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Pharmacological and Genetic Analysis of 90-kDa Heat Shock Isoprotein-Aryl Hydrocarbon Receptor Complexes

Interdisciplinary Program in Molecular and Cellular Biology, Tulane University and Department of Environmental Health Sciences, Tulane University School of Public Health and Tropical Medicine

The 90-kDa heat shock protein (Hsp90) is an abundant chaperone that regulates a diverse set of intracellular signaling proteins. Drugs that inhibit Hsp90 activity have been useful in the identification of novel Hsp90-dependent signaling pathways. One class of inhibitory compounds disrupts Hsp90-dependent processes by binding to the N-terminal ATPase/p23-binding domain of Hsp90, whereas a second inhibitor class binds within the C-terminal domain. We used signaling by aryl hydrocarbon receptor (AhR), an Hsp90-dependent transcription factor, as a functional probe to study the effects of Hsp90 inhibitors in yeast strains with deletion mutations of individual Hsp90 and p23 cochaperone genes. The more abundant and constitutively expressed Hsp90 isoform, Hsc82, functioned best in supporting AhR signaling. Deletion of the more inducible isoform, Hsp82, had no effect on signaling. AhR complexes containing Hsc82 were preferentially sensitive to the effects of low concentrations of the N-terminal inhibitors radicicol and herbimycin A. However, both Hsp90 isoforms were equally sensitive to the AhR-specific effects of novobiocin, which binds to the C terminus. Hsp90 inhibitors had no preferential effects on AhR signaling in strains that lacked p23, suggesting that the inhibitors exert their effects through a p23-independent mechanism. In contrast, overexpression of p23 buffered the effects of radicicol and herbimycin A, but not novobiocin, on AhR signaling. The data collectively suggest preferential use or function of the Hsc82 isoprotein in AhR signaling and provide new insight into the effects of three structurally unrelated Hsp90 inhibitors.

Address correspondence to: Charles A. Miller III, Department of Environmental Health Sciences, Tulane University School of Public Health and Tropical Medicine, 1430 Tulane Ave. Box SL-29, New Orleans, LA 70112. E-mail: rellim{at}tulane.edu

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