scholarly journals Constitutive activation of gene expression by thyroid hormone receptor results from reversal of p53-mediated repression.

1997 ◽  
Vol 17 (12) ◽  
pp. 7195-7207 ◽  
Author(s):  
J S Qi ◽  
V Desai-Yajnik ◽  
Y Yuan ◽  
H H Samuels
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Promoter Activity ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Gene Promoters ◽  
Wild Type ◽  
Constitutive Activation

Thyroid hormone receptor (T3R) is a member of the steroid hormone receptor gene family of nuclear hormone receptors. In most cells T3R activates gene expression only in the presence of its ligand, L-triiodothyronine (T3). However, in certain cell types (e.g., GH4C1 cells) expression of T3R leads to hormone-independent constitutive activation. This activation by unliganded T3R occurs with a variety of gene promoters and appears to be independent of the binding of T3R to specific thyroid hormone response elements (TREs). Previous studies indicate that this constitutive activation results from the titration of an inhibitor of transcription. Since the tumor suppresser p53 is capable of repressing a wide variety of gene promoters, we considered the possibility that the inhibitor is p53. Evidence to support this comes from studies indicating that expression of p53 blocks T3R-mediated constitutive activation in GH4C1 cells. In contrast with hormone-independent activation by T3R, p53 had little or no effect on T3-dependent stimulation which requires TREs. In addition, p53 mutants which oligomerize with wild-type p53 and interfere with its function also increase promoter activity. This enhancement is of similar magnitude to but is not additive with the stimulation mediated by unliganded T3R, suggesting that they target the same factor. Since p53 mutants are known to target wild-type p53 in the cell, this suggests that T3R also interacts with p53 in vivo and that endogenous levels of p53 act to suppress promoter activity. Evidence supporting both functional and physical interactions of T3R and p53 in the cell is presented. The DNA binding domain (DBD) of T3R is important in mediating constitutive activation, and the receptor DBD appears to functionally interact with the N terminus of p53 in the cell. In vitro binding studies indicate that the T3R DBD is important for interaction of T3R with p53 and that this interaction is reduced by T3. These findings are consistent with the in vivo studies indicating that p53 blocks constitutive activation but not ligand-dependent stimulation. These studies provide insight into mechanisms by which unliganded nuclear hormone receptors can modulate gene expression and may provide an explanation for the mechanism of action of the v-erbA oncoprotein, a retroviral homolog of chicken T3R alpha.

scholarly journals The thyroid hormone receptor gene (c-erbA alpha) is expressed in advance of thyroid gland maturation during the early embryonic development of Xenopus laevis.

1991 ◽  
Vol 11 (10) ◽  
pp. 5079-5089 ◽  
Author(s):  
D E Banker ◽  
J Bigler ◽  
R N Eisenman
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Xenopus Laevis ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Thyroid Hormone Receptors ◽  
Stages Of Development ◽  
Xenopus Development

The c-erbA proto-oncogene encodes the thyroid hormone receptor, a ligand-dependent transcription factor which plays an important role in vertebrate growth and development. To define the role of the thyroid hormone receptor in developmental processes, we have begun studying c-erbA gene expression during the ontogeny of Xenopus laevis, an organism in which thyroid hormone has well-documented effects on morphogenesis. Using polymerase chain reactions (PCR) as a sensitive assay of specific gene expression, we found that polyadenylated erbA alpha RNA is present in Xenopus cells at early developmental stages, including the fertilized egg, blastula, gastrula, and neurula. By performing erbA alpha-specific PCR on reverse-transcribed RNAs from high-density sucrose gradient fractions prepared from early-stage embryos, we have demonstrated that these erbA transcripts are recruited to polysomes. Therefore, erbA is expressed in Xenopus development prior to the appearance of the thyroid gland anlage in tailbud-stage embryos. This implies that erbA alpha/thyroid hormone receptors may play ligand-independent roles during the early development of X. laevis. Quantitative PCR revealed a greater than 25-fold range in the steady-state levels of polyadenylated erbA alpha RNA across early stages of development, as expressed relative to equimolar amounts of total embryonic RNA. Substantial increases in the levels of erbA alpha RNA were noted at stages well after the onset of zygotic transcription at the mid-blastula transition, with accumulation of erbA alpha transcripts reaching a relative maximum in advance of metamorphosis. We also show that erbA alpha RNAs are expressed unequally across Xenopus neural tube embryos. This differential expression continues through later stages of development, including metamorphosis. This finding suggests that erbA alpha/thyroid hormone receptors may play roles in tissue-specific processes across all of Xenopus development.

scholarly journals Ligand-dependent enhancement of human antithrombin gene expression by retinoid X receptor α and thyroid hormone receptor β

1996 ◽  
Vol 318 (1) ◽  
pp. 263-270 ◽  
Author(s):  
René W. L. M. NIESSEN ◽  
Farhad REZAEE ◽  
Pieter H. REITSMA ◽  
Marjolein PETERS ◽  
Jan J. M. de VIJLDER ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Promoter Region ◽  
Promoter Activity ◽  
Thyroid Hormone Receptor ◽  
Retinoid X Receptor ◽  
Hepatoma Cell Line ◽  
Promoter Fragment ◽  
Thyroid Hormone Receptor Β

We studied potential modulators of antithrombin gene expression. A putative hormone response element (HRE) was identified by sequence similarity analysis of the antithrombin promoter, situated between nucleotides -92 and -54 relative to the transcription start site. This HRE contains three hexanucleotide motifs with an AGGTCA consensus, which are potential targets of members of the steroid/thyroid superfamily of nuclear receptors. Stimulation of the hepatoma cell line HepG2 with the receptor ligands l-3,5,3´-tri-iodothyronine, all-trans retinoic acid, or their combination, increased production of antithrombin into the culture medium by 1.3-, 1.6-, and 2.0-fold, respectively. In contrast, the receptor ligand 1,25-dihydroxycholecalciferol [1,25-(OH)2VitD3] did not influence antithrombin production. Analysis of promoter chloramphenicol acetyltransferase (CAT) constructs, showed that the first 86 bp of the antithrombin promoter region are sufficient for basal transcription. The DNA length polymorphism of 32 bp or 108 bp, located upstream of position -276, did not influence antithrombin promoter activity. The antithrombin promoter activity dropped to background values when deleting the region -97/-49 of promoter fragment -453/+57. Transactivation of the antithrombin promoter by retinoid X receptor α (RXRα) (5–7-fold) or thyroid hormone receptor β (TRβ) (4–5-fold) was only observed when at least -167/+57 bp of the promoter region is present in CAT constructs, and when the appropriate ligand of the nuclear receptor was added. This transactivation was not observed upon deletion of the antithrombin promoter region -97/-49. With three copies of the antithrombin promoter fragment -109/-42 in front of the thymidine kinase minimal promoter, transactivation was only obtained with RXRα, and not with TRβ. In conclusion, these results indicate that the ligand-dependent enhancement of antithrombin gene expression is regulated by RXRα as well as by TRβ. Transactivation of antithrombin gene expression by RXRα and TRβ appears to be dependent upon the presence of promoter region up to nucleotide -167. The HRE segment (-109/-42) only confers RXRα responsiveness to a heterologous promoter. Further study is needed to unravel the exact nature of this HRE and its 5´-flanking sequences.

scholarly journals Novel Mechanism of Positive versus Negative Regulation by Thyroid Hormone Receptor β1 (TRβ1) Identified by Genome-wide Profiling of Binding Sites in Mouse Liver

2013 ◽  
Vol 289 (3) ◽  
pp. 1313-1328 ◽  
Author(s):  
Preeti Ramadoss ◽  
Brian J. Abraham ◽  
Linus Tsai ◽  
Yiming Zhou ◽  
Ricardo H. Costa-e-Sousa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Thyroid Hormone ◽  
Binding Sites ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Negative Regulation ◽  
Genome Wide

Triiodothyronine (T3) regulates key metabolic processes in the liver through the thyroid hormone receptor, TRβ1. However, the number of known target genes directly regulated by TRβ1 is limited, and the mechanisms by which positive and especially negative transcriptional regulation occur are not well understood. To characterize the TRβ1 cistrome in vivo, we expressed a biotinylated TRβ1 in hypo- and hyperthyroid mouse livers, used ChIP-seq to identify genomic TRβ1 targets, and correlated these data with gene expression changes. As with other nuclear receptors, the majority of TRβ1 binding sites were not in proximal promoters but in the gene body of known genes. Remarkably, T3 can dictate changes in TRβ1 binding, with strong correlation to T3-induced gene expression changes, suggesting that differential TRβ1 binding regulates transcriptional outcome. Additionally, DR-4 and DR-0 motifs were significantly enriched at binding sites where T3 induced an increase or decrease in TRβ1 binding, respectively, leading to either positive or negative regulation by T3. Taken together, the results of this study provide new insights into the mechanisms of transcriptional regulation by TRβ1 in vivo.

scholarly journals Thyroid hormone-stimulated differentiation of primary rib chondrocytes in vitro requires thyroid hormone receptor β

2006 ◽  
Vol 191 (1) ◽  
pp. 221-228 ◽  
Author(s):  
Bénédicte Rabier ◽  
Allan J Williams ◽  
Frederic Mallein-Gerin ◽  
Graham R Williams ◽  
O Chassande
Keyword(s):  
Thyroid Hormone ◽  
Growth Plate ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Primary Cultures ◽  
Wild Type ◽  
Proliferation And Differentiation ◽  
Thyroid Hormone Receptor Β

The active thyroid hormone, triiodothyronine (T3), binds to thyroid hormone receptors (TR) and plays an essential role in the control of chondrocyte proliferation and differentiation. Hypo- and hyperthyroidism alter the structure of growth plate cartilage and modify chondrocyte gene expression in vivo, whilst TR mutations or deletions in mice result in altered growth plate architecture. Nevertheless, the particular roles of individual TR isoforms in mediating T3 action in chondrocytes have not been studied and are difficult to determine in vivo because of complex cellular and molecular interactions that regulate growth plate maturation. Therefore, we studied the effects of TRα and TRβ on chondrocyte growth and differentiation in primary cultures of neonatal rib chondrocytes isolated from TRα- and TRβ-deficient mice. T3 decreased proliferation but accelerated differentiation of rib chondrocytes from wild-type mice. T3 treatment resulted in similar effects in TRα-deficient chondrocytes, but in TRβ-deficient chondrocytes, all T3 responses were abrogated. Furthermore, T3 increased TRβ1 expression in wild-type and TRα-deficient chondrocytes. These data indicate that T3-stimulated differentiation of primary rib chondrocytes in vitro requires TRβ and suggest that the TRβ1 isoform mediates important T3 actions in mouse rib chondrocytes.

The thyroid hormone receptor gene (c-erbA alpha) is expressed in advance of thyroid gland maturation during the early embryonic development of Xenopus laevis

1991 ◽  
Vol 11 (10) ◽  
pp. 5079-5089
Author(s):  
D E Banker ◽  
J Bigler ◽  
R N Eisenman
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Xenopus Laevis ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Thyroid Hormone Receptors ◽  
Stages Of Development ◽  
Xenopus Development

The c-erbA proto-oncogene encodes the thyroid hormone receptor, a ligand-dependent transcription factor which plays an important role in vertebrate growth and development. To define the role of the thyroid hormone receptor in developmental processes, we have begun studying c-erbA gene expression during the ontogeny of Xenopus laevis, an organism in which thyroid hormone has well-documented effects on morphogenesis. Using polymerase chain reactions (PCR) as a sensitive assay of specific gene expression, we found that polyadenylated erbA alpha RNA is present in Xenopus cells at early developmental stages, including the fertilized egg, blastula, gastrula, and neurula. By performing erbA alpha-specific PCR on reverse-transcribed RNAs from high-density sucrose gradient fractions prepared from early-stage embryos, we have demonstrated that these erbA transcripts are recruited to polysomes. Therefore, erbA is expressed in Xenopus development prior to the appearance of the thyroid gland anlage in tailbud-stage embryos. This implies that erbA alpha/thyroid hormone receptors may play ligand-independent roles during the early development of X. laevis. Quantitative PCR revealed a greater than 25-fold range in the steady-state levels of polyadenylated erbA alpha RNA across early stages of development, as expressed relative to equimolar amounts of total embryonic RNA. Substantial increases in the levels of erbA alpha RNA were noted at stages well after the onset of zygotic transcription at the mid-blastula transition, with accumulation of erbA alpha transcripts reaching a relative maximum in advance of metamorphosis. We also show that erbA alpha RNAs are expressed unequally across Xenopus neural tube embryos. This differential expression continues through later stages of development, including metamorphosis. This finding suggests that erbA alpha/thyroid hormone receptors may play roles in tissue-specific processes across all of Xenopus development.

scholarly journals A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

2009 ◽  
Vol 106 (23) ◽  
pp. 9441-9446 ◽  
Author(s):  
D. S. Machado ◽  
A. Sabet ◽  
L. A. Santiago ◽  
A. R. Sidhaye ◽  
M. I. Chiamolera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Regulation Of Gene Expression ◽  
Hormone Regulation

scholarly journals Marked Potentiation of the Dominant Negative Action of a Mutant Thyroid Hormone Receptor β in Mice by the Ablation of One Wild-Type β Allele

2003 ◽  
Vol 17 (5) ◽  
pp. 895-907 ◽  
Author(s):  
H. Suzuki ◽  
X.-Y. Zhang ◽  
D. Forrest ◽  
M. C. Willingham ◽  
S.-Y. Cheng
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Thyroid Function Tests ◽  
Wild Type ◽  
Hormone Response Elements ◽  
Papillary Hyperplasia

Abstract Mutations in the thyroid hormone receptor (TR) β gene result in resistance to thyroid hormone (RTH), characterized by reduced sensitivity of tissues to thyroid hormone. To understand which physiological TR pathways are affected by mutant receptors, we crossed mice with a dominantly negative TRβ mutation (TRβPV) with mice carrying a TRβ null mutation (TRβ−/−) to determine the consequences of the TRβPV mutation in the absence of wild-type TRβ. TRβPV/− mice are distinct from TRβ+/− mice that did not show abnormalities in thyroid function tests. TRβPV/− mice are also distinct from TRβPV/+ and TRβ−/− mice in that the latter shows mild dysfunction in the pituitary-thyroid axis, whereas the former exhibit very severe abnormalities, including extensive papillary hyperplasia of the thyroid epithelium, indistinguishable from that observed in TRβPV/PV mice. Similar to TRβPV/PV mice, TRβPV/− mice exhibited impairment in weight gain. Moreover, the abnormal regulation patterns of T3-target genes in the tissues of TRβPV/− and TRβPV/PV mice were strikingly similar. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed with TRα1 for binding to thyroid hormone response elements in TRβPV/− mice as effectively as in TRβPV/PV mice. Thus, the actions of mutant TRβ are markedly potentiated by the ablation of the second TRβ allele, suggesting that interference with wild-type TRα1-mediated gene regulation by mutant TRβ leads to severe RTH.

scholarly journals Thyroid hormone receptor can modulate retinoic acid-mediated axis formation in frog embryogenesis.

1993 ◽  
Vol 13 (12) ◽  
pp. 7540-7552 ◽  
Author(s):  
D E Banker ◽  
R N Eisenman
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Dna Binding ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Thyroid Hormone Receptors ◽  
Axis Formation

Thyroid hormone receptor acts as a hormone-dependent transcriptional transactivator and as a transcriptional repressor in the absence of thyroid hormone. Specifically, thyroid hormone receptor can repress retinoic acid-induced gene expression through interactions with retinoic acid receptor. (Retinoic acid is a potent teratogen in the frog Xenopus laevis, acting at early embryonic stages to interfere with the formation of anterior structures. Endogenous retinoic acid is thought to act in normal anterior-posterior axis formation.) We have previously shown that thyroid hormone receptor RNA (alpha isotype) is expressed and polysome-associated during Xenopus embryogenesis preceding thyroid gland maturation and endogenous thyroid hormone production (D. E. Banker, J. Bigler, and R. N. Eisenman, Mol. Cell. Biol. 11:5079-5089, 1991). To determine whether thyroid hormone receptor might influence the effects of retinoic acid in early frog development, we have examined the results of ectopic thyroid hormone receptor expression on retinoic acid teratogenesis. We demonstrate that microinjections of full-length thyroid hormone receptor RNA protect injected embryos from retinoic acid teratogenesis. DNA binding is apparently essential to this protective function, as truncated thyroid hormone receptors, lacking DNA-binding domains but including hormone-binding and dimerization domains, do not protect from retinoic acid. We have shown that microinjections of these dominant-interfering thyroid hormone receptors, as well as anti-thyroid hormone receptor antibodies, increase retinoic acid teratogenesis in injected embryos, presumably by inactivating endogenous thyroid hormone receptor. This finding suggests that endogenous thyroid hormone receptors may act to limit retinoic acid sensitivity. On the other hand, after thyroid hormone treatment, ectopic thyroid hormone receptor mediates teratogenesis that is indistinguishable from the dorsoanterior deficiencies produced in retinoic acid teratogenesis. The previously characterized retinoic acid-responsive gene, Xhox.lab2, can be induced by thyroid hormone in embryos ectopically expressing thyroid hormone receptor and is less responsive to retinoic acid in such embryos. The fact that both thyroid hormone and retinoic acid can affect overlapping gene expression pathways to produce abnormal embryonic axes and can regulate the same early-expressed gene suggests a model in which thyroid hormone receptor blocks retinoic acid receptor-mediated teratogenesis by directly repressing retinoic acid-responsive genes.

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