The involvement of coactivators and corepressors, collectively termed as coregulators, increases the complexity of regulation of steroid hormone action. Following the interaction of the steroid hormone-receptor complex with the specific nucleotide sequences of target genes, the coregulators are recruited for activation or suppression of specific genes. The coregulators regulate a number of hormonal events during pregnancy, sex differentiation, development, reproduction and sexual behavior. They also exert equally important functions in non-reproductive tissues like heart, kidney, pancreas, bone and brain. The mutation and/or aberrant expression of these coregulators affect the normal function of steroid hormones and result in physiological abnormalities leading to the development of diseases. Therefore, understanding the role of coregulators in steroid hormone action is important and would help in developing the therapeutic strategy for the treatment of steroid-related diseases. In this review article, we describe the coregulators and their implication in health and pathogenesis of diseases. Furthermore, the possible therapeutic approach has been discussed for the treatment of steroid-related diseases, which will be of future interest in the field of medical sciences.
Following binding to cognate ligand, estrogen receptor (ER) beta interacts with specific responsive elements of the target genes and recruits a host of nuclear proteins for hormone dependent gene regulation. However, it is poorly known which proteins interact with ER beta in mouse brain and whether their interaction and expression change with age. In this report, we have used his-tag mouse ER beta for interaction with nuclear proteins of cerebral cortex of young (6 +/- 1 weeks), adult (25 +/- 2 weeks), and old (70 +/- 5 weeks) female mice. We have identified estrogen receptor-associated protein (ERAP) 140 as one of the interacting proteins and studied its interaction by pull down immunoblotting, far-Western blotting and immunoprecipitation, and expression by western blotting. The data show that ERAP 140 interacts with ER beta and its interaction decreases but its expression increases with age in mouse cerebral cortex, suggesting its role in estrogen-mediated brain functions during aging.
During aging, brain undergoes several changes which influence its function through alteration in the expression of genes. Some of these genes are regulated by estrogen which requires a host of coregulator proteins including CREB. In brain, CREB is expressed in different regions and regulates a wide range of functions such as cellular growth, proliferation and memory in response to a variety of intracellular signaling events including synaptic efficacy and long-lasting changes in synaptic plasticity. In response to signals at the cell surface, CREB is phosphorylated in the nucleus by various protein kinases via secondary messengers such as cAMP and/or Ca +2 for regulating specific genes. Alterations in CREB signaling lead to cognitive deficits as observed in normal aging and neurodegenerative diseases. In brain, the expression of CREB changes with age, but its variation with sex is not known. So, in this review paper, we summarize recent findings indicating age and sex dependent expression of CREB and its interaction with estrogen receptor (ER)β, and the role of CREB signaling in brain aging and diseases. Such understanding of CREB signaling through ER may help to design therapeutic strategies for age related cognitive deficits and neurodegenerative disorders.
Background: Estrogen receptor  and its domain interact with a host of brain mitochondrial and nuclear proteins. Results: Estrogen receptor  interacting brain mitochondrial and nuclear proteins have consensus motifs. Conclusion: Estrogen receptor  interacts with casein kinase 2, phosphokinase C, and N-myristoylation sites present in mitochondrial and nuclear proteins. Significance: This might be useful to regulate estrogen-dependent gene regulation in brain for therapeutics.
Nuclear magnetic resonance (NMR) spectroscopy is a useful biophysical technique to study the ligand-protein interaction. In this report, we have used bacterially produced ERβ and its domains for studying the functional analysis of ligand-protein interaction. Briefly, ERβ and its transactivation domain (TAD) and ligand binding domain (LBD) were subcloned and overexpressed using a prokaryotic expression system. The recombinant proteins were purified using Ni(+2)-IDA affinity chromatography and analyzed by NMR. Purified ERβ and TAD show similar conformation in the absence or presence of 17β-estradiol. However, LBD shows altered conformation in the presence of 17β-estradiol. These findings suggest that ERβ produced in bacteria exhibits a conformation such that its LBD remains masked and consequently it binds less to 17β-estradiol. Such study may help to develop the therapeutic approaches for controlling the estradiol-mediated gene expression in hormone dependent diseases.
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