Glucocorticoid receptor signaling in health and disease

Kadmiel, Mahita; Cidlowski, John A.

doi:10.1016/j.tips.2013.07.003

Cited by 702 publications

(624 citation statements)

References 105 publications

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“…Cortisol acts via the GC receptor in a physiological negative-feedback loop on the hypothalamopituitary-adrenal (HPA) axis to inhibit further cortisol synthesis [ 65 ]. Exogenous GCs inhibit the HPA axis in the same way [ 10 ].…”

Section: Adrenal Suppressionmentioning

confidence: 99%

The Prediction and Monitoring of Toxicity Associated with Long-Term Systemic Glucocorticoid Therapy

et al. 2015

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Glucocorticoids are often required for adequate control of inflammation in many serious inflammatory diseases; common indications for long-term treatment include polymyalgia rheumatica, giant cell arteritis, asthma and chronic obstructive pulmonary disease. Long-term glucocorticoid therapy is, however, associated with many adverse effects involving skin, gastrointestinal, eye, skeletal muscle, bone, adrenal, cardio-metabolic and neuropsychiatric systems. This balance between benefits and risks of glucocorticoids is important for clinical practice and glucocorticoid-related adverse effects can significantly impair health-related quality of life. Understanding the nature and mechanisms of glucocorticoid-related adverse effects may inform how patients are monitored for toxicity and identify those groups, such as older people, that may need closer monitoring. For clinical trials in diseases commonly treated with glucocorticoids, standardised measurement of glucocorticoid-related adverse effects would facilitate future evidence synthesis and meta-analysis.

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Section: Adrenal Suppressionmentioning

confidence: 99%

The Prediction and Monitoring of Toxicity Associated with Long-Term Systemic Glucocorticoid Therapy

et al. 2015

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“…1A). GR down-regulates the transcription of many antiinflammatory genes, making GR agonists a mainstay of treatment of diseases such as asthma and arthritis (15). However, GR's closest paralog, the mineralocorticoid receptor (MR), causes a proinflammatory transcriptional state when activated (16).…”

mentioning

confidence: 99%

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Hudson

Kossmann

Vera

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Many genomes contain families of paralogs-proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and negative glucocorticoid response elements (nGREs). We show that binding to nGREs is a property of the glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other members of the steroid receptor family. Using phylogenetic, structural, biochemical, and molecular dynamics techniques, we show that the ancestral DBD from which GR and its paralogs evolved was capable of binding both nGRE and (+)GRE sequences because of the ancestral DBD's ability to assume multiple DNA-bound conformations. Subsequent amino acid substitutions in duplicated daughter genes selectively restricted protein conformational space, causing this dual DNA-binding specificity to be selectively enhanced in the GR lineage and lost in all others. Key substitutions that determined the receptors' response elementbinding specificity were far from the proteins' DNA-binding interface and interacted epistatically to change the DBD's function through DNA-induced allosteric mechanisms. These amino acid substitutions subdivided both the conformational and functional space of the ancestral DBD among the present-day receptors, allowing a paralogous family of transcription factors to control disparate transcriptional programs despite high sequence identity.evolution | glucocorticoid | epistasis | steroid receptors

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“…The glucocorticoids (GCs) induce immunosuppressive and anti-inflammatory effects predominantly through binding to the glucocorticoid receptor (GCR) [18]. It is known that dexamethasone and other GCs can modulate the immune system in a wide variety of ways, with varying mechanisms of action in different cell types [19,20].…”

Section: Biological Backgroundmentioning

confidence: 99%

Immuno-radiotherapy for brain metastases

Denaro¹,

Occelli²,

maria³

et al. 2017

Int Med Care

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Brain metastases (BM) are a lethal consequence of systemic dissemination of cancer. The most common malignancies that metastasize to the brain are lung, breast, and melanoma. Eighty percent of patients present with brain metastases within the cerebral hemispheres; 15% are within the cerebellar hemispheres and 5% are within the brainstem. The incidence of brain metastases is increasing because of better detection from improved imaging techniques (also for staging asymptomatic patients), and more effective systemic treatment regimens that can prolong life, permitting the cancer to disseminate to the brain, a sanctuary site.

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Glucocorticoid receptor signaling in health and disease

Cited by 702 publications

References 105 publications

The Prediction and Monitoring of Toxicity Associated with Long-Term Systemic Glucocorticoid Therapy

The Prediction and Monitoring of Toxicity Associated with Long-Term Systemic Glucocorticoid Therapy

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Immuno-radiotherapy for brain metastases

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