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

To identify genes that can repress the expression of growth regulatory molecules, a human fetal cDNA library was screened with a degenerate oligonucleotide that corresponds to the conserved stretch of 6 amino acids connecting successive zinc-finger regions in the Wilms' tumor suppressor/Egr-1 family of DNA-binding proteins. One clone, designated zinc-finger protein 174 (ZNF174), corresponds to a putative transcription factor with three zinc fingers and a novel finger-associated domain, designated the SCAN box. The three Cys2-His2-type zinc fingers are positioned at the carboxyl terminus, while the 65-amino acid finger-associated SCAN box is located near the amino terminus. Chromosomal localization using somatic cell hybrid analysis and fluorescent in situ hybridization mapped the gene for ZNF174 to human chromosome 16p13.3. The 2.5-kilobase transcript from this gene is expressed in a variety of human organs, but most strongly in adult testis and ovary. Fusion of the upstream regulatory region of ZNF174 to the DNA-binding domain of GAL4 revealed that the gene could confer a repression function on the heterologous DNA-binding domain. ZNF174 selectively repressed reporter activity driven by the platelet-derived growth factor-B chain and transforming growth factor-beta 1 promoters and bound to DNA in a specific manner. This member of the C2H2-type zinc-finger family is a novel transcriptional repressor.
 ...
PMID:Isolation and characterization of a novel zinc-finger protein with transcription repressor activity. 767 92

The expression of the yeast ADH2 gene is controlled by the transcriptional activator ADR1, a zinc-finger protein that binds to an upstream activating sequence (UAS1) in the ADH2 promoter. We report here the isolation of seven mutations in the ADR1-5c allele, defining five different amino acid changes, that suppress the enhanced ADH2 expression caused by the ADR1-5c allele. Each of the mutations was shown to reduce the activation of ADH2 by a wild-type ADR1 gene, suggesting the mutations disrupt a domain important to the function of both the ADR1 and ADR1-5c proteins. All five amino acid changes occurred within the DNA-binding domain of ADR1 and were shown to severely inhibit the ability of ADR1 to bind UAS1 in vitro. These mutations were found, however, to also affect the ability of ADR1 to activate transcription independent of its ability to bind DNA. These results indicate that the DNA-binding region of ADR1 is involved in both transactivation and DNA binding.
 ...
PMID:Mutations in the zinc-finger region of the yeast regulatory protein ADR1 affect both DNA binding and transcriptional activation. 813 76

A human recombinant cDNA clone that encoded 253 amino acids residues of a zinc-finger protein (THZif-1) was cloned by screening a cDNA library prepared from human promyelocytic leukemia HL60 cells with synthetic oligodeoxynucleotide probes that corresponded to the amino acid sequences of tryptic peptides derived from the DNA-binding protein specific for the nuclease-hypersensitive element (NHE) of the human c-myc gene. The predicted amino acid sequence of THZif-1 included a DNA-binding domain that contained five tandemly repeated zinc finger motifs. The three amino-terminal sets of zinc finger motifs, including the second finger, were found to be responsible for high-affinity interactions with the triple-helical conformation of NHE, as well as for high-affinity binding to the single-pyrimidine-rich strand of NHE in a sequence-specific manner. Cotransfection, trans-activation and in vitro transcription studies using the wild-type form and THZif-1 with a mutated second zinc finger motif demonstrated that the DNA-binding activity specific for H-form DNA of NHE was a prerequisite for the negative regulation of the expression of the c-myc gene.
 ...
PMID:[Negative repressor THZif-1 of protooncogene c-myc]. 853 52

WT1 encodes a zinc-finger protein, expressed as distinct isoforms, that is inactivated in a subset of Wilms tumors. Both constitutional and somatic mutations disrupting the DNA-binding domain of WT1 result in a potentially dominant-negative phenotype. In generating inducible cell lines expressing wild-type isoforms of WT1 and WT1 mutants, we observed dramatic differences in the subnuclear localization of the induced proteins. The WT1 isoform that binds with high affinity to a defined DNA target, WT1(-KTS), was diffusely localized throughout the nucleus. In contrast, expression of an alternative splicing variant with reduced DNA binding affinity, WT1 (+KTS), or WT1 mutants with a disrupted zinc-finger domain resulted in a speckled pattern of expression within the nucleus. Although similar in appearance, the localization of WT1 variants to subnuclear clusters was clearly distinct from that of the essential splicing factor SC35, suggesting that WT1 is not directly involved in pre-mRNA splicing. Localization to subnuclear clusters required the N terminus of WT1, and coexpression of a truncated WT1 mutant and wild-type WT1(-KTS) resulted in their physical association, the redistribution of WT1(-KTS) from a diffuse to a speckled pattern, and the inhibition of its transactivational activity. These observations suggest that different WT1 isoforms and WT1 mutants have distinct subnuclear compartments. Dominant-negative WT1 proteins physically associate with wild-type WT1 in vivo and may result in its sequestration within subnuclear structures.
 ...
PMID:Truncated WT1 mutants alter the subnuclear localization of the wild-type protein. 861 23

Interleukin-4 (IL-4) is a multifunctional cytokine that plays an important role in immune and inflammatory responses. Expression of the IL-4 gene is tightly controlled at the level of gene transcription by both positive and negative regulatory elements in the IL-4 promoter. Several constitutive nuclear factors have been identified that can interact with IL-4 promoter elements in DNA binding assays. Here we report that the zinc-finger protein YY-1 (Yin-Yang 1) can bind to multiple elements within the human IL-4 promoter. Cotransfection of Jurkat T cells with different IL-4 promoter/reporter constructs together with expression vectors encoding antisense, wild-type, or zinc finger-deleted mutant YY-1 suggested that YY-1 enhanced IL-4 promoter activity in a DNA-binding domain-dependent manner. Site-directed mutagenesis revealed that a proximal YY-1-binding site, termed Y0 ((-59)TCATTTT(-53)), was essential for YY-1-driven IL-4 promoter activity. In addition, cotransfected YY-1 enhanced both IL-4 promoter activity and endogenous IL-4 gene expression in nontransformed peripheral blood T cells. Thus, YY-1 positively regulates IL-4 gene expression in lymphocytes.
 ...
PMID:Yin-Yang 1 activates interleukin-4 gene expression in T cells. 1168 71

The zinc-finger protein Ikaros plays an important role in lymphoid homeostasis, and loss of Ikaros expression through germline disruption impairs lymphoid development. However, the role played by Ikaros after commitment to the T-cell lineage is unclear. To address this question, this study used the lck proximal promoter to drive the expression in T-cell progenitors of a naturally occurring short Ikaros isoform (IK5), which lacks the DNA-binding domain, reasoning that IK5 will form heterodimers with long isoforms and perturb their function. The IK5 transgene led to a selective and dramatic decrease in extrathymic intestinal intraepithelial lymphocytes (IELs) and natural killer 1.1+ T (NK T) cells with little effect on conventional alphabeta T cells, which resembles the T-cell phenotype of interleukin-15 receptor alpha chain (IL-15Ralpha) and IL-2/IL-15 receptor beta chain (IL-2Rbeta) knockout mice. The expression of IL-2Rbeta on double-negative T-cell progenitors of bi-5 was reduced, but enforced expression of IL-2Rbeta did not rescue IELs or NK T cells in bi-5 transgenic mice, suggesting that Ikaros or Ikaros family members regulate the expression of additional genes that are essential for the development of IELs and NK T cells. The study concludes that modest changes in the ratio of short to long Ikaros isoforms can substantially perturb T-cell development, and the development of IELs and NK T cells is particularly sensitive to such changes.
 ...
PMID:Enforced expression of the Ikaros isoform IK5 decreases the numbers of extrathymic intraepithelial lymphocytes and natural killer 1.1+ T cells. 1178 Dec 32

Artificial transcription factors containing designer zinc-finger DNA-binding domains (DBDs) have been used to activate or repress expression of a growing number of endogenous genes. We have combined targeted zinc-finger DBD technology with a dimerizer-regulated gene expression system to permit the small-molecule control of endogenous gene transcription. We constructed a dimerizer-responsive transcription factor that incorporates an artificial zinc-finger DBD targeted to the promoter of the human VEGF gene. Introduction of this activator into human cells allowed expression of the chromosomal VEGF gene to be induced by a small-molecule dimerizer compound consisting of a nonimmunosuppressive rapamycin analog. We found that by directly regulating zinc-finger protein (ZFP) activity, we could circumvent difficulties encountered in the generation of cell lines stably expressing conventional unregulated activators. Dimerizer-dependent VEGF induction was rapid, tight, and dose dependent, and resulted in VEGF protein expression levels several-fold greater than those produced by the natural hypoxic response.
 ...
PMID:Regulation of endogenous gene expression with a small-molecule dimerizer. 1208 60

The insulator element from the gypsy transposon is a DNA sequence that blocks activation of a promoter by a transcriptional enhancer when placed between them. The insulator contains reiterated binding sites for the Suppressor of Hairy-wing [Su(Hw)] zinc-finger protein. A protein encoded by another gene, modifier of mdg4 [mod(mdg4)], is also required for the enhancer-blocking activity of the Su(Hw) insulator. Here we present evidence that the Su(Hw) insulator activates a weakened yellow promoter at a distance. Deletion of the upstream promoter region (UPR), located close by the TATA box, significantly reduces yellow expression. The Su(Hw) insulator placed at different positions relative to the yellow promoter partially compensates for loss of the UPR. Su(Hw) is able to stimulate yellow expression even if it is located at a 5-kb distance from the promoter. The stimulatory activity depends on the number of Su(Hw)-binding sites. Mutational analysis demonstrates that only the DNA-binding domain and adjacent regions of the Su(Hw) protein are required for stimulation of yellow transcription.
 ...
PMID:Drosophila Su(Hw) insulator can stimulate transcription of a weakened yellow promoter over a distance. 1552 Feb 54

Transcription factors play an essential role in altering gene expression. A great progress about transcription factors has been made towards the understanding of normal physiological processes, embryonic development, and human diseases. Here we report the identification and characterization of a novel KRAB-containing zinc-finger protein, ZNF569, which is isolated from a human embryonic heart cDNA library. ZNF569 encodes a putative protein of 686 amino acids. The protein is conserved across different species during evolution. Expression of ZNF569 was found in most of the examined human adult and embryonic tissues with a higher level in heart and skeletal muscles. The KRAB and ZNF motifs of ZNF569 represent potent repression domains. When ZNF569 is fused to Gal-4 DNA-binding domain and co-transfected with VP-16, ZNF569 protein suppresses transcriptional activity. Overexpression of ZNF569 in COS-7 cells inhibited the transcriptional activities of SRE and AP-1, which may be silenced by siRNA. The results suggest that ZNF569 protein may act as a transcriptional repressor that suppresses MAPK signaling pathway to mediate cellular functions.
 ...
PMID:ZNF569, a novel KRAB-containing zinc finger protein, suppresses MAPK signaling pathway. 1679 18

Helios is a zinc-finger protein belonging to the Ikaros family of transcriptional regulators. It is expressed, along with Ikaros, throughout early stages of thymocyte development where it quantitatively associates with Ikaros through C-terminal zinc-finger domains that mediate heterodimerization between Ikaros family members. To understand the role of Helios in T-cell development, we used a retroviral vector to express full-length Helios or a Helios isoform that lacked the N-terminal DNA-binding domain in hematopoietic progenitor cells of reconstituted mice. Constitutive expression of full-length Helios resulted in an inhibition of T-cell development at the double-negative stage within the thymus. Although expression of the DNA-binding mutant of Helios did not contribute to developmental abnormalities at early times after transplantation, 60% of animals that expressed the Helios DNA-binding mutant developed an aggressive and transplantable T-cell lymphoma 4 to 10 months after transplantation. These results demonstrate a vital function for Helios in maintaining normal homeostasis of developing T cells and formally show that non-DNA-binding isoforms of Helios are lymphomagenic if aberrantly expressed within the T-cell lineage.
 ...
PMID:Expression of a non-DNA-binding isoform of Helios induces T-cell lymphoma in mice. 1711 Apr 63


1 2 Next >>