Looking for the Mechanism of Action of Thyroid Hormone

The mechanisms of action of thyroid hormone (TH), characterized by multiple physiological activities, proposed over the last 80 years are a reflection of the progression of our knowledge about eukaryotic signalling processes. The cumulative knowledge gained raises the question as to what is so special about the action of this hormone. The discovery in the 1980s that TH receptors belong to the family of nuclear transcription factors that regulate the expression of hormonal target genes was an important milestone. TH receptors are highly organized within the chromatin structure, which itself is modified by several chromosomal and nonchromosomal factors, in the presence and absence of the hormone. Recently, some investigators have suggested that TH acts via both genomic and nongenomic mechanisms and introduced the concept of networking within cellular complexes. While one cannot as yet precisely describe the mechanism of thyroid hormone action, I will attempt here to point out the present thinking and future directions to achieve this goal in the light of the historical background

Autoinduction of nuclear hormone receptors during metamorphosis and its significance

Abstract Metamorphosis is a most dramatic example of hormonally regulated genetic reprogramming during postembryonic development. The initiation and sustenance of the process are under the control of ecdysteroids in invertebrates and thyroid hormone, 3,3Ј,5-triiodothyronine, in oviparous vertebrates. Their actions are inhibited or potentiated by other endogenous or exogenous hormonesjuvenile hormone in invertebrates and prolactin and glucocorticoids in vertebrates. The nuclear receptors for ecdysteroids and thyroid hormone are the most closely related members of the steroid/retinoid/thyroid hormone receptor supergene family. In many premetamorphic amphibia and insects, the onset of natural metamorphosis and the administration of the exogenous hormones to the early larvae are characterized by a substantial and rapid autoinduction of the respective nuclear receptors. This review will largely deal with the phenomenon of receptor autoinduction during amphibian metamorphosis, although many of its features resemble those in insect metamorphosis. In the frog Xenopus, thyroid hormone receptor autoinduction has been shown to be brought about by the direct interaction between the receptor protein and the thyroid-responsive elements in the promoter of its own gene. Three lines of evidence point towards the involvement of receptor autoinduction in the process of initiation of amphibian metamorphosis: (1) a close association between the extent of inhibition or potentiation by prolactin and glucocorticoid, respectively, and metamorphic response in whole tadpoles and in organ and cell cultures; (2) thyroid hormone fails to upregulate the expression of its own receptor in obligatorily neotenic amphibia but does so in facultatively neotenic amphibia; and (3) dominant-negative receptors known to block hormonal response prevent the autoinduction of wild-type Xenopus receptors in vivo and in cell lines. Autoinduction is not restricted to insect and amphibian metamorphic hormones but is also a characteristic of other nuclear receptors (e.g., retinoid, sex steroids, vitamin D 3 receptors) where the ligand is involved in a postembryonic developmental function. A wider significance of such receptor autoregulation is that the process may also be important for mammalian postembryonic development

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The mechanisms of action of thyroid hormone (TH), characterized by multiple physiological activities, proposed over the last 80 years are a reflection of the progression of our knowledge about eukaryotic signalling processes. The cumulative knowledge gained raises the question as to what is so special about the action of this hormone. The discovery in the 1980s that TH receptors belong to the family of nuclear transcription factors that regulate the expression of hormonal target genes was an important milestone. TH receptors are highly organized within the chromatin structure, which itself is modified by several chromosomal and nonchromosomal factors, in the presence and absence of the hormone. Recently, some investigators have suggested that TH acts via both genomic and nongenomic mechanisms and introduced the concept of networking within cellular complexes. While one cannot as yet precisely describe the mechanism of thyroid hormone action, I will attempt here to point out the present thinking and future directions to achieve this goal in the light of the historical background

Differential responses to ligands of overexpressed thyroid hormone and retinoid X receptors in a Xenopus cell line and in vivo

In an attempt to explain the contrasting patterns of expression of Xenopus thyroid hormone (xTR) and retinoid X(xRXR) receptor genes and to extend our understanding of the role of heterodimerization of these receptors during amphibian metamorphosis, we have investigated the response to their respective ligands of cells in which xTR and xRXR were overexpressed. Results obtained with two separate approaches are now described. In the first, 3,3',5-triiodothyronine (T-3) was found to strongly upregulate xTR beta mRNA in XTC-2 cells, but not of xTR alpha or xRXR alpha mRNAs, while xRXR gamma transcripts could not be detected. 9-cis-retinoic acid (9-cis-RA) did not substantially influence the expression of any of these four receptor genes. When transcription from three different thyroid response elements (TREs) (a palindromic TREpal, an inverted repeat + 6 [F2] and a direct repeat + 4 [DR + 4] as present in the promoter of xTR beta gene) was measured in XTC-2 cells in which xTR beta and xRXR alpha were overexpressed, only T-3 upregulated transcription while 9-cis-RA, alone or together with T-3, was ineffective. 9-cis-RA however enhanced transcription from an RXR responsive element (RXR-RE). The second approach involved overexpression of xTR beta and xRXR alpha in premetamorphic Xenopus tadpole tail muscle followed by measuring the response of the tails to T-3 in organ culture. After validating the microinjection/culture procedure histochemically, we found that T-3 enhanced transcription from the xTR beta DR + 4 TRE in tails in which xTR beta was overexpressed but the overexpression of xRXR alpha failed to modify this response. It is concluded that in both XTC-2 cells and tadpole tails, overexpressed xRXR fails to modify the enhanced transcriptional response of endogenous and overexpressed xTR beta to T-3 and that exogenous 9-cis-RA is ineffective. Copyright (C) 1997 Elsevier Science Ireland Ltd