Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q02556 (DNA-binding domain)
 6,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We proposed that a cell-selective regulatory protein coordinately regulates the expression of three enzymes that are required for the biosynthesis of corticosteroids: cholesterol side chain cleavage enzyme, steroid 21-hydroxylase, and the aldosterone synthase isozyme of steroid 11 beta-hydroxylase. In this report, we identify a 53-kilodalton protein, termed steroidogenic factor 1 (SF-1), that interacts with the related promoter elements from these steroidogenic enzymes, and we isolate and characterize a cDNA that very likely encodes this protein. We first showed that nuclear extracts from bovine adrenal glands interact with the mouse steroidogenic regulatory elements, forming complexes indistinguishable from those produced by nuclear extracts from mouse Y1 adrenocortical cells. These bovine adrenal extracts were subjected to sequential ion exchange and affinity chromatography to yield a highly enriched preparation of SF-1. The predominant protein in the affinity-purified preparation comigrated with shift activity and had a mol wt of 53,000; UV cross-linking experiments demonstrated directly that this 53-kilodalton protein interacted with the steroidogenic regulatory element. Even with this marked enrichment, affinity-purified SF-1 bound six steroidogenic regulatory elements. These results support strongly the model that a steroidogenic cell-selective protein interacts with related promoter elements from three steroidogenic enzymes to regulate their coordinate expression. The recognition sequence of SF-1 closely resembles those of nuclear hormone receptor family members, suggesting that SF-1 may belong to this supergene family. By screening a Y1 cell cDNA library with the DNA-binding region of the H-2RIIBP nuclear hormone receptor cDNA, we isolated a cDNA that is selectively expressed in steroidogenic cells. When expressed as a glutathione S-transferase fusion protein in Escherichia. coli, the protein encoded by this cDNA interacts with all six related steroidogenic regulatory elements with a binding specificity indistinguishable from that of SF-1. Surprisingly, the sequence of the putative DNA-binding domain of this cDNA matches exactly the corresponding sequence of the mouse homolog of the Drosophila transcription factor fushi tarazu-factor I. The demonstration that a member of the nuclear hormone receptor family interacts with the steroidogenic regulatory elements provides intriguing insights into possible mechanisms by which these essential genes are regulated.
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PMID:Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. 140 3

H-2RIIBP is a member of the nuclear hormone receptor superfamily that binds to the region II enhancer of major histocompatibility complex (MHC) class I genes. The binding occurs through the GG(T/A)CA motif present also in many other genes. The role of H-2RIIBP in developmental regulation of MHC class I genes has been studied in undifferentiated N-Tera2 embryonal carcinoma cells by transient cotransfection of an expressible H-2RIIBP plasmid and a chloramphenicol acetyltransferase reporter gene linked to the MHC class I promoter. Transfection of the expression plasmid led to production of H-2RIIBP transcripts and enhanced MHC class I promoter activity in cells that were treated with retinoic acid but not yet differentiated. Retinoic acid concentrations required for transactivation overlapped with those capable of inducing morphological differentiation and expression of endogenous MHC class I genes in these cells. This enhancement was mediated by region II, as a heterologous thymidine kinase promoter driven by region II also served as a target for H-2RIIBP transactivation. Deletion of the bulk of the DNA-binding domain or the ligand-binding domain of H-2RIIBP, but not of the N-terminal domain, abolished transactivation, indicating that the former two domains are critical for the enhancement. Moreover, H-2RIIBP transactivation exhibited a strict cell-type restriction. As observed in other cell lines, N-Tera2 cells that had undergone differentiation failed to elicit transactivation, suggesting that H-2RIIBP acts in concert with a cofactor expressed in undifferentiated N-Tera2 cells that requires retinoic acid for its function. These results suggest that H-2RIIBP can function as a developmentally specific transcription factor for MHC class I genes.
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PMID:Retinoic acid-dependent transactivation of major histocompatibility complex class I promoters by the nuclear hormone receptor H-2RIIBP in undifferentiated embryonal carcinoma cells. 173 9

T-lymphocyte proliferation is suppressed by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D3, and is associated with a decrease in interleukin 2 (IL-2), gamma interferon, and granulocyte-macrophage colony-stimulating factor mRNA levels. We report here that 1,25(OH)2D3-mediated repression in Jurkat cells is cycloheximide resistant, suggesting that it is a direct transcriptional repressive effect on IL-2 expression by the vitamin D3 receptor (VDR). We therefore examined vitamin D3-mediated repression of activated IL-2 expression by cotransfecting Jurkat cells with IL-2 promoter/reporter constructs and a VDR overexpression vector and by DNA binding. We delineated an element conferring both DNA binding by the receptor in vitro and 1,25(OH)2D3-mediated repression in vivo to a short 40-bp region encompassing an important positive regulatory element, NF-AT-1, which is bound by a T-cell-specific transcription factor, NFATp, as well as by AP-1. VDR DNA-binding mutants were unable to either bind to this element in vitro or repress in vivo; the VDR DNA-binding domain alone, however, bound the element but also could not repress IL-2 expression. These results indicate that DNA binding by VDR is necessary but not sufficient to mediate IL-2 repression. By combining partially purified proteins in vitro, we observed the loss of the bound NFATp/AP-1-DNA complex upon inclusion of VDR or VDR-retinoid X receptor. Order of addition and off-rate experiments indicate that the VDR-retinoid X receptor heterodimer blocks NFATp/AP-1 complex formation and then stably associates with the NF-AT-1 element. This direct inhibition by a nuclear hormone receptor of transcriptional activators of the IL-2 gene may provide a mechanistic explanation of how vitamin derivatives can act as potent immunosuppressive agents.
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PMID:Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. 756 32

The nuclear hormone receptor gene superfamily encodes structurally related proteins that regulate transcription of target genes. These macromolecules include receptors for steroid and thyroid hormones, vitamins, and other proteins for which no ligands have been found. These receptors have modular domains. The DNA-binding domain directs the receptors to bind specific DNA sequences as monomers, homodimers, or heterodimers. The ligand-binding domain responds to binding of the cognate hormone; this domain and the amino terminal domain interact with other transcription factors. Nuclear receptor-specific actions are derived from a combination of diverse elements, including availability of ligand, receptors, and nonreceptor factors; target-site structure; interactions with other proteins, such as the general transcription factors; and influences of other signaling pathways. These interactions result in ligand-regulated and ligand-independent effects on initiation of transcription of the target genes. Understanding the mechanisms of nuclear receptor action will enhance our knowledge of transcription and hormone influences on disease and facilitate the design of drugs with greater therapeutic value.
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PMID:The nuclear hormone receptor gene superfamily. 759 77

To investigate the role of nuclear hormone receptors on neuropeptide gene expression in the hypothalamo-neurohypophyseal system (HNS) of the rat, a survey was made of members of the nuclear hormone receptor superfamily that are expressed in the supraoptic nucleus (SON). A polymerase chain reaction cloning strategy based on homologies in the DNA-binding domain of AGGTCA-binding factors was devised for the identification of receptors in microdissected SON tissue. Cloning of the amplified products led to the identification of five true receptors, thyroid hormone receptor-alpha (THR alpha), retinoic acid receptor-alpha, retinoic acid receptor-gamma, retinoid X receptor-alpha, and retinoid X receptor-gamma, as well as four orphan receptors, apolipoprotein AI regulatory protein (ARP-1), chicken ovalbumin upstream promoter transcription factor I (COUP-TF I), estrogen-related receptor 2, and testis receptor 4 (TR4). Dot-blot screening of amplified gene fragment analysis showed that THR alpha, ARP-1, TR4, and COUP-TF I were the most abundant factors expressed in the SON region, in the order THR alpha > ARP-1 > TR4 approximately COUP-TF I. THR alpha has previously been localized to HNS neurons. In situ hybridization analysis showed that ARP-1, COUP-TF I, and TR4 were not expressed in magnocellular neurons at appreciable levels, but rather in surrounding structures. Furthermore, in lactating female rats there were no significant differences in the composition of the nine identified nuclear hormone receptors in the SON region compared with control animals. From these experiments, it is concluded that there is a multitude of hypothalamically expressed nuclear hormone receptors, but that only THR alpha is expressed at relatively high abundance in HNS neurons. This indicates that the peptide-producing magnocellular neurons of the SON express a specific set of transcription factors of the nuclear hormone receptor family.
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PMID:Expression of nuclear hormone receptors in the rat supraoptic nucleus. 772 Jun 76

Within the hippocampus, stimulus-transcriptional coupling plays an important role in post-seizure neuronal adaptation, post-ischemic cell death and the induction of long-term potentiation. To identify additional mediators of hippocampal transcriptional responses a targeted approach was developed and used to characterize the spectrum of nuclear hormone receptors expressed within this brain region. cDNAs encoding the DNA-binding domains of six different members of the nuclear hormone receptor superfamily were isolated. A majority were identical or closely related to receptors known to be expressed within the hippocampus. Two additional isolates, HZF-2 and HZF-3, encode the DNA-binding domain of novel members of the nuclear hormone receptor superfamily.
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PMID:Expression of nuclear hormone receptors within the rat hippocampus: identification of novel orphan receptors. 791 60

The retinoid X receptor (RXR) is a member of the nuclear hormone receptor superfamily and has recently been shown to function in a variety of hormonal signaling pathways by virtue of its ability to heterodimerize with other nuclear hormone receptors. Here we describe resonance assignments, the secondary structural elements and the global folding pattern of the DNA-binding domain (residues 130-223) of human RXR alpha, as determined by multidimensional nuclear magnetic resonance spectroscopy. Its overall structure is similar to those reported for the glucocorticoid, estrogen, and retinoic acid receptors, in that the two zinc fingers of RXR fold to form a single structural domain containing two helices, which are located at the carboxy terminal of the two zinc fingers. There is also a short antiparallel beta-sheet formed between two residues in the amino-terminal base of the first finger and two residues in the carboxy terminal of that same finger just before the first helix. However, in contrast to the other nuclear hormone receptor DNA-binding domains, the RXR domain contains a third helix immediately after the conserved Gly-Met sequence that signals the termination of the second helix. The second and third helices lie orthogonal to and wrap around the first helix, generating an extended hydrophobic core. Since helices two and three are separated by only two residues, the backbone flexibility afforded by the presence of the conserved glycine residue between them may be crucial for the proper positioning of the third helix relative to the first helix. A 12-amino-acid region termed the 'T-box', which includes this third helix, was recently shown to be required for homodimeric binding of RXR to its cognate response element [Wilson, T. E., Paulsen, R. E., Padgett, K. A. & Milbrandt, J. (1992) Science 256, 107-110].
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PMID:NMR assignments and secondary structure of the retinoid X receptor alpha DNA-binding domain. Evidence for the novel C-terminal helix. 792 81

X-linked adrenal hypoplasia congenita is a developmental disorder of the human adrenal gland that results in profound hormonal deficiencies and is lethal if untreated. We have isolated the gene responsible for the disease, DAX-1, which is deleted or mutated in X-linked adrenal hypoplasia patients. DAX-1 encodes a new member of the nuclear hormone receptor superfamily displaying a novel DNA-binding domain. The DAX-1 product acts as a dominant negative regulator of transcription mediated by the retinoic acid receptor.
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PMID:An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. 799 Sep 53

The usp locus encodes a member of the nuclear hormone receptor superfamily in Drosophila melanogaster that interacts with EcR (ecdysone receptor) to mediate ecdysteroid-induced gene expression. A 2.7-kb usp mRNA was detected at all developmental times tested, although its abundance varied. Among premetamorphic stages, both the 2.7-kb transcript and Usp protein attained their highest levels in the late third larval instar. The 2.7-kb usp transcript was also found in adult stages and a 1.2-kb transcript was detected in the polyadenylated RNA fraction of both mature adult females and early embryos. Aneuploids carrying two usp mutant alleles and a putative variegating usp+ allele often developed deformities of the adult wing disc that apparently resulted from mutational disruption of usp activity before metamorphosis and whose frequency was affected by maternal genotype. Both of the recessive lethal usp mutations associated with this "cleft thorax" phenotype involved substitutions of conserved arginine residues in the DNA-binding domain, although the frequency of the phenotype was not the same for the two alleles. Both mutant proteins retained the ability to form heterodimers with EcR in vitro but showed reduced affinity for an ecdysone response element.
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PMID:Expression and function of the ultraspiracle (usp) gene during development of Drosophila melanogaster. 808 49

We report the molecular definition of an early late puff locus, at position 78C, that is inducible by ecdysone at the onset of Drosophila metamorphosis. This puff contains a single ecdysone-inducible gene consisting of two nested transcription units, E78A and E78B. E78A mRNA is expressed during a brief interval in mid-pupal development and encodes a novel member of the nuclear hormone receptor superfamily. E78B encodes a truncated receptor isoform that lacks the DNA-binding domain and is predominantly expressed at puparium formation and immediately following E78A in pupae. E78B is directly inducible by ecdysone in late third instar larvae and depends on ecdysone-induced protein synthesis for its maximal level of expression. These observations indicate that E78 represents a distinct subset of early ecdysone-inducible regulatory genes.
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PMID:The Drosophila 78C early late puff contains E78, an ecdysone-inducible gene that encodes a novel member of the nuclear hormone receptor superfamily. 840 14


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