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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear hormone receptors are hormone-regulated transcription factors that play critical roles in chordate development and homeostasis. Aberrant nuclear hormone receptors have been implicated as causal agents in a number of endocrine and neoplastic diseases. The syndrome of Resistance to Thyroid Hormone (RTH) is a human genetic disease characterized by an impaired physiological response to thyroid hormone. RTH is associated with diverse mutations in the thyroid hormone receptor beta-gene. The resulting mutant receptors function as dominant negatives, interfering with the actions of normal thyroid hormone receptors coexpressed in the same cells. We report here that RTH receptors interact aberrantly with a newly recognized family of transcriptional corepressors variously denoted as nuclear receptor corepressor (N-CoR), retinoid X receptor interacting protein-13 (RIP-13), silencing mediator for retinoid and thyroid hormone receptors (SMRT), and thyroid hormone receptor-associating cofactor (TRAC). All RTH receptors tested exhibit an impaired ability to dissociate from corepressors in the presence of thyroid hormone. Two of the RTH mutations uncouple corepressor dissociation from hormone binding; two additional RTH mutants exhibit an unusually strong interaction with corepressor under all hormone conditions tested. Finally, artificial mutants that abolish corepressor binding abrogate the dominant negative activity of RTH mutants. We suggest that an altered corepressor interaction is likely to play a critical role in the dominant negative potency of RTH mutants and may contribute to the variable phenotype in this disorder.
Mol Endocrinol 1997 Apr
PMID:Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. 909 99

TSHbeta is a subunit of TSH that is uniquely expressed and regulated in the thyrotrope cells of the anterior pituitary gland. Thyroid hormone receptors (TR) are known to mediate T3 suppression of TSHbeta gene expression at the level of promoter activity. The role of other nuclear receptors in regulation of this gene is less clearly defined. Retinoid X receptors (RXR) are a family of nuclear transcription factors that function both as 9-cis-retinoic acid (RA) ligand-dependent receptors and heterodimeric partners with TR and other nuclear receptors. Recently, the RXR isoform, RXRgamma, has been identified in the anterior pituitary gland and found to be restricted to thyrotrope cells within the pitutiary. In this report, we have further characterized the distribution of RXRgamma1, the thyrotrope-restricted isoform of RXRgamma, in murine tissues and different cell types. We have found that RXRgamma1 mRNA and protein are expressed in the TtT-97 thyrotropic tumor, but not the thyrotrope-variant alphaTSH cells or somatotrope-derived GH3 cells. Furthermore, we have studied the effects of RXRgamma1 on TSHbeta promoter activity and hormone regulation in these pituitary-derived cell types. Both T3 and 9-cis-RA independently suppressed promoter activity in the TtT-97 thyrotropes. Interestingly, the combination of ligands suppressed promoter activity more than either alone, indicating that these hormones may act cooperatively to regulate TSHbeta gene expression in thyrotropes. The RXRgamma1 isoform was necessary for the 9-cis-RA-mediated suppression of TSHbeta promoter activity in alphaTSH and GH3 cells, both of which lack this isoform. RXRbeta, a more widely distributed isoform, did not mediate these effects. Finally, we showed that the murine TSHbeta promoter region between -200 and -149 mediated a majority of the 9-cis-RA suppression of promoter activity in thyrotropes. This region is distinct from the T3-mediated response region near the transcription start site. These data suggest that retinoids can mediate TSHbeta gene regulation in thyrotropes and the thyrotrope-restricted isoform, RXRgamma1, is required for this effect.
Mol Endocrinol 1997 Apr
PMID:The thyrotrope-restricted isoform of the retinoid-X receptor-gamma1 mediates 9-cis-retinoic acid suppression of thyrotropin-beta promoter activity. 909

We have studied the action of peripheral blood lymphocytes (PBLs) and intrathyroidal lymphocytes (ITLs) on the biochemical and hormonal metabolism of autologous thyrocytes cultured in follicles in a collagen gel. The production of tumour necrosis factor alpha (TNF-alpha) in culture was also measured. Thyroid tissues and lymphocytes were obtained from ten patients with Graves' disease and from five control subjects. Lymphocyte-induced cytotoxicity was evaluated in autologous thyrocytes cultured in a collagen gel by several tests; neutral red uptake, lactate dehydrogenase activity and glutathione level. Hormonal metabolism was assessed by evaluating tri-iodothyronine (T3) and total cAMP production under TSH stimulation. TNF-alpha levels were measured in supernatants after 5 days of coculture. PBLs altered biochemical metabolism, T3 synthesis and cAMP production in autologous thyroid follicles. These inhibitions were greater than those obtained with ITLs. No difference was seen between cells obtained from patients with Graves' disease and those from normal subjects. TNF-alpha levels secreted by PBLs were higher than those secreted by ITLs. The concentrations of this cytokine decreased in coculture. Significant correlations were observed between the decrease in biochemical and hormonal parameters and TNF-alpha levels. Exogenous TNF-alpha and high doses of interferon gamma inhibited follicle metabolism, especially hormone secretion. In conclusion, thyrocytes cultured in follicles provide a more sensitive model than monolayer cultures for analysis of lymphocyte-induced interactions. Lymphocytes gradually inhibit the biochemical and hormonal metabolism of autologous thyroid follicles depending on the isolation method. These alterations may be particularly attributed to TNF-alpha secreted by lymphocytes. The cytokine-induced inhibition of thyroid hormonal function apparently involves the adenylate cyclase system.
J Mol Endocrinol 1997 Apr
PMID:Action of peripheral or intrathyroidal lymphocytes on autologous thyrocytes cultured in follicles in collagen gel. 913

Thyroid hormone (T3) modulates the mRNA levels for cytochrome c and the adenine nucleotide translocator-2 (ANT2) in adult rat liver. Here we show that T3 activates expression of a reporter gene driven from the human cytochrome c1 and ANT2 promoters transfected into human choriocarcinoma JEG3 cells. By contrast, the human F1-ATPase beta-subunit promoter responded marginally, thus providing a pattern of differential expression similar to that earlier observed in rats in vivo. T3-activation is dependent on co-expression of the thyroid hormone receptor (TR alpha1). Co-expression of both the TR and RXR receptors had no additional effect. Transient transfection of deletion constructs showed that T3 activation is retained by the proximal regions of the cytochrome c1 and ANT2 promoters, and, in the case of cytochrome c1, is lost upon removal of a fragment containing the transcription initiator ((nucleotides) (nt) + 1 to + 100). The promoter regions supporting T3-activation of the reporter genes appear to lack strong DNA binding sites for TR and retinoid X receptor (RXR).
Mol Cell Endocrinol 1997 Apr 04
PMID:Thyroid hormone activates transcription from the promoter regions of some human nuclear-encoded genes of the oxidative phosphorylation system. 914 77

Thyroid hormone and retinoic acid receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors that stimulate the transcription of target genes in the presence of activating ligands and repress transcription in their absence. Transcriptional repression by the thyroid hormone and retinoic acid receptors has been proposed to be mediated by the nuclear receptor corepressor, N-CoR, or the related factor, SMRT (silencing mediator of retinoic acid and thyroid hormone receptors). Recent studies have suggested that transcriptional repression by N-CoR involves a corepressor complex that also contains mSin3A/B and the histone deacetylase, RPD3. In this manuscript, we demonstrate that transcriptional repression by the retinoic acid receptor can be either positively or negatively regulated by changes in the levels of N-CoR expression, suggesting a relatively strict stoichiometric relationship between N-CoR and other components of the corepressor complex. Consistent with this interpretation, overexpression of several functionally defined domains of N-CoR also relieve repression by nuclear receptors. N-CoR is distributed throughout the nucleus in a nonuniform pattern, and a subpopulation becomes concentrated into several discrete dot structures when highly expressed. RPD3 is also widely distributed throughout the nucleus in a nonuniform pattern. Simultaneous imaging of RPD3 and N-CoR suggest that a subset of each of these proteins colocalize, consistent with the existence of coactivator complexes containing both proteins. In addition, a substantial fraction of both N-CoR and mSin3 A/B appear to be independently distributed. These observations suggest that interactions between RPD3 and Sin3/N-CoR complexes may be dynamically regulated.
Mol Endocrinol 1997 Jun
PMID:Differential effects of nuclear receptor corepressor (N-CoR) expression levels on retinoic acid receptor-mediated repression support the existence of dynamically regulated corepressor complexes. 917 Dec 32

Thyroid hormone, acting through thyroid hormone receptors (TRs), plays a crucial role in brain development and its insufficiency results in irreversible brain damage. TR alpha mRNA is expressed continuously from early embryonic stages, but the level of TR beta1 mRNA in brain is more abundant in adult than in fetus. To identify important factors which regulate TR beta1 expression, we compared mouse fetal and adult brain nuclear extracts by DNase I footprinting and electrophoretic gel mobility shift assays (EMSA) of the TR beta1 promoter. We carried out transient transfection studies in COS 1 cells using the TR beta1 promoter fused to Luciferase gene, and used mutated promoter vectors and various expression vectors. In DNase I footprinting using the fragment -950 to -717, fetal brain nuclear extracts protected the areas -910 to -884 and -815 to -800 more than did adult extracts. In EMSA, proteins in fetal nuclear extracts bound to a silencer sequence (-924 to -916), GC box (-901 to -887), and E box (-810 to -805), more strongly than did proteins in adult brain extracts. The bands formed on GC box were not supershifted by Sp-1, Sp-2, Sp-3, Sp-4, EGR-1, or EGR-2 antibodies. Three bands were detected on the octamer binding site probe (-913 to -906) and one protein was supershifted by Oct-1 antibody. Adult brain extracts appear to contain more Oct-1 protein than do fetal extracts. The other two bands were more intense in fetal extracts than in adult extracts, but were not supershifted by either Oct-1 or Oct-2 antibodies. Mutation of the silencer response element, mutation of the GC box, and Oct-1 over expression in COS 1 cells increased TR beta1 promoter function as assayed by Luciferase reporter. Mutation of the octamer binding site, to which only Oct-1 bound in COS 1 cells, decreased Luciferase reporter activity. Thus the TR beta1 promoter was regulated negatively by the proteins bound to the silencer sequence and the GC box, and positively by Oct-1. Silencer and GC box binding proteins are more abundant in fetal brain, and Oct-1 is more abundant in adult brain. The results may be responsible for increased amounts of TR beta1 present in late fetal and adult brain.
Mol Cell Endocrinol 1997 Jun 20
PMID:Oct-1, silencer sequence, and GC box regulate thyroid hormone receptor beta1 promoter. 922 31

Thyroid hormones have diverse effects on ovarian function. We examined the expression of thyroid hormone receptor (TR) mRNAs (including TRalpha-1, TRbeta-1, TRbeta-2, and c-erbAalpha-2 isoforms) in three types of cells from human follicles, and determined the concentration of free tri-iodothyronine (T3) present in human follicular fluid. Human failed-fertilized oocytes, granulosa (GC) and cumulus (CC) cells from patients of the in-vitro fertilization (IVF) programme at Alliant Hospital Fertility Center were used to detect TR mRNA expression using reverse transcription-polymerase chain reaction (RT-PCR) followed by Southern blot analysis. Human spermatozoa were also analysed to determine whether results obtained with CC would be affected by the presence of spermatozoa. beta-Actin mRNA was amplified in each cell type as a positive control for the RT-PCR. Our results show that human oocytes express TRalpha-1, TRbeta-1, TRbeta-2, and c-erbAalpha-2 mRNAs and that these same isoforms are expressed in both human granulosa cells and cumulus cells. No differences were detected in the apparent amounts of RT-PCR products when comparing GC with CC, suggesting a similar pattern of expression of these RNAs. beta-actin mRNA was detected in spermatozoa, but TRalpha-1 expression was not detectable. The concentrations of free T3 measured in follicular fluid were similar to, or slightly below, those in serum of euthyroid patients. These data demonstrated that several isoforms of TR mRNA are expressed in the human oocyte, and hence thyroid hormone may have direct affects on the oocyte, as well as on GC and CC. In addition thyroid hormone may have indirect effects on the oocytes via the CC.
Mol Hum Reprod 1997 Jul
PMID:Expression of multiple thyroid hormone receptor mRNAs in human oocytes, cumulus cells, and granulosa cells. 926 32

We have previously reported (Mol. Cell. Endocrinol. (1994) 101, R31-R35) that the proinflammatory cytokines, tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN-gamma), have a marked inhibitory effect on the expression and activity of type I iodothyronine deiodinase (D1) in FRTL-5 rat thyroid cells, while the anti-inflammatory cytokine, transforming growth factor-beta 1 (TGF-beta 1) had no effect. These three proinflammatory cytokines utilize a number of intracellular second messenger systems including the pathways beginning with activation of sphingomyelinase and phospholipase A2. We have studied the time-dependent and dose-dependent effects of sphingomyelinase, ceramide, phospholipase A2 (PLA2), and arachidonic acid on the expression and activity of D1 in FRTL-5 cells. Sphingomyelinase (0.3 U/mL) inhibited D1 activity 55% and reduced D1 mRNA levels 70% to 90% by 8 hours. Similar treatment with 10 U/mL PLA2 inhibited D1 activity 54%. Treatment with 15 microM 5, 8, 11-eicosatriynoic acid (ETI), a nonmetabolizable analog of arachidonic acid, or 15 microM ceramide for 3 hours reduced D1 activity with a half-time of disappearance (t1/2) of 4.2 hours and 3.7 hours, respectively, but ETI and ceramide did not alter the D1 immunoreactivity or mRNA levels. Treatment for 8 hours with cycloheximide (5 or 10 micrograms/mL) had no effect on the D1 mRNA level, but blocked the TNF-induced reduction of this mRNA. We conclude that proinflammatory cytokines inhibit D1 expression and activity in FRTL-5 cells, in part, by activation of sphingomyelinase and PLA2 that results in (1) competitive inhibition of D1 activity by the enzymatic products ceramide and arachidonic acid and (2) reduction of D1 mRNA stability by protein synthesis-dependent mechanisms.
Thyroid 1997 Aug
PMID:Sphingomyelinase and phospholipase A2 regulate type I deiodinase expression in FRTL-5 cells. 929 57

Thyroid hormone receptor (TR) functions as part of multiprotein complexes that also include retinoid X receptor (RXR) and transcriptional coregulators. We have found that both the TR CoR box and ninth heptad are required for RXR interaction and in turn for interaction with corepressor proteins N-CoR and SMRT. Remarkably, the recruitment of RXR to repression-defective CoR box and ninth-heptad mutants via a heterologous dimerization interface restores both corepressor interaction and repression. The addition of thyroid hormone obviates the CoR box requirement for RXR interaction, provided that the AF2 activation helix at the C terminus of TR is intact. These results indicate that RXR differentially recognizes the unliganded and liganded conformations of TR and that these differences appear to play a major role in the recruitment of corepressors to TR-RXR heterodimers.
Mol Cell Biol 1997 Dec
PMID:Differential recognition of liganded and unliganded thyroid hormone receptor by retinoid X receptor regulates transcriptional repression. 937 20

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.
Mol Cell Biol 1997 Dec
PMID:Constitutive activation of gene expression by thyroid hormone receptor results from reversal of p53-mediated repression. 937 52


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