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J. Biol. Chem., Vol. 277, Issue 41, 38772-38780, October 11, 2002

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

Jürgen Zschocke, Dieter Manthey, Nadhim Bayatti, Bart van der Burg^§, Sharon Goodenough, and Christian Behl^¶

From the  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 (ER/ER) 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 ER 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 ER in SK-N-MC cells (SK-ER) leads to a ligand-independent transcriptional suppression of caveolin-1/-2 genes. This suppression is specifically mediated by ER and not ER because ER counteracts the observed caveolin-silencing process. Interestingly, decreased caveolin expression in SK-ER 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-ER cells, whereas the same sites were unmethylated in control, ER-, and ER/ 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-ER. 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 ER and not ER silences caveolin-1/-2 expression in an epigenetic fashion in neuronal cells. The observed mechanism of gene silencing by ER may have implications for the transcriptional regulation of further ER target genes.

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

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