The Experts below are selected from a list of 183 Experts worldwide ranked by ideXlab platform
Anthony N. Hollenberg - One of the best experts on this subject based on the ideXlab platform.
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the in vivo role of nuclear receptor corepressors in thyroid Hormone Action
Biochimica et Biophysica Acta, 2013Co-Authors: Inna Astapova, Anthony N. HollenbergAbstract:Abstract Background The thyroid Hormone receptor (TR) isoforms interact with a variety of coregulators depending upon the availability of T3 to mediate their transcriptional effect. Classically, in the absence of ligand, the TRs recruit the nuclear corepressors, NCoR and SMRT, to mediate transcriptional repression on positively regulated TR target genes. However, new insight into the roles of NCoR and SMRT using in vivo models have better defined the role of nuclear corepressors both in the absence and presence of T3. Scope of review This review will place the variety of in vivo nuclear corepressor mouse models developed to date in context of thyroid Hormone Action. Based on these models, we will also discuss how corepressor availability together with the levels of endogenous nuclear receptor ligands including T3 controls multiple signaling pathways. Major conclusions Nuclear corepressors mediate repression of positive TR targets in the absence of T3 in vivo. Even more importantly they attenuate activation of these targets at the normal physiological levels of ligands by TR and other nuclear receptors. While the role of corepressors in the regulation of negative TR targets and HPT axis remains poorly understood, lack of corepressor recruitment to TR in the animals leads to a compensatory change in the set point of HPT axis that allows to balance the increased sensitivity to T3 Action in other tissues. General significance Available data indicate that targeting specific interActions between corepressors and TR or other nuclear receptors presents a new therapeutic strategy for endocrine and metabolic disorders. This article is part of a Special Issue entitled Thyroid Hormone signalling.
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the nuclear corepressor ncor regulates thyroid Hormone Action in vivo
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Inna Astapova, Larissa J Lee, Crystal Morales, Stefanie Tauber, Martin Bilban, Anthony N. HollenbergAbstract:The thyroid Hormone receptor (TR) has been proposed to regulate expression of target genes in the absence of triiodothyronine (T(3)) through the recruitment of the corepressors, NCoR and SMRT. Thus, NCoR and SMRT may play an essential role in thyroid Hormone Action, although this has never been tested in vivo. To accomplish this, we developed mice that express in the liver a mutant NCoR protein (L-NCoRDeltaID) that cannot interact with the TR. L-NCoRDeltaID mice appear grossly normal, however, when made hypothyroid the repression of many positively regulated T(3)-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by TR in the absence of T(3). Remarkably, in the euthyroid state, expression of many T(3)-targets is also up-regulated in L-NCoRDeltaID mice, demonstrating that NCoR also determines the magnitude of the response to T(3) in euthyroid animals. Although positive T(3) targets were up-regulated in L-NCoRDeltaID mice in the hypo- and euthyroid state, there was little effect seen on negatively regulated T(3) target genes. Thus, NCoR is a specific regulator of T(3)-Action in vivo and mediates repression by the unliganded TR in hypothyroidism. Furthermore, NCoR appears to play a key role in determining the tissue-specific responses to similar levels of circulating T(3). Interestingly, NCoR recruitment to LXR is also impaired in this model, leading to activation of LXR-target genes, further demonstrating that NCoR recruitment regulates multiple nuclear receptor signaling pathways.
Marc J Tetel - One of the best experts on this subject based on the ideXlab platform.
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nuclear receptor coactivators essential players for steroid Hormone Action in the brain and in behaviour
Journal of Neuroendocrinology, 2009Co-Authors: Marc J TetelAbstract:Steroid Hormones act both in the brain and throughout the body to influence behaviour and physiology. Many of these effects of steroid Hormones are elicited by transcriptional events mediated by their respective receptors. A variety of cell culture studies reveal that nuclear receptor coactivators are critical for modulating steroid receptor-dependent transcription. Thus, in addition to the availability of the Hormone and the expression of its receptor, nuclear receptor coactivators are essential for steroid-dependent transactivation of genes. This review discusses the mounting evidence indicating that nuclear receptor coactivators are critical for modulating steroid Hormone Action in the brain and in the regulation of behaviour.
Gregory A Brent - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of thyroid Hormone Action
Journal of Clinical Investigation, 2012Co-Authors: Gregory A BrentAbstract:Our understanding of thyroid Hormone Action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of Hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a number of cancers. The mechanism of thyroid Hormone Action has been informed by these clinical observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid Hormone transporters, corepressors, and coactivators; thyroid Hormone receptor (TR) isoform-specific Action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, especially for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function.
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The Molecular Basis of Thyroid Hormone Action
The New England journal of medicine, 1994Co-Authors: Gregory A BrentAbstract:Progress has been made in understanding the molecular basis of a number of clinical manifestations of thyroid disease, yet many questions remain. Why are there two thyroid Hormone-receptor genes? Is the function of each of the two receptors indeed unique? How T3 receptors interact with other nuclear proteins and DNA-binding sites and how these interActions are influenced by T3 is incompletely understood. The developmental regulatory role of T3 receptor alpha 1 and its non-T3-binding alpha 2 variant needs to be defined. Most T3-regulated processes, especially those related to metabolism, muscle contrAction, and brain development, function in concert with a number of other regulatory factors. The therapeutic applications of knowledge gained about the basic mechanisms of thyroid Hormone Action should ultimately extend beyond thyroid disease to processes regulated or influenced by T3; these include cardiac function, lipid metabolism, pituitary Hormone secretion, and neural development.
Lawrence E. Mallette - One of the best experts on this subject based on the ideXlab platform.
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The Parathyroid PolyHormones: New Concepts in the Spectrum of Peptide Hormone Action*
Endocrine reviews, 1991Co-Authors: Lawrence E. MalletteAbstract:I. Introduction WE WILL review a series of studies in the field of calcium metabolism which, over the last 3 yr, have added a new complexity to our concepts about peptide Hormone Action. The traditional view of peptide Hormone Action holds that a peptide Hormone bears a region that is configured to possess high affinity for a receptor on the membrane of the target cell. InterAction with that receptor alters other membrane components to initiate a cascade of intracellular events, mediated by changes in intracellular AMP, calcium, phosphatidyl inositol metabolites, or other second messengers. An increased ambient concentration of the Hormone will cause an increased occupancy of receptors and greater Action on the target cell. The organ specificity of the Hormone is determined by the spectrum of cell types that bear the appropriate receptor. Additional orders of complexity were added by the findings that receptor number can vary (exposure to the Hormone, for example, can decrease the number of receptors), th...
T M Penning - One of the best experts on this subject based on the ideXlab platform.
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hydroxysteroid dehydrogenases and pre receptor regulation of steroid Hormone Action
Human Reproduction Update, 2003Co-Authors: T M PenningAbstract:Steroid target tissues regulate the local level of steroid Hormone that can bind and trans-activate nuclear receptors (a process known as intracrine modulation). This pre-receptor regulation can be achieved by hydroxysteroid dehydrogenases (HSDs). For each sex Hormone there is a pair of HSD isoforms which act either as reductases or oxidases to convert potent steroid Hormones into their cognate inactive metabolites, or vice-versa. In this manner, HSDs can function as molecular switches to regulate steroid Hormone Action. Because these HSDs show tissue-specific expression, inhibitors of these enzymes are predicted to cause tissue-specific responses to steroid Hormones. These inhibitors would represent a new class of therapeutics called 'selective intracrine modulators' (SIMs). SIMs are expected to have the same tissue-specific effects as selective steroid receptor modulators but a different mode of Action as their effects are enzyme- and not receptor-mediated. HSDs responsible for these interconversions belong to two protein superfamilies: the short-chain dehydrogenases/reductases; and the aldo-keto reductases. Crystal structures exist for HSDs in both families, making rational design of SIMs a reality. Broad-based criteria have been established which must be fulfilled to validate each HSD isoform as a potential SIM target.