Transformation of glucocorticoid and progesterone receptors to the DNA‐binding state

Abstract

This brief review explores some recent observations relating to the structure of untransformed glucocorticoid and progesterone receptors and the mechanism by which the receptors are transformed to the DNA-binding state. In their molybdatestabilized, untransformed state, progesterone and glucocorticoid receptors exist as a heteromeric 8-9S complex containing one unit of steroid binding phosphoprotein and one or two units of the 90 kD heat shock protein hsp90. When the receptors are transformed, the steroid-binding protein dissociates from hsp90. In cytosol preparations, temperature-mediated dissociation proceeds much more rapidly in the presence of hormone. The dissociated receptor binds to DNA with high affinity, regardless of whether it is in the hormone-bound or the hormone-free state. These observations raise the possibility that the primary, and perhaps the only, role for the hormone is to promote dissociation of the receptor-hsp90 complex. Molybdate, vanadate, and tungstate inhibit receptor transformation to the DNA-binding form, an effect that appears to reflect the ability of these transition metal oxyanions to stabilize the complex between the steroid receptor and hsp90. By promoting the formation of disulfide bonds, hydrogen peroxide also stabilizes the glucocorticoid receptor-hsp90 complex and prevents receptor transformation. A small, heat-stable factor present in all cytosol preparations inhibits receptor transformation, and, when the factor is removed, glucocorticoid receptors are rapidly transformed. This ubiquitous factor has the physical properties of a metal anion, and it is proposed that molybdate and vanadate affect steroid receptor complexes by interacting with a metal anion-binding site that is normally occupied by this endogenous receptor-stabilizing factor.

Do heat shock proteins have a role in breast cancer?

“…The association of hsp90 and breast cancer is of considerable interest, following studies showing the association of hsp90 and steroid receptors (Pratt, 1987;Shyamala et al, 1989).…”

Aldosterone and dexamethasone stimulate calcineurin activity through a transcription-independent mechanism involving steroid receptor-associated heat shock proteins.

“…The binding of hormone to the receptor complex stimulates the release of HSPs followed by transnuclear migration and DNA binding of the activated receptor (1). The role of HSPs in receptor function is unknown, but recent studies indicate that HSP-90 facilitates anchoring of unbound glucocorticoid and mineralocorticoid receptors to the cytoskeleton and maintains the hormone binding protein in a high affinity conformation (2,3).…”

Tetrameric structure of the nonactivated glucocorticoid receptor in cell extracts and intact cells

“…It contains only one hormone-binding potypeptide of Mr -I00000 per complex [7,8]. We now know that the heat shock protein hsp90 is a constituent of the heteromeric gtucocorticoid receptor structure [4,6,9,10]: it may be present as Abbreviations: DMS, dimethyl suberimidate; nt i, receptor of 'increased nuclear transfer'; PAGE, polyacrylamide gel electrophoresis a dimer [5,11,12]. The involvement of other molecular components is less clear.…”