Thyroid hormone receptor-associated

J. D. Fondell, M. Guermah, S. Malik, and R G. Roeder. Thyroid hormone receptor-associated proteins and general positive cofactors mediate thyroid hormone receptor function in the absence of the TATA box-binding protein-associated factors of TFIID. Proc Nad Acad. Sci, VSA, 96 (5), 1959-1964, 1999. 

Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG. 1998. The TRAP220 component of a thyroid hormone receptor-associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand dependent fashion. Proc. Natl. Acad Sci. USA 95 7939 14... 

Interaction of the HAT coactivatorcomplex with the ligand-activated receptors is apparently transient as dissociation is believed to occur as a result of acetylation of one or more coactivators on lysine residues adjacent to the signature LXXLL motif (187). Subsequently, the activated receptor presumably recruits a second class of multi-protein, transcriptional coactivator complexes to the template, and this latter complex, referred to as the thyroid hormone receptor-associated protein (TRAP)... 

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. 

Figure 7.4 The effect of bile acids on energy expenditure. Circulating bile acids bind to the G-protein-coupled receptor, TGR5 that stimulates increased cAMP-PKA activation and increased expression of type-2 iodothyronine deiodinase (D2). This response is sensitised by a high-fat diet. D2 converts thyroxine (T4) to active 3,5,3 -tri-iodothyronine (T3). T3 stimulates thyroid hormone receptor binding to target genes. This leads to altered expression of genes associated with energy balance, and increased energy expenditure.

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]. 

Fig. 7. Model for activation by coactivators (A) and inhibition by corepressors (B) of transcription. Abbreviations CBP/p300, cAMP response element binding protein SRC-1, steroid receptor coactivator 1 TBP, TATA-binding protein TAF, TBP-associated factor pol II, RNA polymerase II N-CoR, nuclear receptor corepressor SMRT, silencing mediator of retinoic and thyroid hormone receptors.

B Thyroid hormone receptor, THR All-trans retinoic acid receptor, RAR Vitamin D3 receptor, VDR 9-c/s retinoic acid receptor, RXR, Peroxysome proliferator activating receptor, PPAR Orphan receptors Short A/B domains do not associate with chaperones. Unliganded receptors bind to DNA... 

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... 

Fig. 3.3-9 Analogs that rescue function to TR/3 mutants TR (R320C), TR/3(R320H), and TR/S(R316H) associated with resistance to thyroid hormone. Receptor selectivity of ligand, mut/a, defined as (EC50 with TRa)/(ECso with mutant TR/3).

Most of the intracellular receptors reside principally in the nucleus, and some of these are constitutively bound, as dimers, to their response element in DNA (e.g., the thyroid hormone receptor). Binding of the hormone changes its activity and its ability to associate with, or disassociate from, DNA. Regulation of gene transcription by these receptors is described in Chapter 16. 

Ph. De Nayer and B. Dozin-Van Roye. Effect of chromatin associated factors on the activity of thyroid hormone receptors in rat liver and brain. Biochem. Biophys Res. Commun 98 1-6 (1981). 

Uses Despite the presence of thyroid hormone receptors on hair follicles and associated cells [16 ] and the success of topical T3 as a stimulate of hair growth in animals [17 ], topical treatment of alopecia areata with T3 (3.8 gg T3/30 gg of vehicle Novasome A) for 12 weeks in 10 patients in a double-blind placebo-controlled trial was found to be safe but ineffective in restoring hair growth [18 ]. 

The TAAR receptor system has also been associated with body temperature regulation on the basis of putative thyroid hormone metabolites and their synthetic derivatives (thyronamines) activating TAAR1 in rodents. However, as these effects are only observed with thyronamine concentrations several orders of magnitude above physiological levels, and as the specificity of these compounds has not been determined, the physiological significance of these observations is unclear. 

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