Estrogen-repressed genes – key mediators of estrogen action?

Excerpt

Estrogen receptor (ER)-α is a member of the nuclear receptor family of transcription factors. It is regulated not only by binding to its ligand but also through interaction with co-regulators that can either enhance (coactivators) or repress (corepressors) its transcriptional activity. ER-α regulates the expression of a large number of genes, including components of the signaling, cell cycle, and anti-apoptosis pathways. A great deal of work in this area has increased our understanding of the role of ER-α in activation of genes; we now know that binding of estrogen to ER-α results in repositioning of helix 12 that allows recruitment of coactivators and thus activation of transcription. However, recent gene expression profiling by a number of groups using different model systems has revealed that the majority of estrogen-regulated genes are repressed rather than activated. This has been shown in cells cultured in vitro but also in vivo, where estrogen treatment resulted in downregulation of a significant number of target genes. This repression was lost in ER-α-knockout mice [1], confirming that repression requires ER-α. Although estrogen-mediated repression of genes has received little attention in the past, it is likely to be critical for the role of ER-α in both normal and disease processes. Herein we discuss some important studies on repression by ER-α and try to highlight the most burning (and partially controversial) questions. …