3.1. Estrogen Exerts Its Biological Effects on Cells by Both
Estrogen Receptor-Dependent and -Independent Mechanisms
A concise description of ERs and their interactions with DNA is helpful to appreciate the molecular mode of action of estrogens and to understand the diversity of potential effects of estrogens on the immune system. Estrogen exerts its biological functions on target tissues by both ER-dependent and ER-independent mechanisms. Estrogen binds to two specific, but distinct receptors, ERa and ERP, which belong to the nuclear hormone receptor family. ERs are ligand-activated transcription factors and are located both intracellularly and presumably on the cell surface. Heat shock proteins, such as hsp90, bind to unliganded ERs to maintain the receptors in an inactive but functionally prepared state for ligand binding (Pratt and Toft, 1997). Each type of ER appears to be differentially expressed in various tissues. It is conceivable that the differences in the relative expression of ERs in different tissues may result in the selective actions of estrogen in the immune system. ERa and ERP comprise several domains: A/B domain (located near the NH2 terminus), C domain (DNA-binding domain), D domain (hinge region), and E/F domain (ligand-binding domain, COOH terminal) (Figure 14.1 A). ERa and ERP share an amino acid homology of 97% in the DNA-binding domain, while they have a homology of only 60% in the ligand-binding domain. This suggests that two ERs can interact with the same genes but bind differentially to ligands (Kuiper et al., 1997). ERa has two transactivation functional regions: activation factor-1 (AF-1) in the DNA-binding domain and AF-2 in the ligand-binding domain. These regions synergize with each other and provide the response to estrogen. ERP also has an AF-1 region but most of its activity comes from AF-2 (McInerney et al., 1998). The hinge region contains a nuclear localization signal and links the C domain to the multifunctional carboxyl-terminus E/F domain. The hormone-dependent AF-2 region in the E/F domain is important in ligand-dependent transcriptional activity and in interaction with coactivators. Further, this region is responsible for ligand-dependent activation by nuclear receptors, interactions with heat shock protein (hsp), nuclear translocation, and transactivation of target genes (Meier, 1997). Differential binding of ERs to transcriptional cofactors (coactivators, corepressors, and coregulators) will likely have a profound impact on transcription of estrogen-responsive genes. The coactivator proteins steroid receptor coactivator-1 (SRC-1) and transcrip-tional intermediary factor-2 (GRIP1/TIF2) enhance gene expression by remodeling chromatin and allowing interactions with the basal transcription machinery (Cavailles et al., 1995; Henttu et al., 1997; Johansson et al., 1999). In contrast, corepressors and coregulators inhibit gene activation or turn off the activated genes. For example, coregulatory factors RIP140 and SHP compete with SRC-1 coactivator proteins such as TIF2 for AF-2 regions and may recruit deacetylases to estrogen target genes.
Hsp 90 binding
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