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

Rev-ErbA alpha (Rev-Erb) is a nuclear hormone receptor-related protein encoded on the opposite strand of the alpha-thyroid hormone receptor (TR) gene. This unusual genomic arrangement may have a regulatory role, but the conservation of human and rodent Rev-Erb amino acid sequences suggests that the protein itself has an important function, potentially as a sequence-specific transcriptional regulator. However, despite its relationship to the TR, Rev-Erb bound poorly to TR binding sites. To determine its DNA-binding specificity in an unbiased manner, Rev-Erb was synthesized in Escherichia coli, purified, and used to select specific binding-sites from libraries of random double-stranded DNA sequences. We found that Rev-Erb binds to a unique site consisting of a specific 5-bp A/T-rich sequence adjacent to a TR half-site. Rev-Erb contacts this entire asymmetric 11-bp sequence, which is the longest nonrepetitive element specifically recognized by a member of the thyroid/steroid hormone receptor superfamily, and mutations in either the A/T-rich or TR half-site regions abolished specific binding. The binding specificity of wild-type Rev-Erb was nearly identical to that of C- and N-terminally truncated forms. This binding was not enhanced by retinoid X receptor, TR, or other nuclear proteins, none of which formed heterodimers with Rev-Erb. Rev-Erb also appeared to bind to the selected site as a monomer. Furthermore, Rev-Erb activates transcription through this binding site even in the absence of exogenous ligand. Thus, Rev-Erb is a transcriptional activator whose properties differ dramatically from those of classical nuclear hormone receptors, including the TR encoded on the opposite strand of the same genomic locus.
Mol Cell Biol 1993 May
PMID:The orphan receptor Rev-ErbA alpha activates transcription via a novel response element. 847 64

The glucocorticoid and thyroid hormone receptors have the capacity to bind as dimers to palindromic DNA-binding sites. Protein-protein interactions between the DNA-binding domains of glucocorticoid receptor dimers restrict the DNA-binding to elements where the half-sites are separated by three base pairs, whereas DNA-binding by the thyroid hormone receptor does not appear to require a strict half-site spacing. We have previously shown that a five amino-acid segment close the the C-terminal zinc-binding site (D-box) was involved in dimerization of the glucocorticoid receptor (GR) DNA-binding domain (Dahlman-Wright et al., 1991, J. Biol. Chem., 266, 3107-3112). Here we provide functional evidence, using mutated thyroid hormone receptor DNA-binding domains, that this five amino acid segment (D-box) of the GR interacts with the equivalent segment on the second DNA-binding domain in the dimer. In contrast, the thyroid hormone receptor DNA-binding domain binds to palindromic thyroid hormone response elements in a weakly co-operative manner, independent of the D-box.
J Steroid Biochem Mol Biol 1993 Apr
PMID:Protein-protein interactions between the DNA-binding domains of nuclear receptors: influence on DNA-binding. 849 33

Unliganded human thyroid hormone receptor alpha (hTR alpha) can repress transcription by inhibiting the formation of a functional preinitiation complex (PIC) on promoters bearing thyroid hormone receptor (TR)-binding elements. Here we demonstrate that hTR alpha directly contacts the TATA-binding protein (TBP) and that preincubation of hTR alpha with TBP completely alleviates TR-mediated repression in vitro. Using stepwise preassembled PICs, we show that hTR alpha targets either the TBP/TFIIA or the TBP/TFIIA/TFIIB steps of PIC assembly for repression. We also show that the repression domain of hTR alpha maps to the C-terminal ligand-binding region and that direct TR-TBP interactions can be inhibited by thyroid hormone. Together, these results suggest a model in which unliganded hTR alpha contacts promoter-bound TBP and interferes with later steps in the initiation of transcription.
Mol Cell Biol 1996 Jan
PMID:Unliganded thyroid hormone receptor alpha can target TATA-binding protein for transcriptional repression. 852 5

Glucocorticoids and thyroid hormones induce complex responses in about every mammalian tissue. These effects are mediated by the transcription factor function of the corresponding nuclear receptors, which in most cases achieve the observed regulatory strength in synergy with other factors. Here we describe the functional interaction of the glucocorticoid receptor (GR) with liver-specific transcription factors, the functional synergy of GR with the thyroid hormone receptor (TR), the synergizing sub-domains of the TR, and finally the direct interaction of the GR with other proteins.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Enhancement of nuclear receptor transcriptional signalling. 860 46

COUP-TFs are orphan members of the steroid/thyroid hormone receptor superfamily. COUP-TF homologues have been cloned in several species, from Drosophila to man. The vertebrate COUP-TFs can be classified into four subgroups according to sequence homology in their ligand-binding domain. COUP-TFs bind to AGGTCA direct repeats or palindromes with various spacings. These include the response elements of several other members of the superfamily, the vitamin D receptor, the thyroid hormone receptor, the retinoic acid receptor, the retinoid X receptor, the peroxisome proliferation activated regulator, and the hepatocyte nuclear factor-4. COUP-TF response elements have been identified in the promoters of many genes and COUP-TFs have been shown to act as negative regulators both in vitro and in vivo. They can compete with the above mentioned receptors for binding to the common response elements. The ratio of COUP-TF and the other positive regulator determines the transcriptional state of the particular gene in any given moment. COUP-TFs are expressed in the developing central nervous system of mouse and zebra-fish. In addition, they are also expressed in many organs during mouse organogenesis. The expression pattern and profile of COUP-TFs favor the hypothesis that they are involved in development and differentiation. The expression of COUP-TFs are also highly regulated. P19 embryonal carcinoma cells have been used as a model system to study COUP-TF regulation. COUP-TFs are up-regulated in retinoic acid (RA) treated P19 cells. Transient transfection assay showed that mouse COUP-TFII promoter directly responded to RA treatment, suggesting that COUP-TF expression is directly regulated by RA signaling pathway.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Chicken ovalbumin upstream promoter-transcription factors and their regulation. 860 50

Rev-erbA alpha is an orphan steroid receptor that is expressed in skeletal muscle. Rev-erbA alpha binds to single/tandem copies of an AGGTCA motif, is transcribed on the noncoding strand of the c-erbA- alpha gene locus, and is postulated to modulate the thyroid hormone (T3) response. T3 induces terminal muscle differentiation and regulates fiber type composition via direct activation of the muscle-specific myoD gene family (e.g. myoD, myogenin). The myoD gene family can direct the fate of mesodermal cell lineages and activate muscle differentiation. Hence we investigated the expression and physiological role of Rev-erbA alpha during myogenesis. We observed abundant levels of Rev-erbA alpha mRNA in dividing C2C12 myoblasts, which were suppressed when the cells differentiated into postmitotic multinucleated myotubes. This decrease in Rev-erbA alpha mRNA correlated with the appearance of muscle-specific mRNAs (e.g. myogenin and alpha-actin). Constitutive overexpression of full length Rev-erbA alpha cDNA in the myogenic cells completely abolished differentiation, suppressed myoD mRNA levels, and abrogated the induction of myogenin mRNA. We then demonstrated that 1) GAL4-REV-erbA alpha chimeras that contain the 'AB' region and lack the 'E' region activated transcription of GAL4 response elements in the presence of 8-Br-cAMP and 2) the ligand-binding domain (LBD) contains an active transcriptional silencer. Overexpression of Rev-erbA alpha (delta AB) in myogenic cells had no impact on the ability of these cells to morphologically or biochemically differentiate. Furthermore, this orphan receptor 1) down-regulated thyroid hormone receptor (TR)/T3 mediated transcriptional activity from the myogenin promoter and thyroid hormone response element (TRE) an 2) disrupted TR homodimer and TR/retinoid X receptor (RXR) heterodimer formation on a number of TREs found in the myoD gene family. In conclusion, Rev-erbA alpha functions as a negative regulator of myogenesis by targeting the expression of the myoD gene family. The mechanism of action may involve inhibition of functional TR/RXR heterodimer formation on critical TREs and dominant trans-repression of gene expression.
Mol Endocrinol 1995 Dec
PMID:Constitutive expression of the orphan receptor, Rev-erbA alpha, inhibits muscle differentiation and abrogates the expression of the myoD gene family. 861 3

Vitamin A and other fat-soluble hormones and vitamins have important roles as modulators of essential biological processes such as homeostasis, development, differentiation, and oncogenesis and also as regulators of the immune system. The active form of vitamin A, retinoic acid, as well as vitamin D3 and thyroid hormones exert their actions by binding to specific nuclear receptors that represent one subfamily of the steroid/thyroid hormone receptor superfamily. To identify new members of the retinoid/thyroid hormone receptor subfamily that could play a role in the immune system, a screening of a T cell cDNA library was performed using a retinoid X receptor probe. A clone was isolated encoding a novel nuclear receptor expressed mainly in the thymus and T cell lines. This new receptor, TOR (thymus orphan receptor), is most closely related in both its DNA-binding domain and ligand-binding domain, 90% and 53%, respectively, to ROR alpha/RZR alpha and clusters with these two receptors and RZR beta in a phylogenetic tree, when both the DNA-binding domain and the ligand-binding domain sequences of nuclear receptors are compared. Thus, TOR is part of a subgroup of receptors, one of which has recently been reported to be activated by melatonin. TOR binds specifically to a direct repeat of the half-site sequence 5'-AGGTCA-3' with a four- or five-nucleotide spacer, DNA sequences that also serve as binding sites for thyroid hormone (TR), and retinoic acid receptors (RAR). In transient transfection experiments TOR does not activate a reporter gene carrying these sequences in the absence or the presence of any known nuclear receptor ligands. TOR, however, is able to repress TR and RAR activity on DR-4-TREs or DR-5-RAREs, respectively. Therefore, our data suggest that TOR, similar to COUP-TF, can negatively regulate retinoic acid and thyroid hormone signals. However, the response elements recognized by TOR and COUP-TF differ as do the expression patterns of these receptors. Thus, one important role of TOR could be to modulate retinoid and thyroid hormone signals in the thymus.
Mol Endocrinol 1995 Dec
PMID:TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals. 861 4

Unliganded thyroid hormone receptor (TR) functions as a transcriptional repressor of genes bearing thyroid hormone response elements in their promoters. Binding of hormonal ligand to the receptor releases the transcriptional silencing and leads to gene activation. Previous studies showed that the silencing activity of TR is located within the C-terminal ligand-binding domain (LBD) of the receptor. To dissect the role of the LBD in receptor-mediated silencing, we used a cell-free transcription system containing HeLa nuclear extracts in which exogenously added unliganded TRbeta repressed the basal level of RNA polymerase II-driven transcription from a thyroid hormone response element-linked template. We designed competition experiments with a peptide fragment containing the entire LBD (positions 145 to 456) of TRbeta. This peptide, which lacks the DNA-binding domain, did not affect basal RNA synthesis from the thyroid hormone response element-linked promoter when added to a cell-free transcription reaction mixture. However, the addition of the LBD peptide to a reaction mixture containing TRbeta led to a complete reversal of receptor-mediated transcriptional silencing in the absence of thyroid hormone. An LBD peptide harboring point mutations, which severely impair receptor dimerization, also inhibited efficiently the silencing activity of TR, indicating that the relief of repression by the LBD was not due to the sequestration of TR or its heterodimeric partner retinoid X receptor into inactive homo- or heterodimers. We postulate that the LBD peptide competed with TR for a regulatory molecule, termed a corepressor, that exists in the HeLa nuclear extracts and is essential for efficient receptor-mediated gene repression. We have identified the region from positions 145 to 260 (the D domain) of the LBD as a potential binding site of the putative corepressor. We observed further that a peptide containing the LBD of retinoic acid receptor (RAR) competed for TR-mediated silencing, suggesting that the RAR LBD may bind to the same corepressor activity as the TR LBD. Interestingly, the RAR LBD complexed with its cognate ligand, all-trans retinoic acid, failed to compete for transcriptional silencing by TRbeta, indicating that the association of the LBD with the corepressor is ligand dependent. Finally, we provide strong biochemical evidence supporting the existence of the corepressor activity in the HeLa nuclear extracts. Our studies demonstrated that the silencing activity of TR was greatly reduced in the nuclear extracts preincubated with immobilized, hormone-free glutathione S-transferase-LBD fusion proteins, indicating that the corepressor activity was depleted from these extracts through protein-protein interactions with the LBD. Similar treatment with immobilized, hormone-bound glutathione S-transferase-LBD, on the other hand, failed to deplete the corepressor activity from the nuclear extracts, indicating that ligand binding to the LBD disrupts its interaction with the corepressor. From these results, we propose that a corepressor binds to the LBD of unliganded TR and critically influences the interaction of the receptor with the basal transcription machinery to promote silencing. Ligand binding to TR results in the release of the corepressor from the LBD and triggers the reversal of silencing by allowing the events leading to gene activation to proceed.
Mol Cell Biol 1996 May
PMID:Transcriptional silencing by unliganded thyroid hormone receptor beta requires a soluble corepressor that interacts with the ligand-binding domain of the receptor. 862 57

The action of thyroid hormones on the expression of the mitochondrial ATP synthase beta-subunit gene (ATPsyn beta) is controversial. We detected a binding site for the thyroid hormone receptor between -366 and -380 in the human ATPsyn beta gene by DNase I footprint analysis and band-shift assays. However, expression vectors in which the chloramphenicol acetyl transferase (CAT) reporter gene is driven by the 5' upstream region of ATPsyn beta gene were unresponsive to T3 when transiently transfected to HepG2 or GH4C1 cells. CAT constructs driven by the rat phosphoenolpyruvate carboxykinase (PEPCK) or the growth hormone (GH) promoters were stimulated several fold by T3 in parallel experiments. It is proposed that the biological effects of thyroid hormones on the ATPsyn beta expression occur through indirect mechanisms.
Mol Cell Biochem 1996 Jan 26
PMID:Influence of thyroid hormones on the human ATP synthase beta-subunit gene promoter. 871 24

Ligand-independent transcriptional repression is an important function of nuclear hormone receptors. An interaction screen with the repression domain of the orphan receptor RevErb identified N-CoR, the corepressor for thyroid hormone receptor (TR) and retinoic acid receptor (RAR). N-CoR is likely to be a bona fide transcriptional corepressor for RevErb because (i) RevErb interacts with endogenous N-CoR, (ii) ectopic N-CoR potentiates RevErb-mediated repression, and (iii) transcriptional repression by RevErb correlates with its ability to bind N-CoR. Remarkably, a region homologous to the CoR box which is necessary for TR and RAR to interact with N-CoR is not required for RevErb. Rather, two short regions of RevErb separated by approximately 200 amino acids are required for interaction with N-CoR. The primary amino acid sequence of the N-terminal region of RevErb essential for N-CoR interaction is not homologous to that of TR or RAR, whereas similarities exist among the C-terminal domains of the receptors. N-CoR contains two adjacent but distinct interaction domains, one of which binds tightly to both RevErb and TR whereas the other binds more weakly and differentially interacts with the nuclear receptors. These results indicate that multiple nuclear receptors, utilizing different primary amino acid sequences, repress transcription by interacting with N-CoR.
Mol Cell Biol 1996 Oct
PMID:A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with distinct repression domains. 881 59


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