Aluminum fluoride inhibition of glucocorticoid receptor inactivation and transformation.
Fluoride, in the presence of aluminum ions, reversibly inhibits the temperature-mediated inactivation of unoccupied glucocorticoid receptors in cytosol preparations from mouse L cells. The effect is concentration-dependent, with virtually complete stabilization of specific glucocorticoid-binding capacity at 2 mM fluoride and 100 microM aluminum. These concentrations of aluminum and fluoride are ineffective when used separately. Aluminum fluoride also stabilizes receptors toward inactivation by gel filtration and ammonium sulfate precipitation. Aluminum fluoride prevents temperature-dependent transformation of steroid-receptor complexes to the DNA-binding state. Aluminum fluoride does not inhibit calf intestine alkaline phosphatase, and unoccupied receptors inactivated by this enzyme in the presence of aluminum fluoride can be completely reactivated by dithiothreitol. The effects of aluminum fluoride are due to stabilization of the complex between the glucocorticoid receptor and the 90-kDa mammalian heat-shock protein hsp90, which suggests that aluminum fluoride interacts directly with the receptor. Endogenous thermal inactivation of receptors in cytosol is not accompanied by receptor dephosphorylation. However, inactivation is correlated with dissociation of hsp90 from the unoccupied receptor. These results support the proposal that hsp90 is required for the receptor to bind steroid and dissociation of hsp90 is sufficient to inactivate the unoccupied receptor.
Department of Pharmacology, University of South Carolina School of Medicine, Columbia 29208.
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Housley
D000535:Aluminum / Q000494:pharmacology*; D017607:Aluminum Compounds; D000818:Animals; D002850:Chromatography, Gel; D003600:Cytosol / Q000378:metabolism; D005459:Fluorides / Q000494:pharmacology*; D007700:Kinetics; D007739:L Cells / Q000378:metabolism; D051379:Mice; D010710:Phosphates / Q000378:metabolism; D010761:Phosphorus Radioisotopes; D011865:Radioisotope Dilution Technique; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D013816:Thermodynamics; D014222:Triamcinolone Acetonide / Q000378:metabolism
D017607:Aluminum Compounds; D010710:Phosphates; D010761:Phosphorus Radioisotopes; D011965:Receptors, Glucocorticoid; D000535:Aluminum; D014222:Triamcinolone Acetonide; D005459:Fluorides; C032311:aluminum fluoride