Radicicol represses the transcriptional function of the estrogen receptor by suppressing the stabilization of the receptor by heat shock protein 90.

The estrogen receptor (ER) is a hormone-dependent transcription factor that belongs to the steroid/thyroid hormone receptor superfamily. Since the ER contributes to development and progression in human breast cancer, a number of studies have explored ways to inactivate this receptor. Previous studies have suggested that the 90-kDa heat shock protein ...
(Hsp90) interacts with the ER, thus stabilizing the receptor in an inactive state. Here, we report that radicicol, an Hsp90-specific inhibitor, repressed estrogen-dependent transactivation of the ER as measured by pS2 gene transcription and a reporter gene encoding an estrogen-responsive element. Furthermore, we showed that radicicol induced rapid degradation of ERalpha, while the amount of ubiquitinated ERalpha was increased. A proteasome inhibitor, LLnL, almost completely abrogated the radicicol-induced decrease in expression level, as well as in transcriptional activity of ERalpha. These results suggest that radicicol disrupts the ER-Hsp90 heterodimeric complex, thereby generating ERalpha that is susceptible to ubiquitin/proteasome-induced degradation.
Mesh Terms:
Animals, Binding Sites, Blotting, Northern, Blotting, Western, Breast Neoplasms, Cells, Cultured, Cercopithecus aethiops, DNA, Down-Regulation, Enzyme Inhibitors, Female, HSP90 Heat-Shock Proteins, Humans, Lactones, Macrolides, Multienzyme Complexes, Peptide Hydrolases, Protease Inhibitors, Receptors, Estrogen, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Transcription, Genetic, Transcriptional Activation, Ubiquitins
Mol. Cell. Endocrinol.
Date: Feb. 25, 2002
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