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

Rat Rev-erbA alpha (rRev), which is related to thyroid hormone receptor (TR), is a conserved member of the nuclear hormone receptor superfamily whose physiological roles are unknown ("orphan" receptor). We studied DNA binding of rRev in vitro by electrophoretic mobility shift assay. A fusion protein was constructed, called NGR.Rev, containing part of the N terminus of the glucocorticoid receptor fused to nearly full-length rRev. Inasmuch as rRev and TR share homology in their DNA-binding domains, we tested binding to three different thyroid hormone response elements (TREs) in which the half-sites are arranged in different orientations. NGR.Rev bound direct repeats (DR4), but not palindromic (TREpal) or inverted palindromic (F2H) repeats. Also, transfection of CV1 cells with a reporter gene containing the luciferase gene under control of the inducible thymidine kinase promoter resulted in an increase in luciferase activity when NGR.Rev was cotransfected and when the thymidine kinase promoter contained DR4. In addition, a series of deletions in the ligand-binding domain of NGR.Rev revealed regions that can modulate DNA binding. Finally, we studied DNA binding of bacterially produced fusion proteins that contain the DNA-binding domains of rRev or rTR alpha fused to glutathione S-transferase, to a panel of natural TREs. Our results indicate that Rev binds DNA with a different specificity than TR alpha-1 and might be involved in the regulation of a subset of thyroid hormone-regulated genes.
Mol Endocrinol 1994 Mar
PMID:Rat Rev-erbA alpha, an orphan receptor related to thyroid hormone receptor, binds to specific thyroid hormone response elements. 801 47

Glucocorticoid and thyroid hormones exert their effects in many body tissues by binding to their respective receptors. The search for possible cross-talking mechanisms in overlapping target cells led to the discovery of synergism between a thyroid hormone receptor-binding site and a cryptic glucocorticoid-responsive element. Glucocorticoid responsiveness could only be detected in the presence of thyroid hormone and its receptor. This synergism requires the glucocorticoid receptor (GR) DNA-binding domain and is mediated by the transactivation domains. We found that synergism also occurs when the thyroid hormone receptor is replaced by the retinoic acid receptor or the GR is replaced by the progesterone receptor. Synergism is qualitatively independent of the type of thyroid hormone receptor-binding site and promoter. In several combinations of promoter and response elements, including a retinoic acid response element, T3 induction was only seen in the presence of the cryptic glucocorticoid-responsive element, GR, and glucocorticoids.
Mol Endocrinol 1994 Apr
PMID:A thyroid hormone receptor-dependent glucocorticoid induction. 805 65

The erb A oncogene is a dominant negative allele of a thyroid hormone receptor gene and acts in the cancer cell by encoding a transcriptional repressor. We demonstrate here that the DNA sequence recognition properties of the oncogenic form of the erb A protein are significantly altered from those of the normal thyroid hormone receptors and more closely resemble those of the retinoic acid receptors; this alteration appears to play an important role in defining the targets of erb A action in neoplasia. Unexpectedly, the novel DNA recognition properties of erb A are encoded by an N-terminal region not previously implicated as playing this function in current models of receptor-DNA interaction. Two N-terminal erb A amino acids in particular, histidine 12 and cysteine 32, contribute to this phenomenon, acting in conjunction with amino acids in the zinc finger domain. The effects of the N-terminal domain can be observed at the level of both DNA binding and transcriptional modulation. Our results indicate that unanticipated determinants within the nuclear hormone receptors participate in DNA sequence recognition and may contribute to the differential target gene specificity displayed by different receptor forms.
Mol Cell Biol 1993 Apr
PMID:Nuclear hormone receptors involved in neoplasia: erb A exhibits a novel DNA sequence specificity determined by amino acids outside of the zinc-finger domain. 809 60

One of the chicken lysozyme gene silencers binds two transcription factors, v-ERBA or the thyroid hormone receptor and NeP1 (negative protein 1), a new silencer binding protein. NeP1 is neutral on a monomeric binding site, but mediates weak repression on a multimerized site and strong synergistic repression in conjunction with v-ERBA on the wild-type silencer. Depending on the presence or absence of ligand, synergistic induction or repression is seen with the thyroid hormone receptor. This synergism is not based on cooperative DNA-binding as measured in vitro. The NeP1 DNA-binding activity is dependent on zinc ions, the binding site is characterized by a footprint of approximately 50 bp. NeP1 has a molecular weight of 140 to 160 kDa and has been enriched by affinity columns.
J Mol Biol 1993 Aug 05
PMID:NeP1. A ubiquitous transcription factor synergizes with v-ERBA in transcriptional silencing. 810 52

Genetic lesions that function as dominant negative mutations in microbial systems have long been recognized. It is only relatively recently, however, that similar dominant negative mutations have been implicated as a basis for genetic and neoplastic disorders in vertebrates. We describe here a dissection of the actions of the erbA oncogene protein, an aberrant form of thyroid hormone receptor that acts as a dominant negative inhibitor of other nuclear hormone receptors. We demonstrate that the ErbA oncoprotein interferes with thyroid hormone and trans-retinoic acid receptors by competing for binding to the corresponding response elements. Heterodimerization of the ErbA oncoprotein with these receptors does not play an observable role in repression. In contrast, however, the ErbA oncoprotein does efficiently form a heterodimer with the retinoid X receptor (RXR) class of nuclear hormone receptors; complex formation enhances the DNA-binding properties of the ErbA protein but dramatically interferes with the ability of the RXR component to activate gene expression. Our results indicate that the erbA oncogene may play a previously unanticipated role in neoplasia by interfering with RXR function.
Mol Cell Biol 1993 Oct
PMID:The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms. 810 69

A truncated, recombinant form of the thyroid hormone receptor, including the hormone binding domain, has been co-crystallized with the hormone T3. The crystals are monoclinic, most likely space group P2, with two molecules per asymmetric unit and cell dimensions a = 63.6 A, b = 80.8 A, c = 100.9 A and beta = 92.1 degrees. The crystals diffract to only medium resolution and decay rapidly in the X-ray beam using laboratory sources. By contrast, high resolution, high-quality data are obtained using synchrotron radiation in conjunction with cryocrystallography.
J Mol Biol 1994 Mar 25
PMID:Preliminary crystallographic studies of the ligand-binding domain of the thyroid hormone receptor complexed with triiodothyronine. 812 36

nurr77 and nurr-1 are growth factor-inducible members of the steroid/thyroid hormone receptor gene superfamily. In order to gain insight into the potential roles of nur77 in the living organism, we used pharmacologic treatments to examine the expression of nur77 in the mouse adrenal gland. We found that nur77 and nurr-1 are induced in the adrenal gland upon treatment with pentylene tetrazole (Ptz; Metrazole). This induction is separable into distinct endocrine and neurogenic mechanisms. In situ hybridization analysis demonstrates that nur77 expression upon Ptz treatment in the adrenal cortex is localized primarily to the inner cortical region, the zona fasciculata-reticularis, with minimal induction in the zona glomerulosa. This induction is inhibitable by pretreatment with dexamethasone, indicating involvement of the hypothalamic-pituitary-adrenal axis in the activation of adrenal cortical expression. When mice were injected with adrenocorticotrophic hormone (ACTH), nur77 expression in the adrenal gland spanned all cortical layers including the zona glomerulosa, but medullary expression was not induced. Ptz also induces expression of both nur77 and nurr-1 in the adrenal medulla. Medullary induction is likely to have a neurogenic origin, as nur77 expression was not inhibitable by dexamethasone pretreatment and induction was seen after treatment with the cholinergic neurotransmitter nicotine. nur77 is also inducible by ACTH, forskolin, and the second messenger analog dibutyryl cyclic AMP in the ACTH-responsive adrenal cortical cell line Y-1. Significantly, Nur77 isolated from ACTH-stimulated Y-1 cells bound to its response element whereas Nur77 present in unstimulated cells did not. Moreover, Nur77 in ACTH-treated Y-1 cells was hypophosphorylated at serine 354 compared with that in untreated cells. These results, taken together with the previous observation that dephosphorylation of serine 354 affects DNA binding affinity in vitro, show for the first time that phosphorylation of Nur77 at serine 354 is under hormonal regulation, modulating its DNA binding affinity. Thus, ACTH regulates Nur77 in two ways: activation of its gene and posttranslational modification. A promoter analysis of nur77 induction in Y-1 cells indicates that the regulatory elements mediating ACTH induction differ from those required for induction in the adrenal medullary tumor cell line PC12 and in 3T3 fibroblasts.
Mol Cell Biol 1994 May
PMID:Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands. 816 92

Generalized resistance to thyroid hormone (GRTH) is a disorder of thyroid hormone action which has been linked to the beta thyroid hormone receptor (TR beta) gene. A diverse array of TR beta mutations have been characterized, and these distinct genotypes have been associated with characteristic patterns of severity and tissue distribution of clinical thyroid resistance. In this report, we describe a patient with GRTH caused by a single C-->A base mutation (nucleotide 1623) in one allele of TR beta (exon 10). The mutation produces a premature translation termination signal (UGA) at codon 446 and predicts expression of a mutant TR beta which is truncated by 16 carboxyl-terminal amino acids (TR beta delta 446-461). This sequence was absent in both parents, indicative of a de novo mutation in the proband. To our knowledge, this case represents the first description of a mutation producing premature translation termination of TR beta in association with the syndrome GRTH, and emphasizes the critical role of the carboxyl terminal region of TR beta in mediating both positive and negative regulation of thyroid-responsive target genes in many tissues.
Mol Cell Endocrinol 1994 Feb
PMID:Generalized thyroid hormone resistance due to a deletion of the carboxy terminus of the c-erbA beta receptor. 818 64

The roles in DNA binding and transcriptional activation of individual amino acids in the putative recognition alpha-helix of the first zinc finger of the beta-isoform of the human thyroid hormone receptor (hT3R beta) have been probed by site-directed mutagenesis. Alanine substitutions of highly conserved residues involved in the folding of this zinc finger abolished the binding of hT3R beta to various thyroid response elements. A similar effect was observed for alanine substitutions of those conserved residues in hT3R beta that were expected to make specific contacts to DNA bases common to all hormone response elements. The three P-box amino acids have previously been shown to be essential for discrimination of the base pairs that differ between the DNA binding sites for related steroid/thyroid hormone receptors. In hT3R beta, the P-box residues are E, G, and G; the results of this study show that alanine substitution of the glutamic acid dramatically reduces DNA binding activity by hT3R beta, while the substitution of either glycine has little or no effect on DNA binding. The effects of alanine substitutions on hT3R beta transcriptional activation properties were consistent with the effect of these substitutions on DNA binding properties, with the exception of the second P-box amino acid. T3R beta substituted with alanine at this position is substantially more defective in transcriptional activation than it is in specific DNA binding. These results indicate that there are two separate mechanisms of response element discrimination by P-box amino acids of steroid/thyroid hormone receptors, one which operates at the level of DNA recognition and a second which operates at the level of transcriptional activation.
Mol Endocrinol 1993 Sep
PMID:Functional analysis of the amino acids in the DNA recognition alpha-helix of the human thyroid hormone receptor. 824 21

Using a synthetic peptide that corresponds to a unique region of the N-terminal domain of the human mineralocorticoid receptor (MR), amino acids 87-96, we have generated a polyclonal antibody, human (h) MRsN. This sequence shares no homology with the corresponding sequences of the glucocorticoid receptor or other steroid/thyroid hormone receptor superfamily members. Antibody hMRsN cross-reacts with MR from human, rat, and mouse cells and recognizes denatured MR from either crude preparations or partially purified rat kidney cytosol, rat colon, or recombinant hMR overexpressed in baculovirus-infected Sf9 cells. Immunoprecipitation of the native MR from either partially purified or crude preparations of rat kidney cytosol with hMRsN, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver stain, demonstrated a major protein band with a mol wt of 116 kilodaltons. In addition, using confocal laser scanning microscopy and digital image analysis, the immunocytochemical localization of the recombinant hMR over-expressed in Sf9 cells 24 h post-transfection was determined. In the absence of ligand, the MR was detected solely in the cytoplasm, after a 30-min exposure to 100 nM aldosterone the MR was perinuclear, and after 60 min, the MR was predominantly nuclear. To ascertain that this phenomenon was not unique to insect cells, aldosterone induced MR nuclear translocation in mouse macrophage cells was also demonstrated immunocytochemically, clearly indicating a role for nuclear translocation in MR function.
Mol Endocrinol 1993 Sep
PMID:Demonstration of nuclear translocation of the mineralocorticoid receptor (MR) using an anti-MR antibody and confocal laser scanning microscopy. 824 24


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