Nuclear thyroid receptors

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. 

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. 

In another recent example, Hashimoto reported photoaffinity experiments on retinoic acid receptors (RAR). Retinoic acid plays a critical role in cell proliferation and differentiation. RARs belong to the superfamily of nuclear/ thyroid hormone receptors. They consist of six transmembrane domains (A-F) which is a general feature of these receptors. The A/B domains have an autonomous transactivation function while the C-domain contains the Zn-finger, which binds to DNA. The large E-domain participates in ligand binding, dimerization, and ligand dependent transactivation. Finally, D- and F-domains help the orientation and stabilization of the E-domain. 

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]. 

Cellular Uptake and Intracellular Binding of T3 to Nuclear Thyroid Hormone Receptors... 

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. 

Figure 17.3 The nuclear receptor superfamily. Steroid receptor family members and thyroid receptor family members differ in several structural and functional properties. The estrogen receptors share properties with both steroid and thyroid receptor families and are likely an evolutionary precursor to both families.

A recently identified thyroid hormone cell surface receptor on the extracellular domain of integrin alphaVbeta (3) leads to the activation of the mitogen-activated protein kinase (MAPK) signal transduction cascade in human cell lines, Examples of MAPK-dependent thyroid hormone actions are plasma membrane ion pump stimulation and specific nuclear events, These events include serine phosphorylation of the nuclear thyroid hormone receptor, leading to co-activator protein recruitment and complex tissue responses, such as thyroid hormone-induced angiogenesis, The existence of this cell surface receptor means that the activity of the administered hormone could be limited through structural modification of the molecule to reproduce only those hormone actions initiated at the cell surface (8,9). 

Several lines of evidence indicate that macromolecules of as yet unidentified chemical nature, produced by cancers and released into the systemic circulation, are responsible for the biochemical alterations in the liver and other host organs. In view of the diverse regulatory properties of the many different enzymes that increase or decrease towards their immature level (see Table III), a deficiency or excess in any given endocrine or dietary factor can clearly not explain the phenomenon. Nor has it been possible to implicate reductions in the efficacy of these factors. Subnormal concentration of the nuclear thyroid hormone receptor has been noted in the liver of tumor-bearing animals(24) however, since losses in the T3-inducible catalysts of the same liver occurred at much earlier stages of tumor-bearing,(24) the subnormal receptor concentration could clearly not be the cause of these losses but was probably another, and rather late, reflection of the process of biochemical undifferentiation. 

Thyroid hormone Synthesis of pumps a) Increased gene transcription (through direct interaction of nuclear T3-receptor complex with c/s-regulatory upstream gene element, or secondary to T3 induction of other proteins, or to altered ion fluxes) b) Posttranscriptional effects on mRNA levels c) Translational effects... 

ER Estrogen Receptor, AR Androgen Receptor, GR Glucocorticoid Receptor, TR Thyroid Receptor, RAR Retinoic Acid Receptor, RXR Retinoie X Receptor, PR Progesterone Receptor, VDR Vitamin D Receptor, PPAR Peroxisome Proliferator-Activated Receptor, PXR Pregnane X Receptor, ROR Retinoic Acid-Related Orphan Receptor, NHF-4 Hepatocyte Nuclear Eactor 4, ERR Estrogen-Related Receptor... 

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-... 

All but a few of the thyroid effects that have been identified occur at the level of gene transcription, mediated by nuclear thyroid hormone receptors (Chapter 30). These effects have a longer latency period than for most steroids some of the relatively early responses show a latency period of several hours. 

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