Interaction of the glucocorticoid receptor with the Mr 90,000 heat shock protein: an evolving model of ligand-mediated receptor transformation and translocation.
Reports from several laboratories support a model for glucocorticoid receptor (GR) transformation in cytosol in which a heteromeric 9S complex of GR and the Mr 90,000 heat shock protein undergo a temperature-dependent and hormone-promoted dissociation to yield the free DNA-binding form of the receptor. In this paper, we review evidence that the 9S heteromeric complex is derived from the normal inactive state of the receptor in the intact cell and that both Mr 90,000 heat shock protein and the untransformed GR localize by immunofluorescence with specific monoclonal antibodies to microtubules in a variety of cell types in culture. We propose that an association with cytoskeleton may be required for translocating the GR from its cytoplasmic site of synthesis to its nuclear site of action and that the 9S complex is derived from this cytoskeleton-associated form. Similar molybdate-stabilized 9S complexes can be obtained for all of the steroid receptors, several of which clearly are localized to the nucleus prior to exposure to hormone. These receptors may have moved to the terminus of the translocation pathway where they remain in a cytoskeleton-bound "docking" position. We speculate that, in the intact cell, ligand-dependent dissociation of Mr 90,000 heat shock protein permits the steroid receptors to progress by some ordered mechanism to their high affinity sites of action within the nucleus.
Pratt
W B
WB
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
Sanchez
E R
ER
Bresnick
E H
EH
Meshinchi
S
S
Scherrer
L C
LC
Dalman
F C
FC
Welsh
M J
MJ
D000818:Animals; D001692:Biological Transport; D004247:DNA / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008961:Models, Structural; D008970:Molecular Weight; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction; D014404:Tubulin / Q000378:metabolism
D006360:Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; D014404:Tubulin; D004247:DNA