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.
Lee
Mi Ock
MO
Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-dong, Kwangjin-gu, Seoul 143-747, South Korea. molee@sejong.ac.kr
Kim
Eun Ok
EO
Kwon
Ho Jeong
HJ
Kim
Young Mi
YM
Kang
Hyo Jin
HJ
Kang
Heonjoong
H
Lee
Jong Eun
JE
D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010447:Peptide Hydrolases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation; D014452:Ubiquitins / Q000378:metabolism
D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D018942:Macrolides; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D014452:Ubiquitins; D004247:DNA; D010447:Peptide Hydrolases; C035359:monorden