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

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.
Mol Cell Biol 1991 Oct
PMID:The thyroid hormone receptor gene (c-erbA alpha) is expressed in advance of thyroid gland maturation during the early embryonic development of Xenopus laevis. 165 22

Human thyroid hormone receptor (c-erb A protein) produced by Escherichia coli expression vector plasmid was purified sequentially using polyethylenimine precipitation of DNA, hydroxylapatite column chromatography, ammonium sulphate precipitation, Sephacryl S-300 gel filtration and mono Q-Sepharose column chromatography. These column procedures resulted in 41.3-fold purification of 3,5,3'-tri-iodo-L-thyronine (T3) binding activity over the initial E. coli extract. Purified protein as well as crude preparation showed high-affinity binding to T3. The c-erb A protein enriched by column purification was further purified by electroelution after electrophoresis. Rabbit antibody against the c-erb A protein was prepared and used for the Western blotting analysis. The antibody recognized c-erb A protein but not the bacterial proteins in crude E. coli extract. When partially purified rat hepatic nuclear thyroid hormone receptor was analysed, a 56 kDa receptor was specifically recognized by the antibody.
J Mol Endocrinol 1991 Oct
PMID:Purification of human c-erb A beta protein. 165 20

Thyroid hormone receptors are cellular homologues (c-erbAs) of the v-erbA oncoprotein of the avian erythroblastosis virus. Exclusive of the viral gag region, v-erbA differs from the chick c-erbA-alpha receptor by two amino acid changes N-terminal of the DNA binding domain, two amino acid changes in the DNA binding domain, nine amino acid changes in the C-terminal region corresponding to the ligand binding domain of c-erbA, and a nine-amino acid deletion near the C terminus. v-erbA does not bind thyroid hormone and when expressed in cells inhibits the activity of wild-type thyroid hormone receptors. We reported previously that mutants of chick c-erbA/thyroid hormone receptor which lack the DNA binding domain (DBD-) inhibit transcriptional activition by wild-type thyroid hormone and retinoic acid receptors (Forman, B. M., Yang, C.-R., Au, M., Casanova, J., Ghysdael, J., and Samuels, H. H. (1989) Mol. Endocrinol. 3, 1610-1626). This dominant negative activity mapped to a series of hydrophobic heptad motifs which are conserved in the C terminus of these receptors and have been suggested to play a role in receptor dimerization. In this study we show that unlike DBD- c-erbA, DBD- v-erbA does not block receptor activity, suggesting that v-erbA acts by competing for DNA response elements rather than by formation of nonfunctional v-erbA/c-erbA heterodimers. This difference in activity was localized to a single Pro to Ser change in v-erbA just N-terminal of the last heptad motif. Introduction of this Pro to Ser change into DBD- c-erbA resulted in a protein which was inactive both functionally and in blocking receptor dimer formation in vitro.
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PMID:Thyroid hormone receptor/and v-erbA. A single amino acid difference in the C-terminal region influences dominant negative activity and receptor dimer formation. 167 37

Expression of the glycoprotein hormone alpha gene is regulated divergently by glucocorticoids in different cell types. Coexpression of the glucocorticoid receptor (GR) with an alpha-CAT reporter gene caused activation of alpha promoter activity in fibroblasts, but repression in JEG-3 choriocarcinoma cells, indicating that cell-specific factors dictate positive vs. negative regulation of this promoter by GR. Cell-specific sequences and other enhancer elements in the the alpha gene have been relatively well characterized in JEG-3 cells, and this model was used to further examine the mechanism of transcriptional repression by glucocorticoids. Promoter mutagenesis indicated that the degree of GR-mediated repression was impaired by a variety of deletional and site-directed mutations between -171 and -111 bp, a region that includes both cell-specific and cAMP response elements (CREs). In an attempt to further localize a negative glucocorticoid response element (GRE) sequence, binding studies were used to assess GR interactions with alpha promoter DNA sequences. Using avidin-biotin complex DNA binding assays, a series of overlapping alpha promoter DNA sequences between -170 to 29 basepairs were tested, but each failed to bind GR, whereas a control GRE avidly bound receptor. Similarly, in competition assays in transfected CV-1 cells, the alpha gene 5'-flanking sequence did not compete for GR stimulation of a glucocorticoid responsive reporter gene, whereas a sequence that contains known GR-binding sites (murine mammary tumor virus) effectively inhibited GR-mediated expression. The absence of high affinity GR-binding sites in the alpha promoter suggested that mutations that affected GR inhibition may have eliminated recognition sites for transactivators, which are themselves targets for the GR, rather than altering specific negative GRE sites in the DNA sequence. To examine this possibility, GR repression was studied using chimeric transcription factors. The transcription-activating domains of several different proteins (CREB, thyroid hormone receptor, or VP16) were linked to the DNA-binding domain of Gal-4, and transcription was driven by the Gal-4 recognition site (UAS). GR markedly repressed transactivation by Gal-4-CREB and, to a lesser degree, the Gal-4-thyroid hormone receptor and Gal-4-VP16 chimeric proteins. Repression occurred when UAS was linked to either the alpha promoter or to the E1B promoter. Thus, inhibition occurs in the absence of either the CRE or the proximal alpha promoter. These results support a mechanism in which GR-mediated repression in JEG-3 cells occurs by receptor interference with the transactivating potential of enhancer-binding proteins or associated transcription factors.
Mol Endocrinol 1991 Jan
PMID:Repression of the human glycoprotein hormone alpha-subunit gene by glucocorticoids: evidence for receptor interactions with limiting transcriptional activators. 170 98

We have previously demonstrated that binding of in vitro synthesized thyroid hormone receptor (TR) to thyroid hormone response elements (TREs) is enhanced by the addition of nuclear extracts from several different cell types, suggesting that binding of TR is partially dependent on a T3 receptor auxiliary protein (TRAP). We have used the avidin-biotin complex DNA-binding assay to discriminate between regions of TREs that bind TR alone and sites that are influenced by interactions with TRAP. Mutations in the TREs from rat GH and glycoprotein hormone alpha-subunit genes show that a specific DNA sequence is required for TRAP-mediated enhancement of TR binding. Mutations in the B half-site of the rat GH TRE or in similar sequences [(T/A)GGGA] in the alpha-subunit TRE ablate the enhancement of TR binding by TRAP. Furthermore, binding of TR to a natural half-site in the TSH beta-subunit gene (bases -16 to 6), which lacks an additional AGGGA-like sequence, is not enhanced by the addition of TRAP. Binding of TR to TREs was also tested at physiological salt concentrations in the avidin-biotin complex DNA-binding assay. Binding of human TR beta to TREs decreases dramatically at 140 mM KCl compared to binding at 50 mM KCl; however, the addition of TRAP enhances the binding to almost 4-fold of basal binding, suggesting that TRAP may be important for stabilization of TR binding to TREs in the cell.
Mol Endocrinol 1991 Jan
PMID:3,5,3'-triiodothyronine receptor auxiliary protein (TRAP) enhances receptor binding by interactions within the thyroid hormone response element. 170

Avian chondrocytes and fibroblasts, derived from epiphyseal growth-plate and skin, respectively, were cultured in vitro. In chondrocytes, epidermal growth factor (EGF) caused a dose-dependent stimulation of proliferation. EGF receptor mRNA was not detected with the v-erb B probe in chondrocytes cultured in the presence of 5% fetal calf serum (FCS). In the absence of FCS in the medium, a time-dependent increase in the level of EGF receptor mRNA was observed. Parallel changes were also observed in the level of EGF receptor, as demonstrated by immunofluorescence using antibodies directed against avian EGF receptor. In avian fibroblasts, EGF receptor mRNA and EGF receptor levels were not affected by FCS. Furthermore, FCS did not affect the level of thyroid hormone receptor mRNA (using v-erb A as a probe) in either chondrocytes or fibroblasts. Parathyroid hormone (PTH), which acts as a mitogen in avian chondrocytes attenuated--whereas atrial natriuretic peptide (ANP), a suppressor of chondrocyte proliferation, enhanced--EGF receptor mRNA. The present results show that avian growth-plate chondrocytes respond to EGF and bear EGF receptors. The levels of EGF mRNA and EGF receptor are inversely related to cell proliferation. The results also support previous suggestions that PTH and ANP play important roles in chondrocyte proliferation, possibly through their effect on the synthesis of the EGF receptor.
Mol Cell Endocrinol 1991 Mar
PMID:Epidermal growth factor receptor gene expression in avian epiphyseal growth-plate cartilage cells: effect of serum, parathyroid hormone and atrial natriuretic peptide. 182 15

A 20 amino acid segment within the ligand-binding domain of the rat beta 1-thyroid hormone receptor (T3R; amino acids 286-305) is conserved in all members of the erbA superfamily. Mutations in this region impair T3 induction of reporter gene expression in a transfection system without impairing T3 binding or nuclear localization of the receptors. We postulate that a nuclear protein may need to interact with this domain for full transcriptional activity and provide evidence for the existence of this putative protein. Specifically, a JEG-3 cell protein (denoted TRAP, T3R auxiliary protein) interacts with wild-type T3R-beta 1 to increase binding of the receptor to T3 response elements in vitro. Mutations within amino acids 286-305 impair the ability of TRAP to enhance T3R binding to hormone response elements. Cross-linking studies indicate that TRAP has an apparent mol wt of 63 kDa. Surprisingly, TRAP does not enhance binding of erbA-alpha 2 and v-erbA to DNA, even though these proteins contain highly conserved versions of the 20-amino acid beta 1 T3R sequence under study. TRAP or a similar protein, however, does enhance binding of retinoic acid receptor-beta to a hormone response element. We conclude that the inability of T3Rs with mutations in this domain to fully activate transcription may be due to an inability of these proteins to fully interact with TRAP. We postulate that TRAP or related proteins may be important regulators of ligand-dependent transcriptional activation for other members of the erbA family in addition to the T3R.
Mol Endocrinol 1991 Jan
PMID:Thyroid hormone receptor mutations that interfere with transcriptional activation also interfere with receptor interaction with a nuclear protein. 185 Jan 12

Binding of the thyroid hormone receptor (TR) to thyroid hormone-responsive elements (TREs) is crucial for regulation of gene expression by thyroid hormone. The TR binds to each half-site of a palindromic TRE separately, as a monomer, or simultaneously, as a homodimer. In addition, the TR monomer interacts with a 42-kDa protein that may be responsible for an increase in the apparent size and stability of the TR-TRE complex after incubation with liver nuclear extract. The multiple DNA-binding forms of the TR contact the TRE differently but compete for binding in a dynamic equilibrium which is highly dependent on the relative concentrations of TR and nuclear protein. Thus, protein-protein interactions are likely to determine the context in which the TR binds to target genes and regulates the transcriptional response to thyroid hormone.
Mol Cell Biol 1991 Oct
PMID:Differential DNA binding by monomeric, homodimeric, and potentially heteromeric forms of the thyroid hormone receptor. 192 30

nur77 is a growth factor-inducible immediate early gene that encodes a protein with extensive sequence homology to members of the steroid/thyroid hormone receptor superfamily. By analogy to steroid receptors, the Nur77 protein is thought to act as a ligand-dependent transcription factor that regulates the genomic response to growth factors. Using chimeric gene constructs, we show that Nur77 can indeed function as a transcription activator. Furthermore, Nur77 chimeras can activate transcription in the absence of an exogenously added ligand.
Mol Endocrinol 1991 Jun
PMID:Transcriptional activation by Nur77, a growth factor-inducible member of the steroid hormone receptor superfamily. 192 99

Thyroid hormone receptors (TR) are ligand-dependent, DNA-binding, trans-acting transcriptional factors belonging to the erbA-related steroid/thyroid hormone receptor superfamily. To better understand the structural and functional characteristics of TRs, we isolated the gene encoding human TR beta 1 (hTR beta 1). The coding region of hTR beta 1 is split into at least eight exons. Each exon well correlates with functional domains of hTR beta 1 protein, and the exon/intron organization is highly conserved when compared with the chicken c-erbA gene which encodes an alpha-type chicken TR. We demonstrate that hTR beta has at least two mRNA forms having different lengths of the 3' untranslated region. We also note several nucleotide corrections of hTR beta 1 cDNA sequence.
Mol Cell Endocrinol 1990 Jun 18
PMID:Structural analysis of human thyroid hormone receptor beta gene. 197 14


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