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Figure 2 | BMC Endocrine Disorders

Figure 2

From: Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor

Figure 2

Μolecular mechanisms through which the natural mutant receptor hGRαV423A causes Chrousos syndrome. Both the wild-type hGRα and the mutant hGRαV423A reside in the cytoplasm in the absence of ligand by forming a heterocomplex with heat shock proteins (HSP) and FKBP51 (FKBP). Upon binding to ligand, the wild-type hGRα dissociates from the heterocomplex partners and translocates into the nucleus, while this process of the mutant hGRαV423A is significantly delayed. The wild-type hGRα stimulates or represses the transcriptional activity of glucocorticoid-responsive genes by attracting to GRE DNA several coactivators including the glucocorticoid receptor-interacting protein 1 (GRIP-1), or by interacting with other transcription factors, such as NF-κB and activator protein-1 (AP-1). The hGRαV423A demonstrates reduced transactivation activity due to decreased ability to interact with GREs, while its activity to repress the transcriptional activity of other transcription factors is preserved. The hGRαV423A does not exert a dominant negative effect upon the wild type-induced transactivation of glucocorticoid-responsive genes. WT: wild-type human glucocorticoid receptor; V423A: human glucocorticoid receptor V423A; HSP: heat shock proteins; FKBP: immunophilins; GRIP-1: glucocorticoid receptor-interacting protein 1; p65: transcription factor p65; p50: transcription factor p50.

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BMC Endocrine Disorders

ISSN: 1472-6823

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