ESPE Abstracts (2018) 89 S6.3

Chemical Modification of the Glucocorticoid Receptor as a Determinant of Tissue Glucocorticoid Sensitivity: Implications to Circadian Rhythms, Stress Response and Treatment of Pediatric Leukemia

Tomoshige Kino

Sidra Medicine, Doha, Qatar

Glucocorticoid hormones virtually influence all human functions both in a basal homeostatic condition and under stress. Thus, many other biological pathways adjust glucocorticoid actions in local tissues (tissue glucocorticoid sensitivity) by targeting the single receptor molecule glucocorticoid receptor (GR) as part of the regulatory loop coordinating complex human functions. Among them, chemical modification of GR, such as by acetylation and phosphorylation, is highlighted as one of the important molecular mechanisms for changing local glucocorticoid actions. For example, the circadian transcription factor CLOCK acetylates GR, and participates in the reverse synchronization of local glucocorticoid sensitivity against circadian fluctuation of circulating cortisol. The cyclin-dependent kinase 5 (CDK5) phosphorylates several serine residues of the GR and modulates local glucocorticoid actions in the brain, and participates in the adaptive stress response and pathophysiology of mood disorders. Further, aberrantly activated v-akt murine thymoma viral oncogene homolog 1 (AKT1) develops glucocorticoid resistance in pediatric acute lymphoblastic leukemia by phosphorylating serine 134 of the GR and by inhibiting its cytoplasmic to nuclear translocation in cooperation with 14-3-3 proteins. I review recent progress in the research investigating chemical modification of GR as a determinant of tissue glucocorticoid sensitivity and discuss its physiologic or pathophysiologic implications.

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