Nuclear hormone receptors thyroid hormones

Nuclear Hormone Receptors. Certain hormones interact directly with hormonal receptors that are located on the chromatin within the cell nucleus (see Fig. 28-2).3 Thyroid hormones (T3 and T4) are a primary example of hormones that bind directly to nuclear receptors.29 After binding, thyroid hormones invoke a series of changes similar to those caused by the steroid-cytosolic receptor complex that is, the nucleus begins to transcribe messenger RNA, which is ultimately translated into specific proteins. In the case of the thyroid hormones, these new proteins usually alter the cell s metabolism. Thyroid hormones are discussed in more detail in Chapter 31. 

Like other nuclear receptors (e.g., steroid hormone receptors, thyroid hormone receptors) the PPARs function as ligand-activated transcription factors. As illustrated in Fig. 1 (see color insert) individual PPARs function as dimers with members of the retinoid X receptor (RXR) family (23). Evidence for an interaction of PPARs with RXRs includes co-expression studies that were performed with yeast lacking endogenous nuclear receptors (24). 

The antagonist-induced conformation of nuclear hormone receptors attracts co-repressors like Nco/SMRT (nuclear hormone receptor co-repressor/silencing mediator of retinoid and thyroid receptors) which further recruit other nuclear proteins with histone deacetylase activity. Their action leads to chromatin condensation, thus preventing the general transcription apparatus from binding to promoter regions. 

Nuclear Receptors Retinoic Acid Receptor Thyroid Hormone Receptor... 

An example of the complexity involved in the regulation of nuclear hormone receptors is shown in the case of the ER in the liver. Its synthesis is induced by estradiol, growth hormone, thyroid hormones, and glucocorticoids. 

Nuclear hormone receptors, including those for the principal classes of steroids, retinoids, vitamin D, and thyroid hormones, are transcription factors that influence gene expression. 

In the absence of ligand, some nuclear hormone receptors associate with co-repressors, namely, SMRT (silencing mediator of retinoic acid and thyroid hormone receptors) and N-CoR (nuclear receptor co-repressor). Both, SMRT and N-CoR, recruit coregulatory protein SINS and histone deacetylases (HDACs) to form a large co-repressor complex that contains histone deacetylase activity, implicating histone deacetylation in transcriptional repression [52,53]. 

Retinoids are a family of naturally occurring and synthetic analogues of vitamin A. The skin of subjects deficient in vitamin A becomes hyperplastic and keratotic (phrynoderma, or toad skin). While natural vitamin A is occasionally employed therapeutically, synthetic retinoids are more effective and represent a major advance in dermatological pharmacotherapy. Retinoids have myriad effects on cellular differentiation and proliferation it is likely that nuclear retinoic acid receptors mediate these effects by activating gene expression in a manner analogous to receptors for steroid hormones and thyroid hormones. Despite a common mechanism of action, however, retinoids vary widely in their physiological effects. 

Figure 2 Nuclear hormone receptor structure and ligands, (a) The functional domains of nuclear hormone receptors. They act as either homodimers or heterodimers with a ligand binding domain and a DNA binding domain that are separated by a linker sequence, (b) The conformational change in helix 12 when ligand binding occurs (61, 62). All-trans retinoic acid is shown behind helix 12. (c) Examples of synthetic ligands for estrogen receptor (SERMs) and thyroid hormone receptor (Thyromimetics).

Burris TP, Nawaz Z, Tsai MJ, O Malley BW. 1995. A nuclear hormone receptor-associated protein that inhibits transactivation by the thyroid hormone and retinoic acid receptors. Proc. Natl. Acad. Sci. USA 92 9525-29... 

Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptors superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid receptors. All members of this superfamily have a similar structure the amino-terminal region allows ligand-independent activation, confers con-... 

For this group of patients, there is a requirement for a novel therapeutic approach and several are under investigation. One such area of interest is the use of retinoids, agents that are thought to act as nuclear hormone receptor hgands to restore iodine uptake in thyroid cells, i.e., causing the redifferentiation of the thyroid cells. 

Jeyakumar and Katzenellenbogen developed a dual-acceptor assay to monitor a nuclear receptor (thyroid hormone - retinoid X receptor heterodimer) regulation by measuring both coactivator and corepressor binding by using fluorescein and Cy-5 as acceptors for a terbium chelate-labeled response element-bound receptor complex [47]. 

Nuclear hormone receptor (NHR) A transcription factor whose activity is regulated by a small molecule (the ligand), such as a steroid (estrogen, cortisol, etc.) or an amino acid (thyroid hormone). Most NHRs are transcriptional activators in the presence of ligand some NHRs also act as transcriptional repressors in its absence. 

Fig. 2. Early events in thyroid-hormone action. Interaction of T with cell nuclear receptors (6).

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