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  • br Nuclear estrogen receptors Indirect genomic signaling As


    Nuclear estrogen receptors: Indirect genomic signaling As mentioned earlier, the transcription of several genes that do not contain EREs in their promoter regions can also be regulated by estradiol, without direct binding of the estrogen receptors to the DNA. According to the most recent reports, an estimated 35% of genes targeted by estrogen lack ERE-like sequences (Marino et al., 2006; Vrtačnik et al., 2014). In these, the mechanisms by which estrogen affects gene expression are collectively known as “indirect genomic signaling” or “transcriptional cross-talk”, and are based on activation of gene expression by estrogen receptors not binding DNA directly. Rather, the estrogen receptor complexes act through protein-protein interactions with other transcription factors and response elements (Aranda & Pascual, 2001; Göttlicher, Heck, & Herrlich, 1998). In this way, estrogens indirect signaling influences activation or suppression of target gene expression. An important mediator of indirect genomic signaling is the stimulating protein-1 (Sp-1). Binding of this transcription factor to promoter regions at GC-rich sites is enhanced by the presence of estrogen receptors (Bajic et al., 2003; O\'Lone et al., 2004). Examples of genes induced by estrogen via the Sp-1 mechanism are: low-density lipoprotein (LDL) receptor (Li, Briggs, Ahlborn, Kraemer, & Liu, 2001), progesterone receptor B (O\'Lone et al., 2004), endothelial nitric oxide synthase (eNOS) (Chambliss & Shaul, 2002), GATA binding protein 1 (GATA1), signal transducer and activator of transcription 5 (STAT5) (Björnström & Sjöberg, 2005), and the retinoic ABC294640 receptor-1α genes (Sun, Porter, & Safe, 1998). A few studies have shown that ERα can also interact with the c-rel subunit of the nuclear factor-κB (NF-κB) complex, preventing NF-κB from binding to cytokine genes promoters (Galien & Garcia, 1997; Kalaitzidis & Gilmore, 2005). Moreover, ERα can also interact with other transcriptional modulators such as the activating transcription factor (ATF)-2, c-jun, the ATF-1/cAMP response element binding protein (ATF-1/CREB), and the nuclear transcription factor-Y (NF-Y) (O\'Lone et al., 2004). The nuclear estrogen receptors also induce the expression of genes containing the activator protein-1 (AP-1) sites though protein-protein interactions (Gaub, Bellard, Scheuer, Chambon, & Sassone-Corsi, 1990). AP-1 is a transcription factor that regulates key cellular processes such as cell differentiation, proliferation, and apoptosis. The structure of AP-1 consists of a heterodimer composed of proteins belonging to the c-Fos, c-Jun, ATF, and the Jun dimerization partners (JDP) families (Piu, Aronheim, Katz, & Karin, 2001). The ERα also interacts with c-Fos and c-Jun at these binding regions (O\'Lone et al., 2004). Some examples of genes induced by ERα via the AP-1 mechanism are insulin-like growth factor-1 (IGF1), collagenase, IGF1-receptor, ovalbumin, and cyclin D1 (Fujimoto, Honda, & Kitamura, 2004; Marino, Acconcia, Bresciani, Weisz, & Trentalance, 2002). However, previous studies have shown that ERα and ERβ signal in different ways depending on the ligand and response elements present at the AP-1 sites. In fact, 17β-estradiol activates AP-1-dependent transcription via ERα, whereas ERβ inhibits this mechanism (Paech et al., 1997). Likewise, 17β-estradiol binding to ERα induces transcription when linked to Sp-1 in GC-rich regions, but not when 17β-estradiol is bound to ERβ. One example of this is the contrasting action of ERα and ERβ on the control of cyclin D1 gene expression (Liu et al., 2002), where estrogen-bound ERβ suppresses cyclin D1 expression (Marino et al., 2006) and blocks ERα-mediated production when both receptors are present (Acconcia et al., 2005; Matthews & Gustafsson, 2003). The diversity of mechanisms of transcriptional regulation in different cells by the two estrogen receptors and their interactions with local transcription factors may explain the differences observed in tissue specific biologic responses to estrogens.