A complex picture is emerging of the many ways by which nuclear receptors for the hormone estrogen regulate gene expression. Estrogen receptors alpha and beta (ERα and ERβ) can act through either a ligand-dependent or -independent mechanism, and receptor activity is further influenced by various coactivators and corepressors. The expression of caveolin-1, a protein best known for its role in caveolae development at the cell surface, is regulated in some tissues by estrogen. Because caveolin-1 can itself bind to ERα and potentiate gene transcription, the functional relationship between estrogen, ERs, and caveolin in regulating cellular processes is of interest. Zschocke et al. report that in a neuronal cell line, ectopic expression of ERα inhibited caveolin expression in an estrogen-independent manner. The process involved methylation of specific CpG islands in the caveolin-1 promoter region, a modification that is a hallmark of stable gene silencing. ERβ counteracted the effect of ERα on caveolin expression. Although it remains unclear whether ERα directly suppresses caveolin expression, the inverse relationship of ERα and caveolin expression observed in some cancer cell lines may be attributed to this epigenetic effect. Furthermore, exposure of embryonic mice to estrogen resulted in decreased caveolin-1 expression in certain brain regions. The authors propose that persistent down-regulation of caveolin expression by estrogen would not only decrease the availability of this ER coregulator but might also prevent formation of caveolae, thus impairing the integration and transduction of signals from the cell surface.
J. Zschocke, D. Manthey, N. Bayatti, B. van der Burg, S. Goodenough, C. Behl, Estrogen receptor α-mediated silencing of caveolin gene expression in neuronal cells. J. Biol. Chem. 277, 38772-38780 (2002). [Abstract] [Full Text]