Disruption of the glucocorticoid receptor assembly with heat shock protein 90 by a peptidic antiglucocorticoid

Molecular Endocrinology
H P Dao-PhanP Lefebvre

Abstract

Association of glucocorticoid (GR) and progesterone (PR) receptors with a set of molecular chaperones, including the 90-kDa heat shock protein (hsp90), is a dynamic process required for proper folding and maintaining these nuclear receptors under a transcriptionally inactive, ligand-responsive state. Mutational studies of the chicken hsp90 complementary DNA suggested that three regions of this protein (A, B, and Z) interact with the hormone-binding domain of GR, whereas region A is dispensable for hsp90 binding to PR. We found that this 69-amino acid region can be narrowed down to a 35-mer alpha-helical, acidic peptide, which is by itself able to inhibit hsp90 association to GR translated in vitro. The hsp90-free GR did not bind ligand, but was devoid of any specific DNA-binding activity, and higher peptide concentrations specifically inhibited the binding of activated GR to DNA. When overexpressed in cultured cells, this peptide acted as an antiglucocorticoid and inhibited the antiactivating protein-1 activity and the ligand-dependent nuclear transfer of GR. None of these effects, either in vivo and in vitro, was observed for PR. The region from residue 232 to residue 265 of hsp90 is, therefore, a domain critical for its assoc...Continue Reading

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Citations

Dec 20, 2013·Cell and Tissue Research·Ellaine SalvadorCarola Förster
Jul 22, 2004·Annals of the New York Academy of Sciences·Salvatore AlesciIoannis Ilias
Apr 24, 2002·Pulmonary Pharmacology & Therapeutics·Shelby P UmlandSebastian L Johnston

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