Thyroid hormone, receptor

Thyroid hormone receptors (THRs) are subdivided intoa and P types, each having two isoforms. In rat brain, THR, mRNA is present in hippocampus, hypothalmus, cortex, cerebellum, and amygdala. Thyroxine (l-T (284) and triiodothyronine (l-T ) (285) are endogenous ligands for the THRs. TRIAC (286) is a THR antagonist. Selective ligands for PPARs have yet to be identified (Table 16). 

Van Beeren HC, Jong WMC, Kaptein E et al (2003) Dronedarone acts as a selective inhibitor of 3,5,3 -triiodothyronine binding to thyroid hormone receptor-a. in vitro and in vivo evidence. Endocrinology 144 552-558... 

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

Nuclear Receptors Retinoic Acid Receptor Thyroid Hormone Receptor... 

R, Samuels HH. Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking. Proc Natl Acad Sci USA 2003 100 7354-9. 

A comparison of several different steroid receptors with thyroid hormone receptors revealed a remarkable conservation of the amino acid sequence in certain regions, particularly in the DNA-binding domains. This led to the realization that receptors of the steroid or thyroid type are members of a large superfamily of nuclear receptors. Many related members of this family have no known ligand at present and thus are called orphan receptors. The nuclear receptor superfamily plays a critical role in the regulation of gene transcription by hormones, as described in Chapter 43. 

Steroid and thyroid hormone receptors NFkB-IKB family Serum response factors... 

As summarized in Figure 52-3, steroid/thyroid hormone receptors bind to other proteins as well as to DNA [7-9]. 

Cell fractionation procedures were fundamental to the biochemical identification of steroid and thyroid hormone receptors in brain as well as in other tissues. Isolation of highly purified cell nuclei from small amounts of tissue from discrete brain regions generally is accomplished with the aid of a nonionic detergent, such as Triton X-100 [7],... 

Understanding of the intracellular localization of steroid receptors has gone through a number of phases, beginning with the view that receptors translocated from cytoplasm to nucleus in the presence of hormone. Indeed, with the exception of thyroid hormone receptors, which are exclusively nuclear in location, cell fractionation studies have revealed that in the absence of hormone, steroid receptors are extracted in the soluble or cytosolic fraction. However, when steroid is present in the cell, many occupied receptors are retained by purified cell nuclei. Histological procedures, such as immunocytochemistry, have confirmed the largely nuclear localization of occupied receptors, but... 

Forrest, D., Reh, T. A. and Rusch, A. Neurodevelopmental control by thyroid hormone receptors. Curr. Opin. Neurobiol. 12 49-56,2002. 

The normal form of interaction between receptor and DNA requires the hormone to have broken the native structure of the receptor and the dimer to have been formed. That is to say, the receptor-DNA interaction comes after the hormone-receptor interaction. Nevertheless, situations have been described in vitro in which the receptor is able to be previously associated to the HRE. This situation occurs in vivo for the thyroid hormone receptors, in which case it seems that the hormone-free dimer acts as an expression repressor of genes dependent on these hormones (Evans et al. 1988). The arrival of the hormone activates the dimer in situ and inverts its role as regulator. 

Vasudevan N, Ogawa S, Pfaff D (2002) Estrogen and thyroid hormone receptor interactions physiological flexibility by molecular specificity. Physiol Rev 82 923... 

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. 

Lee, j. W., Choi, H. S., Gyueis, J., Beent, R., Mooee, D. D. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol. Endocrinol. 1995, 9, 243-254. 

Cheng SY (2005) Thyroid hormone receptor mutations and disease beyond thyroid hormone resistance. Trends Endocrinol Metab 16 176-182... 

Monden T, Wondisford FE, Hollenberg AN (1997) Isolation and characterization of a novel ligand-dependent thyroid hormone receptor-coactivating protein. J Biol Chem 272 29834-29841 Moore SD, Herrick SR, Ince TA, Kleinman MS, Cin PD, Morton CC, Quade BJ (2004) Uterine leiomyomata with t(10 17) disrupt the histone acetyltransferase MORF. Cancer Res 64 5570-5577... 

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