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J. Biol. Chem. 277 (41): 38772-38780

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Estrogen Receptor alpha -mediated Silencing of Caveolin Gene Expression in Neuronal Cells*

Jürgen ZschockeDagger , Dieter MantheyDagger , Nadhim BayattiDagger , Bart van der Burg§, Sharon GoodenoughDagger , and Christian BehlDagger

From the Dagger  Neurodegeneration Group, Max Planck Institute of Psychiatry, 80804 Munich, Germany, and § Hubrecht Laboratory/Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands

Estrogen receptors (ERalpha /ERbeta ) are expressed in neuronal cells and exhibit a variety of activities in the central nervous system. ER activity is regulated in a ligand-dependent manner and by co-regulatory factors. Caveolin-1 is a recently identified co-activator of ERalpha mediating the ligand-independent activation of this steroid receptor. Here the influence of ERs on caveolin expression in human neuroblastoma SK-N-MC cells as well as in rodent brain was investigated. We found that ectopic expression of ERalpha in SK-N-MC cells (SK-ERalpha ) leads to a ligand-independent transcriptional suppression of caveolin-1/-2 genes. This suppression is specifically mediated by ERalpha and not ERbeta because ERbeta counteracts the observed caveolin-silencing process. Interestingly, decreased caveolin expression in SK-ERalpha is accompanied by changes in the methylation pattern of caveolin promoters. The analysis of selected promoter regions of the human caveolin-1 gene showed that certain CpG dinucleotides were hypermethylated in SK-ERalpha cells, whereas the same sites were unmethylated in control, ERbeta -, and ERalpha /beta co-expressing SK-N-MC cells. Inhibition of DNA methylation or histone deacetylation led to partial re-expression of caveolin-1/-2 genes in SK-ERalpha . In vivo analysis revealed a down-regulation of caveolin-1 expression after long term estrogen exposure in certain regions of the mouse brain. In conclusion, we have shown for the first time that ERalpha and not ERbeta silences caveolin-1/-2 expression in an epigenetic fashion in neuronal cells. The observed mechanism of gene silencing by ERalpha may have implications for the transcriptional regulation of further ERalpha target genes.

* This work was supported in part by the Commission of the European Communities Grant QLK4-2000-00305, specific RTD programs "Quality of Life and Management of Living Resources" and "The Impact of Developmental Exposure to Weak (Environmental) Estrogens on the Incidence of Diseases in Target Organs Later in Life," and by Grant SFB 596 of the Deutsche Forschungsgemeinschaft (to C. B).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AJ133269.

To whom correspondence should be addressed: Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University, 55099 Mainz, Germany. Tel.: 49-89-30622-246; Fax: 49-89-30622-642; E-mail:

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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