Glucocorticoids: Synthesis and molecular mechanisms of action

Professor Evangelia Charmandari

Professor of Pediatrics – Pediatric and Adolescent Endocrinology
National and Kapodistrian University of Athens Medical School
First Department of Pediatrics, ‘Aghia Sophia’ Children’s Hospital

In humans, glucocorticoids regulate a broad spectrum of physiological 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 glucocorticoid receptor (GR), which functions as a ligand-dependent transcription factor that regulates the expression of glucocorticoid-responsive genes positively or negatively.

In her studies, Professor Evangelia Charmandari investigated the molecular mechanisms of glucocorticoid action, as well as the interaction of hGR with other transcription factors. She also investigated the molecular mechanisms underlying the dominant negative effect of the hGRβ upon the hGRα, and showed that hGRβ suppresses the transcriptional activity of hGRα by competing with hGRα for binding to coactivators.

More recently, she supervised studies that investigated the molecular mechanisms underlying the non-genomic actions of glucocorticoids, and in particular the role of S-palmitoylation, as well as the effects of antenatal stress obesity on leukocyte telomere length. She also determined the transcriptomic profile of patients with increased glucocorticoid sensitivity compared with healthy volunteers.

Finally, she supervised studies that investigated the in vivo role of hGRβ and Gas5 in glucocorticoid signal transduction in transgenic mice transiently overexpressing hGRβ and Gas5, respectively. The findings of these studies might lead to the development of new strategies and/or pharmaceutical approaches for the management of glucocorticoid-treated disorders.

14. Nicolaides NC, Polyzos A, Koniari E, Lamprokostopoulou A, Papageorgiou I, Golfinopoulou E, Papathanasiou C, Sertedaki A, Thanos D, Chrousos GP, Charmandari E. Transcriptomics in tissue glucocorticoid sensitivityEuropean Journal of Clinical Investigation 2019; e13129.

13. Nicolaides NC, Charmandari E. Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromesHormones (Athens). 2017; 16(2): 124-138.

12. Nicolaides NC, Kino T, Roberts ML, Katsantoni E, Sertedaki A, Moutsatsou P, Psarra AG, Chrousos GP, Charmandari E. The role of S-palmitoylation of the human glucocorticoid receptor (hGR) in mediating the nongenomic glucocorticoid actionsJournal of Molecular Biochemistry 2017; 6(1): 3-12.

11. Nicolaides NC, Charmandari E, Chrousos GP, Kino T. Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptorBMC Endocrine Disorders 2014; 14: 71.

10. Charmandari E, Nicolaides N, Chrousos GP. Adrenal InsufficiencyLancet 2014; 383(9935): 2152-67.

9.Kino T, Charmandari E, Chrousos GP. Glucocorticoid receptor: Implications for rheumatic diseasesClinical and Experimental Rheumatology, 2011; 29(5 Suppl 68): S32-41.

8. Charmandari E, Chrousos GP, Lambrou GI, Pavlaki A, Koide H, Ng SSM, Kino T. Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man. PLoS One 2011; 6(9): e25612.

7. Nicolaides N, Galata Z, Chrousos GP, Charmandari EThe glucocorticoid receptor: Evolution, structure and molecular basis of biologic functionSteroids 2010; 75(1): 1-12.

6. Kino T, Souvatzoglou E, Charmandari E, Ichijo T, Driggers P, Mayers C, Alatsatianos A, Manoli I, Westphal H, Chrousos GP, Segars JH. RHO family guanine nucleotide exchange factor BRX couples extracellular signals to the glucocorticoid signaling systemJournal of Biological Chemistry 2006; 281(14): 9118-9126.

5. Kino T, DeMartino MU, Charmandari E, Outas T, Ichijo T, Pavlakis GN, Chrousos GP. The human immunodeficiency virus type-1 (HIV-1) accessory protein Vpr inhibits the effect of insulin on the Foxo subfamily of Forkhead transcription factors by interfering with their binding to 14-3-3 proteins: Potential clinical implications regarding the insulin resistance of HIV-1-infected patientsDiabetes 2005; 54(1): 23-31.

4. Charmandari E, Chrousos GP, Ichijo T, Bhattacharyya N, Vottero A, Souvatzoglou E, Kino T. The human glucocorticoid receptor (GR) β isoform suppresses the transcriptional activity of GRα by interfering with formation of active coactivator complexesMolecular Endocrinology 2005; 19(1): 52-64.

3. Charmandari E, Kino T, Chrousos GP. Glucocorticoids and their actionsAnnals of the New York Academy of Sciences 2004; 1024: 1-8.

2. Chrousos GP, Charmandari E, Kino T. Glucocorticoid action networks: An introduction to systems biologyJournal of Clinical Endocrinology & Metabolism 2004; 89(2): 563-564.

1. Kino T, Charmandari E, Chrousos GP. Basic and clinical implications of glucocorticoi15gd action – Focus on development: Conference ProceedingsHormone and Metabolic Research 2003; 35(10): 628-648.