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Reviews 22 451 –476. Ishihara A , Sawatsubashi S & Yamauchi K 2003a Endocrine disrupting chemicals: interference of thyroid hormone binding to transthyretins and to thyroid hormone receptors. Molecular and Cellular
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circulating binding proteins, modified entry of thyroid hormone into tissue, changes in thyroid hormone metabolism due to modified expression of the intracellular iodothyronine deiodinases and changes in thyroid hormone receptor (THR) expression or function
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Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 North 5th Street, Phoenix, Arizona 85004-2157, USA
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Department of Basic Medical Sciences, School of Mathematical and Natural Sciences, University of Arizona College of Medicine, 425 North 5th Street, Phoenix, Arizona 85004-2157, USA
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/Hr interaction is that Hr inhibits the ability of VDR to activate transcription of its target genes in response to the 1,25D ligand ( Hsieh et al . 2003 a , Xie et al . 2006 ). Hr also has been shown to attenuate transactivation by the thyroid hormone receptor
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Hormonal responsiveness in peripheral tissues is variable in patients with resistance to thyroid hormone (RTH). One cause of this may be differential interaction of RTH mutants of thyroid hormone receptor beta (TR beta) with TR auxiliary proteins (TRAPs). We used gel shift mobility assays to examine the interaction of wild-type and mutant TR beta s with retinoid X receptors (RXRs) and endogenous TRAPs. Some mutants showed reduced homodimerization but retained heterodimerization with recombinant RXRs. Wild-type TR beta formed heterodimeric complexes with multiple TRAPs in nuclear extracts of rat tissues, but RTH mutants showed variably altered heterodimerization with each TRAP. With liver nuclear extract, all mutants with impaired homodimerization also showed impaired TR beta-TRAP heterodimerization. Thus heterodimerizations with RXRs and TRAPs are differently affected by RTH mutations. Our results suggest that multiple TRAPs are expressed in tissue-specific patterns. The variability of TR beta heterodimerization with TRAPs may account, in part, for the variable tissue responsiveness in RTH.
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Introduction
Retinoic acid and thyroid hormones regulate gene expression by binding to intracellular proteins that are members of the nuclear receptor superfamily of transcription factors. Members of this gene family activate transcription by binding to specific DNA sequences, termed response elements, that are generally located in the vicinity of target genes. Thyroid hormone receptors (TRs) and retinoic acid receptors (RARs) can exert either of two effects on the transcription of target genes. In the absence of ligand, both the RAR and TR strongly repress transcription from promoters to which they bind. In the presence of an activating ligand, this repressive effect is relieved and transcription is markedly stimulated. As a result, a very large dynamic range in the level of transcriptional activity can be achieved. Recognition of DNA response elements by nuclear receptors is mediated by a central, highly conserved DNA binding domain, while ligand binding, dimerization and transcriptional activation
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Introduction
Prostate cancer constitutes a major health issue in Western countries where it is now the most frequently diagnosed invasive tumour and second leading cause of cancer deaths (Wingo et al. 1995). Androgen action in prostate cancers, as in the normal prostate gland and other target organs, is mediated by the androgen receptor (AR), a ligand-activated nuclear transcription factor that is a member of the steroid/thyroid hormone receptor gene superfamily (O'Malley 1990, Truss & Beato 1993). Although the human AR has only recently been cloned (Chang et al. 1988, Lubahn et al. 1988, Trapman et al. 1988, Tilley et al. 1989), specific actions of androgens on the growth, differentiation and function of the prostate gland were elucidated early this century. In 1941, Huggins and Hodges demonstrated that, similar to non-malignant prostate, prostate cancers were androgen-responsive and that tumour regression was evident following removal of testicular androgens by castration. More than
INSERM UMR 788, INSERM UMR 854, University Paris-Sud 11, Stéroïdes, neuroprotection et neurogénération, 94275 Le Kremlin-Bicêtre cedex, France
INSERM UMR 788, INSERM UMR 854, University Paris-Sud 11, Stéroïdes, neuroprotection et neurogénération, 94275 Le Kremlin-Bicêtre cedex, France
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INSERM UMR 788, INSERM UMR 854, University Paris-Sud 11, Stéroïdes, neuroprotection et neurogénération, 94275 Le Kremlin-Bicêtre cedex, France
INSERM UMR 788, INSERM UMR 854, University Paris-Sud 11, Stéroïdes, neuroprotection et neurogénération, 94275 Le Kremlin-Bicêtre cedex, France
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INSERM UMR 788, INSERM UMR 854, University Paris-Sud 11, Stéroïdes, neuroprotection et neurogénération, 94275 Le Kremlin-Bicêtre cedex, France
INSERM UMR 788, INSERM UMR 854, University Paris-Sud 11, Stéroïdes, neuroprotection et neurogénération, 94275 Le Kremlin-Bicêtre cedex, France
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INSERM UMR 788, INSERM UMR 854, University Paris-Sud 11, Stéroïdes, neuroprotection et neurogénération, 94275 Le Kremlin-Bicêtre cedex, France
INSERM UMR 788, INSERM UMR 854, University Paris-Sud 11, Stéroïdes, neuroprotection et neurogénération, 94275 Le Kremlin-Bicêtre cedex, France
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In the brain, 3,5,3′-triiodothyronine, which binds to the thyroid hormone receptor with high affinity, is locally generated from thyroxine by type 2 iodothyronine deiodinase (D2) expressed mainly in astrocytes and tanycytes. We have investigated the effects of bacterial lipopolysaccharide (LPS) on D2 in cultured rat astrocytes. LPS induced D2 activity with a lag-time of 4–8 h and a maximum at 24 h. LPS also promoted D2 mRNA accumulation. Glucocorticoids enhanced both the basal and LPS-stimulated D2 activity and mRNA accumulation. These glucocorticoid effects were blocked by the glucocorticoid receptor antagonist RU486. Our results obtained with different specific signaling pathway inhibitors indicated that D2 induction by LPS required ERK and p38-MAPK signaling pathways. NF-κB inhibitor sulfasalazine blocked the effects of LPS on both D2 activity and mRNA accumulation. Hence, D2 induction by LPS appeared to implicate NF-κB pathway in astrocytes. NF-κB responsiveness of the rat dio2 gene was studied in astrocytes with dio2 5′-flanking region promoter assays. The long form of the dio2 promoter was transactivated by NF-κB. CCAAT/enhancer-binding protein β, which is upregulated by LPS in astrocytes, increased the transcriptional activity of the dio2 promoter in its long or truncated forms containing CCAATs. Our observations, which demonstrate D2 induction by LPS in astrocytes and specify some characteristics of D2 induction mechanism, support the possible implication of brain D2 in adaptative responses to an infectious stress.
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The thyromimetic compound SK&F L-94901 shows more potent thyromimetic activity in the liver than in the pituitary gland or heart when administered to rats. The mechanisms of liver-selectivity of SK&F L-94901 were examined using cultured rat hepatoma cells (dRLH-84) and rat pituitary tumor cells (GH3), both of which showed saturable cellular uptake of tri-iodothyronine (T(3)). When isolated nuclei with partial disruption of the outer nuclear membrane were used, SK L-94901 competed for [(125)I]T(3) binding to nuclear receptors almost equally in dRLH-84 and GH3 cells. SK L-94901 also did not discriminate thyroid hormone receptors (TR) alpha1 and beta1 in terms of binding affinity and activation of the thyroid hormone responsive element. In intact cells, however, SK L-94901 was a more potent inhibitor of nuclear [(125)I]T(3) binding in dRLH-84 cells than in GH3 cells at an early phase of the nuclear uptake process and after binding equilibrium. These data suggest that SK L-94901 is more effectively transported to nuclear TRs in hepatic cells than in pituitary cells and therefore shows liver-selective thyromimetic activity. In conclusion, SK L-94901 discriminates hepatic cells and pituitary cells at the nuclear transport process. The cellular transporters responsible for this discrimination were not evident.
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Thyroid hormones (THs) regulate growth, development, differentiation and metabolic processes by interacting and activating thyroid hormone receptors (TRs). Although much progress has been made in our understanding of the transcriptional regulation of many TR target genes, little is known of the regulation of plasma protein gene expression by TRs. To investigate the role of TRs in plasma protein expression we used human hepatocellular carcinoma cell lines and carried out cDNA microarray analysis. Our results indicate that several plasma proteins including transferrin, prothrombin, angiotensinogen, haptoglobin, alpha-2-HS-glycoprotein alpha and beta chain, complement, lipoproteins and fibrinogen are up-regulated by THs. Furthermore, clusterin, alpha-2-macroglobulin precursor, prothymosin alpha and alpha-fetoprotein were found to be down-regulated by THs.Transferrin, an iron-binding protein expressed in all mammals, and mainly synthesized in the liver, was investigated further. Immunoblot and Northern blot analyses revealed that exposure of HepG2-TRalpha1 sub-lines and HepG2-Neo cells to tri-iodothyronine (T(3)) induced time- and dose-dependent increases in the abundance of transferrin mRNA and protein, with the extent of these effects correlating with the level of expression of TRalpha1. Nuclear run-on experiments indicate that this induction is functioning at the transcriptional level. Moreover, cyclohexamide treatment did not eliminate the induction of transferrin by TH. Thus, our results suggest that the induction of transferrin by TH is direct and may in fact be mediated by an as yet unidentified response element in the promoter region.
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The expression of TSH receptor (TSHR) gene is frequently lost in thyroid cancers during the process of dedifferentiation that involves perturbation of several nuclear transcription factors. We have established that thyroid hormone receptor beta1 (TRbeta1) is associated with the loss of TSHR gene expression in an anaplastic human thyroid cancer cell line, ARO. To demonstrate that TRbeta1 regulates TSHR gene expression, we performed electrophoresis mobility shift and 3,5,3'-triiodothyronine (T3) transactivation assays. As expected, TRbeta1 bound the synthesized oligomer containing TSHR promoter sequence by heterodimerizing with retinoid X receptor. When a chimeric reporter pTRCAT5'-146 enclosing the minimal TSHR promoter was applied for T3 transactivation assay, two TRbeta1-overexpressing transfectants of ARO cells (ARO1 and ARO2) demonstrated higher basal activity than their parental cells. Consequentially, T3 suppressed the reporter gene activity only in ARO1 and ARO2, but not in ARO cells. A point mutation creating a cAMP response element (CRE) in the reporter pTRCAT5'-146 CRE led to T3-induced suppression of the reporter gene in ARO cells without changing the basal or T3-induced activities in ARO1 and ARO2 cells. We conclude that the regulatory effect of T3 on TSHR gene expression is TR- and promoter DNA sequence-determined.
