The Experts below are selected from a list of 288 Experts worldwide ranked by ideXlab platform
Ellis R. Levin - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Receptors outside the nucleus: extranuclear signalling by Steroid Receptors
Nature Reviews Molecular Cell Biology, 2016Co-Authors: Ellis R. Levin, Stephen R. HammesAbstract:Steroid hormone Receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that Steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most Steroid Receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a Steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear Steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of Steroid hormone signalling and its roles in health and disease. Steroid Receptors classically function in the nucleus, regulating the expression of genes that are important for a wide range of cellular functions. It has now become clear that many classic Steroid Receptors also localize to other cellular compartments (including, prominently, the plasma membrane) to activate various signalling pathways. Signalling from membrane-localized Steroid Receptors can elicit non-genomic responses, such as G protein and kinase signalling. Steroid receptor signalling from the membrane can also be involved in the regulation of gene expression, sometimes by engaging in crosstalk with nuclear pools of the respective receptor. Membrane-initiated Steroid signalling has been shown to have various physiological functions and has been associated with the development and propagation of cancer. Transgenic mice that selectively express only one functional oestrogen receptor-α pool — either membrane or nuclear — display phenotypes that overlap significantly with those of mice completely lacking oestrogen receptor-α, indicating that both pools are necessary for most oestrogen-dependent processes. More broadly, it can be concluded that extranuclear Steroid signalling is required for full Steroid hormone action during development and organ homeostasis. Steroid hormone Receptors are well known to regulate various aspects of animal physiology by acting as transcriptional regulators in the nucleus. However, it is now evident that these Receptors can also be targeted to extranuclear locations (such as the plasma membrane), where they instigate rapid signals that contribute to Steroid-mediated cellular responses.
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nuclear Receptors outside the nucleus extranuclear signalling by Steroid Receptors
Nature Reviews Molecular Cell Biology, 2016Co-Authors: Ellis R. Levin, Stephen R. HammesAbstract:Steroid hormone Receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that Steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most Steroid Receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a Steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear Steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of Steroid hormone signalling and its roles in health and disease.
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extranuclear Steroid Receptors are essential for Steroid hormone actions
Annual Review of Medicine, 2015Co-Authors: Ellis R. LevinAbstract:Steroid hormones are produced throughout the phylogenetic tree, from plants to mammals. In the past 40 years, Steroid Receptors localized to the nucleus have been recognized as being important to mediating Steroid action in many organs. This action mainly arises from the regulation of key genes that are important for organ development and function. These include but are not limited to genes influencing the reproductive tract, mammary glands, bone, brain, fat differentiation, pituitary hormone regulation, and metabolic effects in many organs. Unfortunately, Steroids also promote the development of hormone-responsive cancers, including breast, uterus, and prostate cancer. It has also been shown that Steroid Receptors exist outside the nucleus in many organs and cells, with unclear impact for normal development, health, and disease. This review describes the evidence from many laboratories that these Receptors exist and function with nuclear Receptors to provide the full impact of all Steroid hormones.
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DHHC-7 and -21 are palmitoylacyltransferases for sex Steroid Receptors
Molecular biology of the cell, 2011Co-Authors: Ali Pedram, Mahnaz Razandi, Robert J. Deschenes, Ellis R. LevinAbstract:Classical estrogen, progesterone, and androgen Receptors (ERs, PRs, and ARs) localize outside the nucleus at the plasma membrane of target cells. From the membrane, the Receptors signal to activate kinase cascades that are essential for the modulation of transcription and nongenomic functions in many target cells. ER, PR, and AR trafficking to the membrane requires receptor palmitoylation by palmitoylacyltransferase (PAT) protein(s). However, the identity of the Steroid receptor PAT(s) is unknown. We identified the DHHC-7 and -21 proteins as conserved PATs for the sex Steroid Receptors. From DHHC-7 and -21 knockdown studies, the PATs are required for endogenous ER, PR, and AR palmitoylation, membrane trafficking, and rapid signal transduction in cancer cells. Thus the DHHC-7 and -21 proteins are novel targets to selectively inhibit membrane sex Steroid receptor localization and function.
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minireview extranuclear Steroid Receptors roles in modulation of cell functions
Molecular Endocrinology, 2011Co-Authors: Ellis R. LevinAbstract:Steroid Receptors existing outside the nucleus are increasingly being recognized in many organs and cell types, impacting the biology of bone, the heart and blood vessels, and the central nervous system. Some controversy exists as to the nature of the Receptors at the plasma membrane. However, compelling evidence has been advanced that at least some classical Steroid Receptors mediate Steroid ligand actions originating as signaling from the cell surface. Here I review the recent findings in this evolving field emphasizing the in vivo impact of these receptor pools with a focus on estrogen Receptors.
Michael E. Baker - One of the best experts on this subject based on the ideXlab platform.
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Steroid Receptors and vertebrate evolution
Molecular and cellular endocrinology, 2019Co-Authors: Michael E. BakerAbstract:Considering that life on earth evolved about 3.7 billion years ago, vertebrates are young, appearing in the fossil record during the Cambrian explosion about 542 to 515 million years ago. Results from sequence analyses of genomes from bacteria, yeast, plants, invertebrates and vertebrates indicate that Receptors for adrenal Steroids (aldosterone, cortisol), and sex Steroids (estrogen, progesterone, testosterone) also are young, with an estrogen receptor and a 3-ketoSteroid receptor first appearing in basal chordates (cephalochordates: amphioxus), which are close ancestors of vertebrates. Duplication and divergence of the 3-ketoSteroid receptor yielded an ancestral progesterone receptor and an ancestral corticoid receptor, the common ancestor of the glucocorticoid and mineralocorticoid Receptors, in jawless vertebrates (cyclostomes: lampreys, hagfish). This was followed by evolution of an androgen receptor, distinct glucocorticoid and mineralocorticoid Receptors and estrogen receptor-α and -β in cartilaginous fishes (Chondrichthyes: sharks). Further evolution of mineralocorticoid signaling occurred with the evolution of aldosterone synthase in lungfish, a forerunner of terrestrial vertebrates. Adrenal and sex Steroid Receptors are not found in echinoderms and hemichordates, which are ancestors in the lineage of cephalochordates and vertebrates. The evolution of Steroid Receptors at key nodes in the evolution of vertebrates, in which Steroid Receptors act as master switches to regulate differentiation, development, reproduction, immune responses, electrolyte homeostasis and stress responses, suggests an important role for Steroid Receptors in the evolutionary success of vertebrates, considering that the human genome contains about 22,000 genes, which is not much larger than genomes of invertebrates, such as Caenorhabditis elegans (~18,000 genes) and Drosophila (~14,000 genes).
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origin of the response to adrenal and sex Steroids roles of promiscuity and co evolution of enzymes and Steroid Receptors
The Journal of Steroid Biochemistry and Molecular Biology, 2015Co-Authors: Michael E. Baker, David R Nelson, Romain A StuderAbstract:Many responses to adrenal and sex Steroids are mediated by Receptors that belong to the nuclear receptor family of transcription factors. We investigated the co-evolution of these vertebrate Steroid Receptors and the enzymes that synthesize adrenal and sex Steroids through data mining of genomes from cephalochordates [amphioxus], cyclostomes [lampreys, hagfish], chondrichthyes [sharks, rays, skates], actinopterygii [ray-finned fish], sarcopterygii [coelacanths, lungfishes and terrestrial vertebrates]. An ancestor of the estrogen receptor and 3-ketoSteroid Receptors evolved in amphioxus. A corticoid receptor and a progesterone receptor evolved in cyclostomes, and an androgen receptor evolved in gnathostomes. Amphioxus contains CYP11, CYP17, CYP19, 3β/Δ5-4-HSD and 17β-HSD14, which suffice for the synthesis of estradiol and Δ5-androstenediol. Amphioxus also contains CYP27, which catalyzes the synthesis of 27-hydroxy-cholesterol, another estrogen. Lamprey contains, in addition, CYP21, which catalyzes the synthesis of 11-deoxycortisol. Chondrichthyes contain, in addition, CYP11A, CYP11C, CYP17A1, CYP17A2. Coelacanth also contains CYP11C1, the current descendent from a common ancestor with modern land vertebrate CYP11B genes, which catalyze the synthesis of cortisol, corticosterone and aldosterone. Interestingly, CYP11B2, aldosterone synthase, evolved from separate gene duplications in at least old world monkeys and two suborders of rodents. Sciurognathi (including mice and rats) and Hystricomorpha (including guinea pigs). Thus, Steroid Receptors and Steroidogenic enzymes co-evolved at key transitions in the evolution of vertebrates. Together, this suite of Receptors and enzymes through their roles in transcriptional regulation of reproduction, development, homeostasis and the response to stress contributed to the evolutionary diversification of vertebrates. This article is part of a Special Issue entitled 'Steroid/Sterol signaling'.
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Evolution of Steroid Receptors
Reference Module in Biomedical Sciences, 2014Co-Authors: Michael E. BakerAbstract:Adrenal Steroids (aldosterone, cortisol) and sex Steroids (estradiol, progesterone, testosterone) regulate diverse physiological responses in vertebrates. Many actions of these Steroids are mediated by Receptors that belong to the nuclear receptor family of transcription factors, which evolved in multicellular animals; Plants, yeast or bacteria do not contain nuclear Receptors. Analysis of animal genomes indicates that an estrogen receptor [ER] evolved in amphioxus, a protochordate ancestor of vertebrates. Amphioxus also contains another Steroid receptor [SR], which is the ancestor of the other adrenal and sex Steroid Receptors. A corticoSteroid receptor [CR] and a progesterone receptor [PR] evolved in cyclostomes [lampreys, hagfish]. An androgen receptor [AR], glucocorticoid receptor [GR] and mineralocorticoid receptor [MR] evolved in elasmobranches [sharks, skates, rays]. Further evolutionary fine-tuning of the responses of these Receptors to adrenal and sex Steroids occurred during the evolution of lobe-finned fish (coelacanths, lungfish), ray-finned fish and terrestrial vertebrates (amphibians, reptiles, birds, mammals).
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Recent insights into the origins of adrenal and sex Steroid Receptors
Journal of molecular endocrinology, 2002Co-Authors: Michael E. BakerAbstract:The recent cloning by Thornton (2001) of estrogen, progesterone and corticoid Receptors from lamprey provides important insights into the early evolution of adrenal and sex Steroid Receptors and an opportunity to elucidate the ancient Steroids that regulated gene transcription. Inclusion of lamprey sequences in a Steroid receptor phylogeny indicates that the estrogen receptor is the most ancient of these Receptors, followed by the progesterone receptor and the corticoid receptor. Thornton proposed that estradiol was the earliest of the Steroids to activate a Steroid receptor. An alternative hypothesis is that a Steroid in the ∆ 5 pathway activated the ancestral estrogen receptor.
Sunil K Halder - One of the best experts on this subject based on the ideXlab platform.
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1 25 dihydroxyvitamin d3 regulates expression of sex Steroid Receptors in human uterine fibroid cells
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Ayman Alhendy, Ahmed Elsohemy, Michael P Diamond, Sunil K HalderAbstract:Context: Uterine fibroids (UFs) are the most common benign tumors in premenopausal women. In this study, we evaluated the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] for the treatment of UFs. Objective: To determine the role of 1,25(OH)2D3 on the expression of sex Steroid Receptors in human UF cells. Design: Human UFs and their adjacent myometrium were analyzed for expression of estrogen receptor (ER)-α, progesterone receptor (PR)-A, and PR-B, as well as members of the Steroid receptor coactivator (SRC) family. Immortalized human uterine fibroid (human uterine leiomyoma [HuLM]) cells were treated with 1,25(OH)2D3 and assayed for the expression and localization of the aforementioned Receptors and SRCs using Western blot, immunohistochemistry, immunofluorescence, and immunoprecipitation assays. Main Outcome Measures: We discovered a correlation between reduced levels of vitamin D receptor (VDR) and increased levels of ER-α, PR-A, and PR-B in these tissues. We evaluated the effects of 1,25(OH)2D3 on th...
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1 25 dihydroxyvitamin d3 regulates expression of sex Steroid Receptors in human uterine fibroid cells
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Ayman Alhendy, Ahmed Elsohemy, Michael P Diamond, Sunil K HalderAbstract:Context: Uterine fibroids (UFs) are the most common benign tumors in premenopausal women. In this study, we evaluated the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] for the treatment of UFs. Objective: To determine the role of 1,25(OH)2D3 on the expression of sex Steroid Receptors in human UF cells. Design: Human UFs and their adjacent myometrium were analyzed for expression of estrogen receptor (ER)-α, progesterone receptor (PR)-A, and PR-B, as well as members of the Steroid receptor coactivator (SRC) family. Immortalized human uterine fibroid (human uterine leiomyoma [HuLM]) cells were treated with 1,25(OH)2D3 and assayed for the expression and localization of the aforementioned Receptors and SRCs using Western blot, immunohistochemistry, immunofluorescence, and immunoprecipitation assays. Main Outcome Measures: We discovered a correlation between reduced levels of vitamin D receptor (VDR) and increased levels of ER-α, PR-A, and PR-B in these tissues. We evaluated the effects of 1,25(OH)2D3 on th...
Stephen R. Hammes - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Receptors outside the nucleus: extranuclear signalling by Steroid Receptors
Nature Reviews Molecular Cell Biology, 2016Co-Authors: Ellis R. Levin, Stephen R. HammesAbstract:Steroid hormone Receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that Steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most Steroid Receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a Steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear Steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of Steroid hormone signalling and its roles in health and disease. Steroid Receptors classically function in the nucleus, regulating the expression of genes that are important for a wide range of cellular functions. It has now become clear that many classic Steroid Receptors also localize to other cellular compartments (including, prominently, the plasma membrane) to activate various signalling pathways. Signalling from membrane-localized Steroid Receptors can elicit non-genomic responses, such as G protein and kinase signalling. Steroid receptor signalling from the membrane can also be involved in the regulation of gene expression, sometimes by engaging in crosstalk with nuclear pools of the respective receptor. Membrane-initiated Steroid signalling has been shown to have various physiological functions and has been associated with the development and propagation of cancer. Transgenic mice that selectively express only one functional oestrogen receptor-α pool — either membrane or nuclear — display phenotypes that overlap significantly with those of mice completely lacking oestrogen receptor-α, indicating that both pools are necessary for most oestrogen-dependent processes. More broadly, it can be concluded that extranuclear Steroid signalling is required for full Steroid hormone action during development and organ homeostasis. Steroid hormone Receptors are well known to regulate various aspects of animal physiology by acting as transcriptional regulators in the nucleus. However, it is now evident that these Receptors can also be targeted to extranuclear locations (such as the plasma membrane), where they instigate rapid signals that contribute to Steroid-mediated cellular responses.
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nuclear Receptors outside the nucleus extranuclear signalling by Steroid Receptors
Nature Reviews Molecular Cell Biology, 2016Co-Authors: Ellis R. Levin, Stephen R. HammesAbstract:Steroid hormone Receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that Steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most Steroid Receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a Steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear Steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of Steroid hormone signalling and its roles in health and disease.
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Extranuclear Steroid Receptors: nature and actions.
Endocrine reviews, 2007Co-Authors: Stephen R. Hammes, Ellis R. LevinAbstract:Rapid effects of Steroid hormones result from the actions of specific Receptors localized most often to the plasma membrane. Fast-acting membrane-initiated Steroid signaling (MISS) leads to the modification of existing proteins and cell behaviors. Rapid Steroid-triggered signaling through calcium, amine release, and kinase activation also impacts the regulation of gene expression by Steroids, sometimes requiring integration with nuclear Steroid receptor function. In this and other ways, the integration of all Steroid actions in the cell coordinates outcomes such as cell fate, proliferation, differentiation, and migration. The nature of the Receptors is of intense interest, and significant data suggest that extranuclear and nuclear Steroid receptor pools are the same proteins. Insights regarding the structural determinants for membrane localization and function, as well as the nature of interactions with G proteins and other signaling molecules in confined areas of the membrane, have led to a fuller understanding of how Steroid Receptors effect rapid actions. Increasingly, the relevance of rapid signaling for the in vivo functions of Steroid hormones has been established. Examples include Steroid effects on reproductive organ development and function, cardiovascular responsiveness, and cancer biology. However, although great strides have been made, much remains to be understood concerning the integration of extranuclear and nuclear receptor functions to organ biology. In this review, we highlight the significant progress that has been made in these areas.
Donald B. Defranco - One of the best experts on this subject based on the ideXlab platform.
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Molecular chaperones and subcellular trafficking of Steroid Receptors.
The Journal of Steroid Biochemistry and Molecular Biology, 1998Co-Authors: Donald B. Defranco, Charu Ramakrishnan, Yuting TangAbstract:Abstract Unliganded Steroid Receptors exist as heteromeric complexes comprised of heat shock and immunophilin proteins that associate either directly or indirectly with receptor carboxyl–terminal ligand-binding domains. Molecular chaperons, and other proteins associated with Steroid Receptors, play an important role in the maturation of Receptors to a hormone-binding competent state. Steroid receptor-associated 90 and 70 kDa heat shock proteins, hsp90 and hsp70, respectively, have well established roles in protein folding in addition to participating in numerous subcellular trafficking pathways. In this review, we discuss the possible roles that molecular chaperons, such as hsp90, hsp70 and DnaJ proteins, have in Steroid receptor trafficking within two distinct subcellular compartments, i.e. the cytoplasm and nucleus.
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Subcellular and Subnuclear Trafficking of Steroid Receptors
Molecular Biology of Steroid and Nuclear Hormone Receptors, 1998Co-Authors: Donald B. DefrancoAbstract:Many external signals affect cell physiology through alterations in gene expression. Cell surface Receptors, once they have been activated by the binding of appropriate ligands, mobilize signal transduction cascades that may ultimately affect the activity of defined sets of transcription factors. Receptors for Steroid hormones, in contrast, are soluble, intracellular proteins that function as transcription factors to directly regulate the transcriptional activity of target genes. Thus, Steroid hormones utilize a streamlined signal transduction system in which a single protein, the Steroid hormone receptor, has the capacity both to recognize an external signal and to transduce that signal to alterations in specific gene expression. The delivery of activated Steroid Receptors to genomic target sites must be efficient to account for the rapidity and selectivity of many transcriptional responses to Steroid hormones. This review will focus on recent advances in subcellular trafficking of Steroid Receptors, and will include discussions both of receptor trafficking between different subcellular compartments (i.e., the cytoplasm and nucleus) and of the trafficking of Receptors within a specific compartment (i.e., the nucleus).
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Nucleocytoplasmic shuttling of Steroid Receptors.
Vitamins and hormones, 1995Co-Authors: Donald B. Defranco, Anuradha Madan, Yuting Tang, Uma R. Chandran, Nianxing Xiao, Jun YangAbstract:Publisher Summary This chapter elaborates the nucleocytoplasmic shuttling of Steroid Receptors. The activity of various Steroid Receptors hormone-independent nuclear localization signal sequences (NLSs) is suppressed, in cis, by the unoccupied glucocorticoid Receptors ligand binding domain (GR LBD). This repressive function is relieved upon the binding of hormone, most likely reflecting exposure of the NLS from a site within a receptor heteromeric complex. In some cells, heat-shock protein (hsp)70 appears to remain bound to GR following its activation and tight association with nuclei, prompting speculation that hsp70 may influence some nuclear functions of the receptor or directly participate in the nuclear transport of GR. Analogous effects on GR nuclear retention were also observed in nontransformed NRK cells treated with okadaic acid, a specific inhibitor of protein phosphatase types 1 and 2A. The nucleocytoplasmic shuttling of other Steroid Receptors could likewise be influenced by their association in nuclear anchoring complexes, while still accounting for the unique equilibrium subcellular distributions observed among different Receptors. The reformation of a GR heteromeric complex could represent the ATP-dependent step that has been postulated to be required for GR recycling and perhaps for nuclear export.