and C) as previously described (7,8). Mutations S839D or S839E did not change naïve MR subcellular localization (Fig.…”

Section: Resultsmentioning

confidence: 52%

Phosphorylation of Mineralocorticoid Receptor Ligand Binding Domain Impairs Receptor Activation and Has a Dominant Negative Effect over Non-phosphorylated Receptors

Jimenez-Canino¹,

Fernandes

Rosa

2016

Journal of Biological Chemistry

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Post-translational modification of steroid receptors allows fine-tuning different properties of this family of proteins, including stability, activation, or interaction with co-regulators. Recently, a novel effect of phosphorylation on steroid receptor biology was described. Phosphorylation of human mineralocorticoid receptor (MR) on Ser-843, a residue placed on the ligand binding domain, lowers affinity for agonists, producing inhibition of gene transactivation. We now show that MR inhibition by phosphorylation occurs even at high agonist concentration, suggesting that phosphorylation may also impair coupling between ligand binding and receptor activation. Our results demonstrate that agonists are able to induce partial nuclear translocation of MR but fail to produce transactivation due at least in part to impaired co-activator recruitment. The inhibitory effect of phosphorylation on MR acts in a dominant-negative manner, effectively amplifying its functional effect on gene transactivation.Steroid receptors (SRs) 3 are part of the nuclear receptor superfamily of ligand-dependent transcription factors that modulate gene transcription in response to changes in steroid hormone levels (1). SRs present a modular architecture, with three well defined domains: an NH 2 -terminal activation domain (NTD), a central DNA binding domain, and a COOHterminal ligand binding domain (LBD). Generally, the apo receptor resides in the cytosol forming a heterocomplex with other proteins including chaperones such as heat-shock protein 90 (Hsp90). Ligand binding alters SR conformation, releasing it from the complex and promoting translocation to the nucleus, where it binds specific DNA sequences as a dimer and alters transcription of target genes by recruiting transcriptional co-regulators (2). Post-translational modifications, including phosphorylation, ubiquitylation, sumoylation, and acetylation, modulate SR stability and different steps on the activation pathway, including receptor dimerization, DNA binding, and interaction with co-regulators (3).Until recently, it was widely assumed that SR ligand affinity is an intrinsic property defined by the structure of the LBD and not subject to modulation by post-translational modifications. However, Shibata et al. (4) have shown that regulated phosphorylation of Ser-843 in the LBD of human mineralocorticoid receptor (MR), a canonical member of the SR subfamily of nuclear receptors, impairs its ability to mediate gene transactivation by lowering ligand affinity. MR is closely related to the glucocorticoid receptor (GR) and can be activated under physiological conditions by mineralocorticoids such as aldosterone and glucocorticoids such as cortisol or corticosterone. MR has a wide variety of physiological and pathophysiological functions, with a prominent role in regulating transepithelial ion and fluid transport, which is essential for extracellular volume homeostasis and, therefore, blood pressure control. Phosphorylation of MR Ser-843 is restricted to intercalated cells of the distal ...

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A Serine/Threonine-rich Motif Is One of Three Nuclear Localization Signals That Determine Unidirectional Transport of the Mineralocorticoid Receptor to the Nucleus

Cited by 64 publications

References 64 publications

Functional characterization of chicken glucocorticoid and mineralocorticoid receptors

Functional characterization of chicken glucocorticoid and mineralocorticoid receptors

Histone Deacetylase Inhibition Attenuates Cardiac Hypertrophy and Fibrosis through Acetylation of Mineralocorticoid Receptor in Spontaneously Hypertensive Rats

Phosphorylation of Mineralocorticoid Receptor Ligand Binding Domain Impairs Receptor Activation and Has a Dominant Negative Effect over Non-phosphorylated Receptors

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