Membrane estrogen receptors: Genomic actions and post transcriptional regulation
Introduction
The steroid hormone 17-β estradiol is a key regulator of a wide variety of biological processes including growth, development and reproduction. The various estrogen target tissues include the male and female reproductive tracts, mammary tissues, and the skeletal, cardiovascular and central nervous systems (Couse and Korach, 1999). Biological effects of estrogens are mainly mediated through estrogen receptor alpha (ERα) (Green et al., 1986, Walter et al., 1985) and estrogen receptor beta (ERβ) (Kuiper et al., 1997) which are coded by separate genes and are ligand inducible transcription factors that belong to the nuclear receptor superfamily. Both ERα and ERβ possess three major functional domains. The N terminal A/B domain which contains the ligand independent transactivation function-1 (AF-1) shows 18% similarity between human ERα and ERβ (Enmark et al., 1997). AF-1 is a region of site specific phosphorylation by mitogen activated protein kinase (MAPK) pathways in response to growth factors and by cyclin A2-CDK2 (Ali et al., 1993, Joel et al., 1998, Rogatsky et al., 1999). The central DNA binding domain (DBD) which primarily functions in tightly binding the receptor to DNA helix possess two zinc fingers and this region is highly conserved (97%) in ERα and ERβ (Enmark et al., 1997, Tremblay et al., 1997) like other members of nuclear receptor superfamily. The ligand binding domain (LBD) that contains the activation function-2 (AF-2) shows 60% conservation of residues (Enmark et al., 1997) and this region shows distinct conformational changes depending on the type of ligand (Brzozowski et al., 1997, Pike et al., 1999) with striking difference in the position of helix12. ERα and ERβ differ significantly in their tissue distribution and ligand binding characteristics, a major reason for tissue selective actions of estrogens (Nilsson and Gustafsson, 2000). Ligand binding induces conformational changes in the receptor, which promotes the homodimerisation and binding of the receptor to specific estrogen responsive element (ERE) in the promoter region of the target gene. DNA bound receptor complex interacts with the basal transcription apparatus which in turn facilitates the formation of a transcription pre-initiation complex either enhancing or repressing the target gene transcription depending on the promoter context (Hall and Korach, 2002). Estrogen receptors can also modulate the expression of genes without directly binding to DNA, through interaction with other promoter bound proteins (Jakacka et al., 2001) or by preventing the recruitment of other transcription factors to the promoter (Galien and Garcia, 1997).
However, these mechanisms of action could not explain the rapid effects of 17-β estradiol that occur on a time scale of seconds to minutes. These rapid effects are mediated mainly through activation of various signal transduction pathways (Stirone et al., 2005, Toran-Allerand et al., 2002, Wyckoff et al., 2001) and are detected in the presence of membrane impermeable estradiol-protein conjugates, suggesting a role for plasma membrane localized estrogen receptors.
Section snippets
Membrane estrogen receptors
Involvement of plasma membrane receptors in estrogen action has been a target of investigation for more than three decades. Specific binding sites for estrogen at the outer surface of isolated endometrial cells were reported by Pietras and Szego during the 70s (Pietras and Szego, 1977). Similar binding sites have been detected subsequently in various tissues such as spermatozoa (Hernandez-Perez et al., 1979) hepatocytes (Pietras and Szego, 1980) and the mammary gland (Zanker et al., 1981).
Signaling from membrane estrogen receptors
Signaling from mER occurs mainly through the activation of various signal transduction pathways that are often associated with G protein coupled receptors (GPCRs), ion channels and enzyme linked receptors. In addition to this, nuclear movement of membrane estrogen receptors in the presence of estradiol and its direct involvement in transcription have also been reported.
Estrogen dependent ribonucleoprotein transport
Pre-mRNA splicing is among the last known nuclear events before the export of mature mRNA to the cytoplasm. The mechanistic basis for this coupling is the formation of a specific nucleoprotein complex that targets the spliced mRNA for rapid and efficient export. From the studies that have been reported earlier (Thampan, 1985, Thampan, 1988, Vazquez-Nin et al., 1991) it appears that estradiol has a functional role to play in mRNP transport. In the absence of estradiol the RNPs were retained
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