Estrogen receptors expression and functions

More than 30 years ago, Jensen and Jacobsen (Jensen and Jacobsen et al., 1962) came to the conclusion, based on the specific binding of estrogen in the uterus, that the biological effects of estrogens have to be mediated by a intracellular receptor protein, and in 1986, the first cloning of this ER was reported (Greene et al., 1986) by the Pierre Chambon´s group. Almost 10 years later, a second ER was found in the laboratory of Jan-Åke Gustafsson . The ERβ, was cloned from a rat prostate cDNA library (Kuiper et al., 1996) and the former ER was now called ERα. Interesting to note, these two commonly occurring forms of estrogen receptor ERα and ERβ along with their splice variants are encoded by two genes with distinct tissue expression patterns in humans Hetero- and homodimers of the ERs exhibit unique transcriptional properties and belong to the steroid/thyroid hormone superfamily of nuclear receptors, members of which share a common structural architecture. Despite the differences, both ERs share similar multi-domain organization, exhibit comparable estrogen-binding affinities and can recognize the same DNA sequences in the promoters of estrogen responsive genes. In general, estrogens, and non-steroid xeno- and phytoestrogens bind to estrogen receptors and then the ER-ligand complex subsequently interacts with estrogen response elements (ERE). Transcription factors are recruited to the ERα-ligand/ ERE complex, resulting in enhancement or suppression of gene expression. The EREs sequences normally are protected by proteins in the ER-containing nuclear extracts. But the extent of the protection is dependent on the sequence of the EREs. However, they can exert different transcriptional activities in response to estrogen and other ligands. Binding of a ligand to ER triggers conformational changes in the receptor and this leads, via a number of events, to changes in the rate of transcription of estrogen-regulated genes.
These events, and the order in which they occur in the overall process, are not completely understood, but they include receptor dimerization, receptor-DNA interaction, recruitment and interaction with coactivators and other transcription factors, and formation of a preinitiation complex.
Therefore, our group is investigating mechanisms leading to recognizing and characterizing genes and epigenetic effects controlling susceptibility to estrogens. Furhermore, we want to understand the mechanisms of action for known estrogens at cellular and molecular levels.