Connections and Regulation of the Human Estrogen Receptor

Abstract

Estrogen regulates a plethora of functionally dissimilar processes in a broad range of tissues. Recent progress in the study of the molecular mechanism of action of estrogen(s) has revealed why different cells can respond to the same hormone in a different manner. Three of these findings are of particular importance: (i) There are two genetically and functionally distinct estrogen receptors that have distinct expression patterns in vivo; (ii) the positive and negative transcriptional activities of these receptors require them to engage transcription cofactors (coactivators or corepressors) in target cells; and (iii) not all cofactors are functionally equivalent, nor are they expressed in the same manner in all cells. Thus, although the estrogen receptor is required for a cell to respond to an estrogenic stimulus, the nature and extent of that response are determined by the proteins, pathways, and processes with which the receptor interacts.

A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

“…Estrogen is nonselective for the two receptors and the binding of estrogen results in a receptor-ligand complex that binds with high affinity to estrogen responsive elements (EREs) on DNA. Transcriptional regulation by the ERs may occur through a direct interaction of ERs with EREs or through an interaction of ER with other transcription factors (Sp1, AP-1 and NF-kB; McDonnell and Norris, 2002). The two receptors can heterodimerize, and they may modulate each other's effects (Gustafsson, 2006).…”

Epigenetic Information and Estrogen Receptor Alpha Expression in Breast Cancer

“…Therefore, reducing estrogen levels or altering the activity of the receptor can induce these cancers to regress. E2 action involves ligand-mediated activation of nuclear ER-α and ER-β, which interact directly with estrogen response elements (EREs) in the promoter and/or enhancer regions of target genes and recruit various coactivators to mediate transcriptional regulation [3]. ER regulation is not limited to direct ligand binding.…”

The clock gene Per2 links the circadian system to the estrogen receptor

“…Upon binding to E2, ERa undergoes conformational changes facilitating cofactor binding and nuclear localization (McDonnell and Norris, 2002). Immunoprecipitation experiments showed that Per2 associates with ERa in 293T and MCF-7 cells, and E2 stimulation enhances the interaction (Figure 2a).…”