Steroid hormone antagonists at the receptor level: A role for the heat‐shock protein MW 90,000 (hsp 90)

Abstract

Antisteroid hormones compete for hormone binding at the receptor level and prevent the hormonal response. A new concept is proposed for explaining the antiglucocorticosteroid activity of RU 486 in the chick oviduct system. It is based on the ability of the antisteroid to stabilize the hetero-oligomeric 8S-form of the glucocorticosteroid receptor (GR), which involves the interaction of the 94k-receptor and heat-shock protein MW 90,000 (hsp 90). It is proposed that hsp 90 caps the DNA binding site of the receptor, and this prevents it from binding to the DNA of hormone regulatory elements (HRE) and increasing transcription of regulated genes. This paper reviews other antiglucocorticosteroid and antiestrogen systems with reference to this hypothesis and also describes a four-step analysis of the molecular mechanism of antisteroid hormone action at the receptor level.

Sequence and regulation of a gene encoding a human 89-kilodalton heat shock protein.

“…The steroid receptors are also inactive in DNA binding while associated with hsp89 (30,58,66). These observations have led to the suggestion that hsp89 functions in transport of regulatory proteins to their final cellular locations on the membrane or in the nucleus (3,67). It has also been suggested that hsp89 sequesters regulatory proteins in an inactive form after synthesis (3, 25) until they reach their destination within the cell or until the appropriate signal for their activity is received.…”

“…hsp89 appears to stimulate the activity of this enzyme. In avian (3,85) and calf (60) cells, hsp89 has been identified as the non-steroidbinding subunit of the estrogen receptor complex and has since been shown to be a common component of other steroid hormone receptors (33). The steroid-binding component of these receptors appears to be inactive with respect to DNA binding when complexed with hsp89 (30,58,66).…”

Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

“…In short, binding of the corticosteroid hormone to its receptor induces a conformational change which leads to dissociation of the receptor from the attached heat shock protein (HSP90; Baulieu, 1987), activation of nuclear translocation signals and dimerization of activated receptor complexes. The receptor dimer binds to hormone responsive elements of the nuclear DNA and transcription is initiated.…”

Syndromes of glucocorticoid and mineralocorticoid resistance

“…hsp90 seems to be required to maintain receptors in a non-functional state, as well as to ensure the correct receptor conformation to allow ligand binding (32)(33)(34). After ligand binding and hsp90 release, receptors become activated and are able to bind DNA and to modulate transcription (35). Recently it has been shown that other proteins participate in the multimeric receptor complex.…”