title: Acetylation-mediated epigenetic regulation of glucocorticoid receptor activity: circadian rhythm-associated alterations of glucocorticoid actions in target tissues.
abstract: Glucocorticoids influence organ functions through the glucocorticoid receptor, a protein acetylated and deacetylated by several histone acetyltransferases and deacetylases. We reported that the circadian rhythm-related transcription factor "Clock", a key component of the biological CLOCK with inherent histone acetyltransferase activity, acetylates glucocorticoid receptor lysines within its hinge region--a "lysine cluster" containing a KXKK motif--and represses its transcriptional activity. This Clock-induced repression of the glucocorticoid receptor activity is inversely phased to the diurnally circulating glucocorticoids and may act as a local counter regulatory mechanism to the actions of these hormones. Importantly, uncoupling of the central CLOCK-regulated hypothalamic-pituitary-adrenal axis and peripheral CLOCK-mediated alterations of glucocorticoid action, such as chronic stress and frequent trans-time zone travel or night-shift work, may cause functional hypercortisolism and contribute to various pathologies. Thus, acetylation-mediated epigenetic regulation of the glucocorticoid receptor may be essential for the maintenance of proper time-integrated glucocorticoid action, significantly influencing human well-being and longevity.
authors.affiliation: Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 10, CRC, Rm. 1-3140, 10 Center Drive MSC 1109, Bethesda, MD 20892-1109, USA. kinot@mail.nih.gov
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
mesh_terms: D000107:Acetylation / Q000187:drug effects; D056926:CLOCK Proteins / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D009928:Organ Specificity / Q000187:drug effects*; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D056926:CLOCK Proteins