Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hormonal induction of 3T3-L1 preadipocytes triggers a cascade of events that initiate differentiation into adipocytes. CCAAT/enhancer-binding proteins beta and delta (C/EBPbeta/delta) are expressed early in the differentiation program, but are not immediately active. After a long lag, C/EBPbeta/delta become competent to bind to the C/EBP regulatory element in the C/EBPalpha gene promoter, C/EBPalpha being a transcriptional activator of numerous adipocyte genes. As C/EBPbeta/delta acquire binding activity, they become localized to centromeres as preadipocytes synchronously enter S phase at the onset of mitotic clonal expansion. Localization to centromeres occurs through C/EBP consensus-binding sites in centromeric satellite DNA. C/EBPalpha, which is antimitotic, becomes centromere-associated much later in the differentiation program as mitotic clonal expansion ceases and the cells become terminally differentiated.
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PMID:Activation and centromeric localization of CCAAT/enhancer-binding proteins during the mitotic clonal expansion of adipocyte differentiation. 1048 46

For successful transformation of prototrophic industrial yeast strains dominant selectable markers are necessary. In the present study we show the applicability of a selection system based on the phenotype of multidrug resistance. The mutant pdr3-9 allele on centromeric or episomal vector, encoding a more efficient transcriptional activator with Y276H amino acid substitution, was used as a dominant selectable marker for selection of transformants. The pdr3-9 allele conferred resistance of transformed cells to cycloheximide, chloramphenicol, mucidin and oligomycin both in the absence and in the presence of a chromosomal copy of the PDR3 gene. Both multicopy YEp352/pdr3-9 and centromeric pFL38/pdr3-9 vectors bearing the mutant pdr3-9 allele have proved to be a valuable tool for a direct selection of transformants of industrial strains of Saccharomyces cerevisiae.
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PMID:Use of mutated PDR3 gene as a dominant selectable marker in transformation of prototrophic yeast strains. 1058 52

Murine erythroleukemia (MEL) cells are a model system to study reorganization of the eukaryotic nucleus during terminal differentiation. Upon chemical induction, MEL cells undergo erythroid differentiation, leading to activation of globin gene expression. Both processes strongly depend on the transcriptional activator NF-E2. Before induction of differentiation, both subunits of the NF-E2 heterodimer are present, but little DNA-binding activity is detectable. Using immunofluorescence microscopy, we show that the two NF-E2 subunits occupy distinct nuclear compartments in uninduced MEL cells; the smaller subunit NF-E2p18 is found primarily in the centromeric heterochromatin compartment, whereas the larger subunit NF-E2p45 occupies the euchromatin compartment. Concomitant with the commitment period of differentiation that precedes globin gene activation, NF-E2p18, along with other transcriptional repressors, relocates to the euchromatin compartment. Thus, relocation of NF-E2 p18 may be a rate-limiting step in formation of an active NF-E2 complex. To understand the mechanisms of NF-E2 localization, we show that centromeric targeting of NF-E2p18 requires dimerization, but not with an erythroid-specific partner, and that the transactivation domain of NF-E2p45 may be necessary and sufficient to prevent its localization in centromeric heterochromatin. Finally, using fluorescence in situ hybridization, we show that, upon differentiation, the beta-globin gene loci relocate away from heterochromatin compartments to euchromatin. This relocation correlates with both transcriptional activation of the globin locus and relocation of NF-E2p18 away from heterochromatin, suggesting that these processes are linked.
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PMID:Nuclear relocation of a transactivator subunit precedes target gene activation. 1159 25

The DNA-binding protein Rap1p fulfills many different functions in the yeast cell. It targets 5% of the promoters, acting both as a transcriptional activator and as a repressor, depending on the DNA sequence context. In addition, Rap1p is an essential structural component of yeast telomeres, where it contributes to telomeric silencing. Here we review the evidence indicating that Rap1p function is modulated by the precise architecture of the its binding site and its surroundings: long tracts of telomeric repeats for telomeric functions, specific sequences and orientation for maximal transcriptional activation, and specific DNA recognition sequences for complementary factors in other cases. Many of these functions are probably related to chromatin organization around Rap1p DNA binding sites, resulting from the very tight binding of Rap1p to DNA. We propose that Rap1p alters its structure to bind to different versions of its DNA binding sequence. These structural changes may modulate the function of Rap1p domains, providing different interacting surfaces for binding to specific co-operating factors, and thus contributing to the diversity of Rap1p function.
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PMID:The different (sur)faces of Rap1p. 1265 5

TLX1/HOX11, a DNA-binding homeodomain protein, was originally identified by virtue of its aberrant expression in T-cell leukemia and subsequently found to be crucial for normal spleen development. The precise mechanism of TLX1 function remains poorly understood, although it is known that it can act as both a transcriptional activator and repressor and can downregulate the Aldh1a1 gene in embryonic mouse spleen. Using a whole-genome PCR approach, we show here that TLX1 protein directly interacts with pericentromeric human satellite 2 DNA sequences. Such DNA is known to localize to heterochromatin, which among other roles has been implicated in gene silencing. The interaction was confirmed in vitro and in vivo by gel retardation and chromatin immunoprecipitation assays involving satellite 2 DNA, which contained sequences resembling TLX1 binding sites. Using immunofluorescence microscopy, TLX1 demonstrated a punctate pattern of staining in the nuclei of leukemic T-cells (ALL-SIL). Double labelling indicated that TLX1 colocalized with the centromeric protein CENP-B, demonstrating that the TLX1 foci corresponded to clusters of centromeric DNA. The novel interaction of TLX1 with constitutive heterochromatin adds an additional level of complexity to the intracellular functions of this transcriptional regulator and may have relevance to its roles in transcriptional repression and T-cell immortalization.
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PMID:The nuclear oncoprotein TLX1/HOX11 associates with pericentromeric satellite 2 DNA in leukemic T-cells. 1635 34

The ALX4 (aristaless-like homeobox 4) gene encodes a paired-type homeodomain transcriptional activator and plays a major role in anterior-posterior pattern formation during limb development. Here, the cloning, genomic structure and expression of the bovine ortholog of the ALX4 gene are reported. The bovine ALX4 gene consists of four exons and is located on BTA15q28-->q29 in a region syntenic to HSA11p11.2. The transcribed ALX4 mRNA encodes a 397-amino-acid protein showing a paired-type homeodomain and a C-terminal stretch of amino acids known as the OAR- or aristaless domain. The predicted protein shares 92.5% identity to human and mouse ALX4 proteins and all three species share almost complete identity in the conserved domains. ALX4 expression was detected by reverse transcriptase polymerase chain reaction in bovine fetal limb bones. The ALX4 gene was evaluated as a candidate gene for bovine syndactyly which has been mapped on the telomeric region of cattle chromosome 15. Sequencing of the four exons with flanking sequences of the bovine ALX4 gene from a panel of 14 affected animals belonging to German Holstein, German Fleckvieh and crossbreds, and 27 unaffected individuals from German Holstein revealed five silent SNPs within the coding region out of eleven SNPs in total. Four SNPs were polymorphic in the affected animals, but in comparison to the genotyped unaffected individuals the genotype distribution showed no evidence for an association to the phenotype. Therefore our data indicate that the ALX4 gene can probably be excluded as candidate gene for bovine syndactyly in the examined animals.
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PMID:The bovine aristaless-like homeobox 4 (ALX4) as a candidate gene for syndactyly. 1706 92

We have used a human artificial chromosome (HAC) to manipulate the epigenetic state of chromatin within an active kinetochore. The HAC has a dimeric alpha-satellite repeat containing one natural monomer with a CENP-B binding site, and one completely artificial synthetic monomer with the CENP-B box replaced by a tetracycline operator (tetO). This HAC exhibits normal kinetochore protein composition and mitotic stability. Targeting of several tet-repressor (tetR) fusions into the centromere had no effect on kinetochore function. However, altering the chromatin state to a more open configuration with the tTA transcriptional activator or to a more closed state with the tTS transcription silencer caused missegregation and loss of the HAC. tTS binding caused the loss of CENP-A, CENP-B, CENP-C, and H3K4me2 from the centromere accompanied by an accumulation of histone H3K9me3. Our results reveal that a dynamic balance between centromeric chromatin and heterochromatin is essential for vertebrate kinetochore activity.
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PMID:Inactivation of a human kinetochore by specific targeting of chromatin modifiers. 1841 Jul 28

SHOX deficiency is a frequent cause of short stature. The short stature homeobox-containing gene resides in the telomeric PAR1 region on the short arm of both sex chromosomes and escapes X inactivation. For this review, abstracts of 207 publications presented by PubMed for the search term 'SHOX' were screened. Heterozygote SHOX mutations (80% deletions) were detected in 2-15% of individuals with formerly idiopathic short stature, in 50-90% of individuals with Leri-Weill dyschondrosteosis, and in almost 100% of girls with Turner syndrome. Mutational analysis is primarily performed by MLPA analysis followed by gene sequencing if necessary. SHOX is a nuclear protein that binds to DNA and acts as a transcriptional activator. Orthologs are present in many vertebrates but not in rodents. Gene expression starting as early as 33 days postconception in humans is predominant in the mid portion of the buds and in the first and second pharyngeal arches. In the growth plate, hypertrophic chondrocytes express SHOX where it seems to have antiproliferative potency. The penetrance of SHOX deficiency is high, but its clinical expression is very variable becoming more pronounced with age and being more severe in females. Growth failure starts early during the first years of life and the height deficit present at preschool age seems not to deteriorate further. The mean adult height is -2.2 SDS. Auxological analysis of the body proportions (mesomelia), the presence of minor abnormalities, and the search for subtle radiographic signs are important keys to the diagnosis which has to be confirmed by genetic analysis. The growth-promoting effect of GH therapy approved for individuals with SHOX mutations seems to be equal to the effect seen in Turner syndrome.
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PMID:Short stature due to SHOX deficiency: genotype, phenotype, and therapy. 2132 65

Telomeres constitute the ends of linear chromosomes and together with the shelterin complex form a structure essential for genome maintenance and stability. In addition to the constitutive binding of the shelterin complex, other direct, yet more transient interactions are mediated by the CST complex and HOT1/HMBOX1, while subtelomeric variant repeats are recognized by NR2C/F transcription factors. Recently, the Kruppel-like zinc finger protein ZBTB48/HKR3/TZAP has been described as a novel telomere-associated factor in the vertebrate lineage. Here, we show that ZBTB48 binds directly both to telomeric and to subtelomeric variant repeat sequences. ZBTB48 is found at telomeres of human cancer cells regardless of the mode of telomere maintenance and it acts as a negative regulator of telomere length. In addition to its telomeric function, we demonstrate through a combination of RNAseq, ChIPseq and expression proteomics experiments that ZBTB48 acts as a transcriptional activator on a small set of target genes, including mitochondrial fission process 1 (MTFP1). This discovery places ZBTB48 at the interface of telomere length regulation, transcriptional control and mitochondrial metabolism.
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PMID:ZBTB48 is both a vertebrate telomere-binding protein and a transcriptional activator. 2850 Feb 56