Glucocorticoid and mineralocorticoid resistance/hypersensitivity syndromes

Kino, Tomoshige; Chrousos, G. P.

doi:10.1677/joe.0.1690437

Cited by 102 publications

(75 citation statements)

References 65 publications

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“…Irritability and weakness were also reported as symptoms in affected individuals. The clinical picture can vary from mild to severe (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.

Raef¹,

Baitei²,

Zou³

et al. 2008

European Journal of Endocrinology

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Objective: Glucocorticoid resistance is a rare sporadic or familial condition that is characterized by generalized, partial resistance to glucocorticoids. It is caused by a mutation in the glucocorticoid receptor-a (GR-a) gene. We aimed to understand the reasons for different phenotypes (severe to asymptomatic) observed in a family with primary cortisol resistance. Design: The genotype leading to cortisol resistance in the family members was investigated and correlated to the clinical phenotype. Method: Three siblings were presented with clinical cortisol resistance, featuring severe hypertension, hypokalemia and hyperandrogenism. Three other siblings and both parents were asymptomatic. Genomic DNA from peripheral lymphocytes was isolated from family members. The entire GR-a coding sequence (exons 2-9) was amplified by PCR and sequenced. Results: A homozygous G679S mutation was present in the three clinically affected subjects. Heterozygous G66A (E22E) and G68A (R23K) polymorphisms and G2035A (G679S) mutation were found in the father and two siblings. Mother and one sibling had only heterozygous G679S mutation. The clinically unaffected subjects showed two different responses to dexamethason. Those with heterozygous G679S mutation and ER22/23EK polymorphism had normal cortisol suppression, whereas those with only heterozygous G679S mutation failed to suppress normally. Conclusions: A homozygous G679S mutation of the GR-a gene is associated with severe cortisol resistance, whereas a heterozygous mutation of the same gene can lead to subclinical cortisol resistance. The effect of the heterozygous mutation was abolished in subjects carrying the ER22/23EK polymorphism.

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“…Irritability and weakness were also reported as symptoms in affected individuals. The clinical picture can vary from mild to severe (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.

Raef¹,

Baitei²,

Zou³

et al. 2008

European Journal of Endocrinology

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“…This implies that resistance to GC-induced apoptosis may occur by reducing GR␣ levels. In humans, GC resistance can occur by two major mechanisms: loss-of-function mutations in GR␣ (15), or by increased expression of GR␤, which acts as a dominant-negative inhibitor to GR␣ (11). Although GR␣ mutations can result in a type of GC resistance that is both systemic and severe, these mutations are rare.…”

mentioning

confidence: 99%

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

Stechschulte

Wuescher

Marino

et al. 2014

Journal of Biological Chemistry

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Background:The glucocorticoid receptor ␤ (GR␤) is a positive regulator of growth. Results: GR␤ suppression of PTEN resulted in enhanced phosphorylation of Akt and growth. Conclusion: GR␤ enhances insulin-induced proliferation by suppressing PTEN and activating Akt1. Significance: GR␤ suppression of PTEN indicates that it has an important role in growth factor signaling and potentially cancer.

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“…ance of the inflamed tissues to glucocorticoids (14,16,17). In addition, the acute respiratory distress syndrome and septic shock have been associated with systemic glucocorticoid resistance (18).…”

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confidence: 99%

Tumor Necrosis Factor α Receptor- and Fas-associated FLASH Inhibit Transcriptional Activity of the Glucocorticoid Receptor by Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators

Kino

Chrousos

2003

Journal of Biological Chemistry

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Tumor necrosis factor ␣ (TNF␣) and its downstream transcription factor nuclear factor B (NF-B) suppress glucocorticoid action, contributing to tissue resistance to glucocorticoids in several pathologic inflammatory states. p160 nuclear receptor coactivators on the other hand, contribute to the transcriptional signal of the glucocorticoid receptor (GR) through interaction with it via LXXLL motifs in their nuclear receptor-binding (NRB) domain. To discover TNF␣-induced factors that regulate GR activity at the coactivator level, we performed yeast two-hybrid screening using the NRB domain of the glucocorticoid receptor-interacting protein 1 (GRIP1) as bait. We found that FLICE-associated huge protein (FLASH), which transduces TNF␣ and Fas ligand signals, bound the NRB domain of GRIP1 at a region between the second and third LXXLL motifs. FLASH suppressed both GR transactivation and GRIP1 enhancement of the glucocorticoid signal and inhibited the physical interaction between GR and the GRIP1 NRB domain. Transfected green fluorescent proteinfused FLASH was located in both the cytoplasm and nucleus, while endogenous FLASH shifted its subcellular localization from the cytoplasm into the nucleus in response to TNF␣. FLASH antisense and super-repressor IB␣ inhibited the action of TNF␣ independently of each other and additively. These findings indicate that FLASH participates in TNF␣-induced blockade of GR transactivation at the nuclear receptor coactivator level, upstream and independently of NF-B.

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Glucocorticoid and mineralocorticoid resistance/hypersensitivity syndromes

Abstract: Glucocorticoids and mineralocorticoids regulate diverse functions important to maintain central nervous system, cardiovascular, metabolic, and immune homeostasis.

Cited by 102 publications

References 65 publications

Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.

Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

Tumor Necrosis Factor α Receptor- and Fas-associated FLASH Inhibit Transcriptional Activity of the Glucocorticoid Receptor by Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators

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