Receptor Specific Nuclear Actions Genomic Actions

Thyroid hormone receptors belong to a large superfamily of nuclear hormone receptors that include the steroid hormone, retinoic acid, vitamin D and peroxysomal proliferator receptors (PPARs). The receptors have a central DNA-binding domain and a carboxy-terminal ligand-binding domain (fig. 4). The two major isoforms, the thyroid hormone receptor a-1, a-2 (TRa) and (-1, (3-2, (3-3 (TR() have a high homology in these two domains, while the amino-terminal regions are more variable. Two thyroid hormone receptor genes located on chromosomes 17 and 3, respectively [89, 93-94] encoding for TRa and TR(, respectively. TRa-1, TRa-2, TR(-1 and TR(-3 are expressed widely, whereas TR(-2 is predominantly restricted to the hypothalamic/pituitary axis in the negative feedback regulation of TSH.

T3 binds to TR-a and TR-( resulting in nuclear gene expression. The receptors are ligand-regulatable transcription factors that recognize and interact with specific DNA sequences (thyroid hormone response elements) in the promoter region of target genes leading to consequent effects on transcription [95, 96] (fig. 5a). The transcriptional activity of target genes is either increased or decreased. Examples of target genes that are positively regulated by TH are: fatty acid synthetase, growth hormone, lysosome silencer, malic enzyme, type I 5'-deiodinase and negative regulated: epidermal growth factor receptor, prolactin, TSH, thyrotropin-releasing hormones, type II 5'-diodinase [96] The genomic effects have response times of hours to days. After TR binding to TH

Fig. 5. a The genomic pathway of TH action. T3 is converted from T4 by deiodinase or transported directly into the cell whereupon it binds to nuclear TRs. In positively regulated target genes, corepressors are subsequently released and coactivators recruited, resulting in histone acetylation and RNA polymerase II-mediated transcription. b Schematic representation of the proposed model of the nongenomic pathway of thyroid hormone action. T4 and T3 binds to integrin aV^3 and activates the MAPK pathway. It is possible that nuclear hormone receptors are serine phosphorylated and with down-stream transcriptional regulation result in angiogenesis. Other TH-regulated pathways have been depicted but little is known about their mechanisms. ERa = estrogen receptor a; PLC = Phospholipase C; PKC = protein kinase C; STAT1a = signal transducer and activator of transcription 1a. Reproduced with kind permission from Yen [109].

Fig. 5. a The genomic pathway of TH action. T3 is converted from T4 by deiodinase or transported directly into the cell whereupon it binds to nuclear TRs. In positively regulated target genes, corepressors are subsequently released and coactivators recruited, resulting in histone acetylation and RNA polymerase II-mediated transcription. b Schematic representation of the proposed model of the nongenomic pathway of thyroid hormone action. T4 and T3 binds to integrin aV^3 and activates the MAPK pathway. It is possible that nuclear hormone receptors are serine phosphorylated and with down-stream transcriptional regulation result in angiogenesis. Other TH-regulated pathways have been depicted but little is known about their mechanisms. ERa = estrogen receptor a; PLC = Phospholipase C; PKC = protein kinase C; STAT1a = signal transducer and activator of transcription 1a. Reproduced with kind permission from Yen [109].

response elements the transcriptional activity is altered by an interaction directly or indirectly with a complex array of transcriptional cofactors including corepressors, coactivators, integrators. Even unliganded TRs interact with core-pressors and repress expression rather than being an inactive passive receptor. This also explains that TR knockout mice are not suffering from as pronounced a hypothyroidism as might be expected [97].

Mutations have been demonstrated in the TR-p gene with resultant familial resistance to thyroid hormones. These patients are identified by their persistent elevation of circulating free T3 and T4 without a suppressed TSH concentration. The thyroid hormone resistance syndrome will be dealt with in more detail in a subsequent chapter.

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