Identification of natural human glucocorticoid receptor (hGR) mutations or polymorphisms and their functional consequences at the hormone-receptor interaction level.

Evangelia Charmandari, George P. Chrousos, Tomoshige Kino

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Glucocorticoids regulate a broad spectrum of physiologic functions essential for life and play an important role in the maintenance of basal and stress-related homeostasis. At the cellular level, the actions of glucocorticoids are mediated by the human glucocorticoid receptor alpha (hGRalpha), a ligand-dependent transcription factor ubiquitously expressed in almost all tissues and cells. The molecular mechanisms of hGRalpha action involve (a) binding to glucocorticoids, (b) cytoplasmic to nuclear translocation, (c) binding/association to DNA/chromatin, and (d) transcriptional activation or repression by interacting with cofactors and other transcription factors. Mutations or polymorphisms in the hGR gene may impair these molecular mechanisms of hGRalpha action, thereby altering tissue sensitivity to glucocorticoids. The latter may take the form of glucocorticoid resistance or glucocorticoid hypersensitivity and may be associated with significant morbidity. The identification of natural pathologic mutations in patients' hGR gene and the subsequent examination of the functional defects of the natural mutant hGRalpha receptors would enhance our understanding of the molecular mechanisms of hGRalpha action and highlight the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.

Original languageEnglish
Pages (from-to)33-60
Number of pages28
JournalMethods in molecular biology (Clifton, N.J.)
Volume590
Publication statusPublished - 2009
Externally publishedYes

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Forensic Anthropology
Glucocorticoid Receptors
Hormones
Glucocorticoids
Mutation
Homeostasis
Transcription Factors
Transcriptional Activation
Genes
Chromatin
Hypersensitivity
Maintenance
glucocorticoid receptor alpha
Ligands
Morbidity
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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abstract = "Glucocorticoids regulate a broad spectrum of physiologic functions essential for life and play an important role in the maintenance of basal and stress-related homeostasis. At the cellular level, the actions of glucocorticoids are mediated by the human glucocorticoid receptor alpha (hGRalpha), a ligand-dependent transcription factor ubiquitously expressed in almost all tissues and cells. The molecular mechanisms of hGRalpha action involve (a) binding to glucocorticoids, (b) cytoplasmic to nuclear translocation, (c) binding/association to DNA/chromatin, and (d) transcriptional activation or repression by interacting with cofactors and other transcription factors. Mutations or polymorphisms in the hGR gene may impair these molecular mechanisms of hGRalpha action, thereby altering tissue sensitivity to glucocorticoids. The latter may take the form of glucocorticoid resistance or glucocorticoid hypersensitivity and may be associated with significant morbidity. The identification of natural pathologic mutations in patients' hGR gene and the subsequent examination of the functional defects of the natural mutant hGRalpha receptors would enhance our understanding of the molecular mechanisms of hGRalpha action and highlight the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.",
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