Coactivation of the N-terminal Transactivation of Mineralocorticoid Receptor by Ubc9

Yokota, Kenichi; Shibata, Hirotaka; Kurihara, Isao; Kobayashi, Sakiko; Suda, Norio; Murai‐Takeda, Ayano; Saito, Ikuo; Kitagawa, Hirochika; Kato, Shigeaki; Saruta, Takao; Itoh, Hiroshi

doi:10.1074/jbc.m607741200

Cited by 76 publications

(57 citation statements)

References 58 publications

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“…Multiple factors regulate sodium balance; in this study, we focused on mineralocorticoid receptor (MR). In recent studies, we identified novel coregulators of MR3, 4 and proposed a new pathological condition associated with aberrant MR activation, designated MR‐associated hypertension 5…”

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confidence: 99%

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

Nakamura

Kurihara

Kobayashi

et al. 2018

JAHA

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BackgroundMineralocorticoid receptor (MR) has pathological roles in various cell types, including renal tubule cells, myocytes, and smooth muscle cells; however, the role of MR in intestinal epithelial cells (IECs) has not been sufficiently evaluated. The intestine is the sensing organ of ingested sodium; accordingly, intestinal MR is expected to have essential roles in blood pressure (BP) regulation.Methods and ResultsWe generated IEC‐specific MR knockout (IEC‐MR‐KO) mice. With a standard diet, fecal sodium excretion was 1.5‐fold higher in IEC‐MR‐KO mice, with markedly decreased colonic expression of β‐ and γ‐epithelial sodium channel, than in control mice. Urinary sodium excretion in IEC‐MR‐KO mice decreased by 30%, maintaining sodium balance; however, a low‐salt diet caused significant reductions in body weight and BP in IEC‐MR‐KO mice, and plasma aldosterone exhibited a compensatory increase. With a high‐salt diet, intestinal sodium absorption markedly increased to similar levels in both genotypes, without an elevation in BP. Deoxycorticosterone/salt treatment elevated BP and increased intestinal sodium absorption in both genotypes. Notably, the increase in BP was significantly smaller in IEC‐MR‐KO mice than in control mice. The addition of the MR antagonist spironolactone to deoxycorticosterone/salt treatment eliminated the differences in BP and intestinal sodium absorption between genotypes.ConclusionsIntestinal MR regulates intestinal sodium absorption in the colon and contributes to BP regulation. These regulatory effects are associated with variation in epithelial sodium channel expression. These findings suggest that intestinal MR is a new target for studying the molecular mechanism of hypertension and cardiovascular diseases.

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Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

Nakamura

Kurihara

Kobayashi

et al. 2018

JAHA

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“…We have previously reported that Ubc9 functions as a coactivator of MR by forming a complex with the MR N terminus and SRC-1, independently of its E2 SUMO-1-conjugating enzyme activity (17). In this study, we have identified NF-YC as a novel molecular partner of MR using a yeast two-hybrid screening with a full-length MR. NF-Y is a ubiquitous heterotrimeric transcription factor, composed of NF-YA, NF-YB, and NF-YC subunits, which recognizes a CCAAT box motif found in many eukaryotic promoter and enhancer elements (18 -22).…”

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confidence: 81%

“…Plasmid Constructs-Several MR fragments, such as MR-(1-984), MR-(1-670), and MR-(671-984), were subcloned into pGBKT7, pcDNA3.1/His, and pDsRed vectors as described previously (17). MR-(602-984) was subcloned into pGBKT7.…”

Section: Methodsmentioning

confidence: 99%

“…293-MR cells stably expressing human MR have been established and described in detail previously (17).…”

Section: Methodsmentioning

confidence: 99%

“…MR ligand-binding domain interacts strongly with only a few specific coactivator peptides, such as p160 family coacti-* This work was supported by an investigator-initiated research grant from vators, steroid receptor coactivator-1 (SRC-1), SRC-2, and SRC-3, activating signal cointegrator 2, and peroxisome proliferator-activated receptor ␥ coactivator-1␣ in the presence of aldosterone (9,(13)(14)(15). In addition, several coactivators, such as RHA (16), ELL (12), and Ubc9 (17), interact with the MR N-terminal AF-1 domain. It is now recognized that coregulators play an important role in a range of diseases, including cancer, inflammatory disease, and metabolic disorders.…”

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confidence: 99%

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NF-YC Functions as a Corepressor of Agonist-bound Mineralocorticoid Receptor

Murai‐Takeda

Shibata

Kurihara

et al. 2010

Journal of Biological Chemistry

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The Multifaceted Mineralocorticoid Receptor

Gómez-Sánchez

2014

Comprehensive Physiology

277

224

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The primary adrenal cortical steroid hormones, aldosterone, and the glucocorticoids cortisol and corticosterone, act through the structurally similar mineralocorticoid (MR) and glucocorticoid receptors (GRs). Aldosterone is crucial for fluid, electrolyte, and hemodynamic homeostasis and tissue repair; the significantly more abundant glucocorticoids are indispensable for energy homeostasis, appropriate responses to stress, and limiting inflammation. Steroid receptors initiate gene transcription for proteins that effect their actions as well as rapid non-genomic effects through classical cell signaling pathways. GR and MR are expressed in many tissues types, often in the same cells, where they interact at molecular and functional levels, at times in synergy, others in opposition. Thus the appropriate balance of MR and GR activation is crucial for homeostasis. MR has the same binding affinity for aldosterone, cortisol, and corticosterone. Glucocorticoids activate MR in most tissues at basal levels and GR at stress levels. Inactivation of cortisol and corticosterone by 11β-HSD2 allows aldosterone to activate MR within aldosterone target cells and limits activation of the GR. Under most conditions, 11β-HSD1 acts as a reductase and activates cortisol/corticosterone, amplifying circulating levels. 11β-HSD1 and MR antagonists mitigate inappropriate activation of MR under conditions of oxidative stress that contributes to the pathophysiology of the cardiometabolic syndrome; however, MR antagonists decrease normal MR/GR functional interactions, a particular concern for neurons mediating cognition, memory, and affect.

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Coactivation of the N-terminal Transactivation of Mineralocorticoid Receptor by Ubc9

Cited by 76 publications

References 58 publications

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

NF-YC Functions as a Corepressor of Agonist-bound Mineralocorticoid Receptor

The Multifaceted Mineralocorticoid Receptor

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