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This version published online on July 21, 2005
Molecular Endocrinology, doi:10.1210/me.2005-0111
Molecular Endocrinology Vol. 0, No. 2005 200501111-
doi:10.1210/me.2005-0111
Copyright © 2005 by the Endocrine Society.
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Submitted on March 4, 2005
Accepted on July 14, 2005

CHIP (Carboxyl Terminus of Hsc70-Interacting Protein) Promotes Basal and Geldanamycin-Induced Degradation of Estrogen Receptor-alpha

Meiyun Fan, Annie Park, and Kenneth P. Nephew*

Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, Indiana University Cancer Center, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202

* To whom correspondence should be addressed. E-mail: knephew{at}indiana.edu.

In estrogen target cells, estrogen receptor-alpha (ER{alpha}) protein levels are strictly regulated. Although receptor turnover is a continuous process, dynamic fluctuations in receptor levels, mediated primarily by the ubiquitin-proteasome pathway, occur in response to changing cellular conditions. In the absence of ligand, ER{alpha} is sequestered within a stable chaperone protein complex consisting of heat shock protein 90 (Hsp90) and co-chaperones. However, the molecular mechanism(s) regulating ER{alpha} stability and turnover remain undefined. One potential mechanism involves CHIP, the carboxyl terminus of Hsc70-interacting protein, previously shown to target Hsp90 interacting proteins for ubiquitination and proteasomal degradation. In the present study, a role for CHIP in ER{alpha} protein degradation was investigated. In ER-negative HeLa cells transfected with ER{alpha} and CHIP, ER{alpha} proteasomal degradation increased, while ER{alpha}-mediated gene transcription decreased. In contrast, CHIP depletion by siRNA resulted in increased ER{alpha} accumulation and reporter gene transactivation. Transfection of mutant CHIP constructs demonstrated that both the U-box (containing ubiquitin ligase activity) and the tetratricopeptide repeat (TPR, essential for chaperone binding) domains within CHIP are required for CHIP-mediated ER{alpha} down-regulation. In addition, coimmunoprecipitation assays demonstrated that ER{alpha} and CHIP associate through the CHIP TPR domain. In ER{alpha}-positive breast cancer MCF7 cells, CHIP overexpression resulted in decreased levels of endogenous ER{alpha} protein and attenuation of ER{alpha}-mediated gene expression. Furthermore, the ER{alpha}-CHIP interaction was stimulated by the Hsp90 inhibitor geldanamycin (GA), resulting in enhanced ER{alpha} degradation; this GA effect was further augmented by CHIP overexpression, but was abolished by CHIP depletion. Finally, ER{alpha} dissociation from CHIP by various ER{alpha} ligands, including E2, OHT, and ICI, interrupted CHIP-mediated ER{alpha} degradation. These results demonstrate a role for CHIP in both basal and GA-induced ER{alpha} degradation. Furthermore, based on our observations that CHIP promotes ER{alpha} degradation and attenuates receptor-mediated gene transcription, we suggest that CHIP, by modulating ER{alpha} stability, contributes to the regulation of functional receptor levels, and thus hormone responsiveness, in estrogen target cells.
Key words: estrogen receptor • CHIP • geldanamycin • ubiquitin • Hsp90

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα
Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen



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