Estrogens and receptors: an evolving concept.

Estrogens elicit most of their physiological effects through specific nuclear receptors (ERalpha and ERbeta), which belong to a superfamily of hormone-activated transcription factors. They regulate gene expression either through direct binding to DNA (as homo- or heterodimers) or via protein-protein interactions with other transcription factors. The hormone induces a conformational change that creates a new interface for molecules acting as transcription intermediary factors. These cofactors bind directly to estrogen receptors and mediate transcription activation or repression, usually as part of multimolecular complexes, acting either by stabilization of the basal transcription machinery or by chromatin remodelling; these involve the activities of various enzymes such as histone acetyltransferases and deacetylases. Moreover, different types of post-translational modifications (phosphorylation, acetylation, ubiquitination) also regulate estrogen receptor stability and/or transcriptional activation, and these effects, together with the non-genomic effects of estrogens, are important parameters of this signalling pathway. Finally, all these processes have their own dynamics, which may lead, depending on whether the hormone is provided continuously or as a pulse, to the same or different effects according to the end-point and the cell considered.