Datensatz

Zusammenfassung

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 gene