br Genomic and non genomic signaling crosstalk As exemplifie
Genomic and non-genomic signaling crosstalk As exemplified in the previous sections, it is evident that the mechanisms of action of estrogen in the various cell targets represent a combination of complex multifactorial processes. Besides the independent genomic and non-genomic pathways described above, many authors have proposed the existence of additional convergent pathways involving both genomic and non-genomic factors that result in regulation of gene transcription (Björnström & Sjöberg, 2005; Silva, Kabil, & Kortenkamp, 2010; Vrtačnik et al., 2014). Two mechanisms of “cross-talk” have been described, and involve protein-protein interactions of components of both pathways. In one mechanism, estrogen-bound nuclear estrogen receptor complexes are dimerized and translocated to the nucleus, where they bind to phosphorylated transcription factors resulting from GPER1-mediated signaling. The complexes then bind to either ERE sequences via the nuclear estrogen receptors, or to AP-1, STATs, ATF-2/c-Jun, Sp1, and/or NF-κB cognate DNA gpr55 agonist (Björnström & Sjöberg, 2005). In the second mechanism, interaction of GPER1 and ERα and ERβ located at the plasma membrane activate protein kinase cascades that result in phosphorylation of AP-1, STATs, Elk-1, CREB, and NF-κB, and other transcription factors, as well as estrogen receptors themselves, that can then interact with DNA sequences to regulate transcription (Björnström & Sjöberg, 2005). Thus, convergence of the two classical estrogen receptor regulation pathways can result in enhanced transcriptional activity in specific tissues and physiological processes.
Estrogen receptor ligand independent signaling An interesting phenomenon observed in many cells is that estrogen receptors can actually be activated in the absence of estrogens or other receptor agonists (Bennesch & Picard, 2015; Maggi, 2011; Vrtačnik et al., 2014). This ligand-independent estrogen receptor activation is mainly triggered by phosphorylation on specific residues (e.g., serine and tyrosine) in the receptors themselves, or their association with coregulators (described below). This independent mechanism requires the action of regulatory molecules necessary for phosphorylation, such as protein kinase A (PKA), protein kinase C (PKC), MAPK phosphorylation cascade components, as well as inflammatory cytokines (e.g., interleukin-2), cell adhesion molecules (e.g., heregulin), cell cycle regulators (e.g., RAS p21 protein activator cyclins A and D1), and peptide growth factors including EGF, insulin, IGF1, and transforming growth factor beta (TGFβ) (Nilsson et al., 2001).
Estrogen receptor coregulators and transcriptional control In addition to the regulatory pathways described above, the cell also expresses a battery of coregulators that can either enhance or decrease transcriptional activity of steroid hormone receptors. These are called estrogen receptor coactivators and corepressors, respectively. Coregulators are involved in many steps of the gene expression process, including chromatin modification and remodeling, transcription initiation, elongation of RNA chains, mRNA splicing, mRNA translation, miRNA processing, and degradation of the activated NR-coregulator complexes (Lonard & O\'malley, 2007). Currently, there are hundreds of coregulators of nuclear receptors described that play a key role in promoting gene expression and transcriptional activity. Coregulators are a dynamic group of proteins able to act as integrators of signals from steroid hormones, and have been linked to many diseases affected by sex hormones, such as cancer (Lonard & O\'Malley, 2006). One of the first coregulators of ERα, known as steroid receptor coactivator (SRC-1), was identified in 1995 (Oñate, Tsai, Tsai, & O\'Malley, 1995). Since then, many additional coregulators have been discovered for ERα, although very few are known for ERβ (Lonard & O\'Malley, 2006). Coregulators for ERα comprise members of the steroid receptor coactivator (SRC)/p160 group, the histone acetyltransferase cAMP responsive element binding protein (CREB)-binding protein (CBP)/p300, ATP-dependent chromatin remodeling complexes like SWI/SNF, E3 ubiquitin-protein ligases, and steroid RNA activator (SRA) (Lonard & O\'Malley, 2006; Manavathi, Samanthapudi, & Gajulapalli, 2014). Therefore, as indicated above, even though both nuclear estrogen receptors are able to use estradiol as their physiological ligand, they exert multiple effects and functions in different cells and tissues that are mediated by several intermediaries and differential utilization of coregulators (Manavathi et al., 2014).