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

In petunia flowers, the loci an1, an2, and an11 control the pigmentation of the flower by stimulating the transcription of anthocyanin biosynthetic genes. The an1 and an2 locus were recently cloned and encode a basic helix-loop-helix (bHLH) and MYB-domain transcriptional activator, respectively. Here, we report the isolation of the an11 locus by transposon tagging. RNA gel blot experiments show that an11 is expressed independently from an1 and an2 throughout plant development, as well as in tissues that do not express the anthocyanin pathway. It encodes a novel WD-repeat protein that is highly conserved even in species that do not produce anthocyanins such as yeast, nematodes, and mammals. The observation that the human an11 homolog partially complements the an11 petunia mutant in transient assays shows that sequence similarity reflects functional conservation. Overexpression of an2 in an11- petals restored the activity of a structural anthocyanin gene in transient assays, indicating that AN11 acts upstream of AN2. Cell fractionation experiments show that the bulk of the AN11 protein is localized in the cytoplasm. Taken together, this indicates that AN11 is a cytoplasmic component of a conserved signal transduction cascade that modulates AN2 function in petunia, thereby linking cellular signals with transcriptional activation.
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PMID:The an11 locus controlling flower pigmentation in petunia encodes a novel WD-repeat protein conserved in yeast, plants, and animals. 919 70

TFEC is a transcriptional repressor originally identified in rat chondrosarcoma and contains a basic helix-loop-helix and leucine zipper (bHLH/LZ) structure. TFEC shares a closely related bHLH/LZ structure with microphthalmia-associated transcription factor (MITF) and TFE3. In the course of cDNA cloning for a factor structurally related to MITF which is also a regulator for cell differentiation, we have isolated cDNA clones from a THP-1 human monocytic leukemia cell line. These cDNAs encode a protein of 347 amino acids, termed TFECL, a human homolog of a putative rat TFEC isoform. TFECL contains an acidic domain that corresponds to a transcriptional activation domain of TFE3 but its equivalent region is deleted in rat TFEC. We explored a function of TFECL using a melanocyte-specific tyrosinase gene and a ubiquitously expressed heme oxygenase-1 gene, each promoter containing the cis-acting CANNTG motifs. By transient coexpression assays, we showed that TFECL is able to activate or inhibit transcription of a reporter gene linked to either the tyrosinase or the heme oxygenase-1 gene promoter, depending on cell types. These results suggest that TFECL may function as a transcriptional activator under certain conditions.
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PMID:Molecular cloning of cDNA encoding a human TFEC isoform, a newly identified transcriptional regulator. 925 61

In Drosophila embryos, dorsal-ventral polarity is defined by a signal transduction pathway that regulates nuclear import of the Dorsal protein. Dorsal protein's ability to act as a transcriptional activator of some zygotic genes and a repressor of others defines structure along the dorsal-ventral axis. Dorsal is a member of a group of proteins, the Rel-homologous proteins, whose activity is regulated at the level of nuclear localization. Dif, a more recently identified Drosophila Rel-homologue, has been proposed to act as a mediator of the immune response in Drosophila. In an effort to understand the function and regulation of Rel-homologous proteins in Drosophila, we have expressed Dif protein in Drosophila embryos derived from dorsal mutant mothers. We found that the Dif protein was capable of restoring embryonic dorsal-ventral pattern elements and was able to define polarity correctly with respect to the orientation of the egg shell. This, together with the observation that the ability of Dif to restore a dorsal-ventral axis depended on the signal transduction pathway that normally regulates Dorsal, suggests that Dif protein formed a nuclear concentration gradient similar to that seen for Dorsal. By studying the expression of Dorsal target genes we found that Dif could activate the zygotic genes that Dorsal activates and repress the genes repressed by Dorsal. Differences in the expression of these target genes, as well as the results from interaction studies carried out in yeast, suggest that Dif is not capable of synergizing with the basic helix-loop-helix transcription factors with which Dorsal normally interacts, and thereby lacks an important component of Dorsal-mediated pattern formation.
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PMID:The Dorsal-related immunity factor (Dif) can define the dorsal-ventral axis of polarity in the Drosophila embryo. 957 Jul 79

Hairy-related proteins are a distinct subfamily of basic helix-loop-helix (bHLH) proteins that generally function as DNA-binding transcriptional repressors. These proteins act in opposition to bHLH transcriptional activator proteins such as the proneural and myogenic proteins; together, the activator and repressor genes that encode these proteins have co-evolved as a regulatory gene "cassette" or "module" for controlling cell fate decisions. In the development of the Drosophila peripheral nervous system, Hairy-related genes function at multiple steps during neurogenesis, for example, as positional information genes that establish the "prepattern" that controls where "proneural cluster" equivalence groups will form, and later as nuclear effectors of the Notch signaling pathway to "single out" individual precursor cells within the equivalence group. Hairy-related genes also function in the establishment and restriction of other types of equivalence groups, such as those for muscle and Malphigian tubule precursors. This general function in cell fate specification has been conserved from Drosophila to vertebrates and has implications for human disease pathogenesis.
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PMID:The function of hairy-related bHLH repressor proteins in cell fate decisions. 961 1

Glucose-regulated transcription of the L-type pyruvate kinase (L-PK) gene is mediated through its glucose response element (GlRE/L4 box) composed of two degenerated E-boxes. Upstream stimulatory factor (USF) is a component of the transcriptional glucose response complex built up on the GlRE. Cooperation of the GlRE with the contiguous binding site (L3 box) for the orphan nuclear receptor hepatocyte nuclear factor 4 (HNF4) has also been suggested. We compared by transient transfection assays the effects of USF2a and other basic helix-loop-helix leucine zipper (bHLH-LZ) factors (TFE3, c-Myc, SREBP/ADD1) on the activity and glucose responsiveness of a minimal L-PK promoter directed by oligomerized glucose response units (L4L3 boxes). We found that: (i) although USF2a is intrinsically a moderate transcriptional activator, it has a strong stimulatory effect on the activity of the L4L3-based reporter construct in hepatocyte-derived cells and interferes with the glucose responsiveness; (ii) despite its potent ability as a transactivator, TFE3 alone is barely active on the GlRE in hepatocyte-derived cells; (iii) TFE3 as USF2a acts synergistically with HNF4 and abolishes glucose responsiveness of the promoter when overexpressed; (iv) in contrast, overexpression of HNF4 alone stimulates activity of the promoter without interfering with glucose responsiveness; (v) SREBP/ADD1 has a very weak activity on the L4L3 elements, only detectable in the presence of HNF4, and c-Myc does not interact with the GIRE of the L-PK promoter. Our studies indicate that different bHLH-LZ transcription factors known to recognize CACGTG-type E-boxes are not equivalent in acting through the L-PK glucose response element, with USF proteins being especially efficient in hepatocyte-derived cells.
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PMID:Effect of different basic helix-loop-helix leucine zipper factors on the glucose response unit of the L-type pyruvate kinase gene. 969 82

The GATA-3 transcription factor is required for development of the T-cell lineage and Th2 cytokine gene expression in CD4 T-cells. We have mapped the DNase-I-hypersensitive (HS) regions of the human GATA-3 gene in T-cells and non-T-cells and studied their transcriptional activities. HS I-III, located 5' from the transcriptional initiation site, were found in hematopoietic and non-hematopoietic cells, whereas HS IV-VII, located 3' from the transcriptional start site, were exclusively observed in T-cells. Among these hypersensitive sites, two transcriptional control elements were found, one in the first intron of the GATA-3 gene and the other between 8.3 and 5.9 kilobases 5' from the GATA-3 transcriptional initiation site. The first intron acted as a strong transcriptional activator in a position-dependent manner and with no cell-type specificity. The upstream regulatory element could confer T-cell specificity to the GATA-3 promoter activity, and analysis of this region revealed a 707-base pair silencer that drastically inhibited GATA-3 promoter activity in non-T-cells. Two CAGGTG E-boxes, located at the 5'- and 3'-ends of the silencer, were necessary for this silencer activity. The 3'-CAGGTG E-box could bind USF proteins, the ubiquitous repressor ZEB, or the basic helix-loop-helix proteins E2A and HEB, and we showed that a competition between ZEB and E2A/HEB proteins is involved in the silencer activity.
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PMID:T-cell expression of the human GATA-3 gene is regulated by a non-lineage-specific silencer. 1003 51

The Clock gene is an essential regulator of circadian rhythms. It encodes a member of the basic helix-loop-helix/PER-ARNT-SIM family of transcription factors known to play a central role in the control of diverse cellular events. Previously we described the functional identification and molecular isolation of the Clock gene in the mouse, its interaction with the BMAL1 protein, and the role of this complex as a transcriptional activator in the circadian pacemaker. Here, we report the cloning, exon organization, chromosomal location, and mRNA expression of the human CLOCK gene. The coding sequence of human CLOCK extends for 2538 bp and is 89% identical to its mouse ortholog; its deduced amino acid sequence is 846 residues long and is 96% identical to mouse CLOCK. Radiation hybrid mapping localized human CLOCK to the long arm of human chromosome 4 (4q12). Direct sequencing of a genomic CLOCK clone indicated that the coding sequence of human CLOCK extends over 20 exons and that its intron/exon organization is identical to that of the mouse ortholog. Northern blot analysis indicated widespread expression of two major transcripts of 8 and 10 kb, and in situ hybridization of human brain tissue revealed elevated expression of CLOCK mRNA in the suprachiasmatic nuclei, the locus of circadian control in mammals, and in the cerebellum. Comparison of cDNA clones revealed two single nucleotide polymorphisms in noncoding sequence flanking the CLOCK open reading frame. The central role of Clock in the organization of circadian rhythms suggests that it will be a useful candidate gene for genetic analyses of disorders associated with dysfunction of the circadian system.
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PMID:Molecular cloning and characterization of the human CLOCK gene: expression in the suprachiasmatic nuclei. 1019 58

We report that the neuronal-specific basic helix-loop-helix (bHLH) gene NSCL-1 is expressed at multiple and distinct stages of cerebellar granule cell differentiation. During embryonic development, NSCI-1 expression is initially evenly distributed in the cerebellar primordium and then becomes restricted to the ventricular zone. At the early steps of granule cell development, NSCL-1 is not expressed in rhombic lip cells, but instead in migrating granule cell precursors. Its expression culminates during postnatal proliferation of the external germinal layer, and remains only transiently in the newly formed internal granular layer, and at a much lower level. Thus, NSCL-1 expression is linked to the onset of granule cell differentiation, but is not involved in the maintenance of the differentiated state. These findings suggest that NSCL-1 does not behave as a specification factor, but rather as a factor promoting expansion of progenitor external germinal layer (EGL) cells. Gel mobility shift assays show that NSCL-1 only binds DNA as a heterodimeric complex with the ME1a E-protein. We also provide the first evidence that NSCL-1 functions as a transcriptional activator when heterodimerized with the ME1a E-protein. Taken together, these results suggest that NSCL-1 participates in the regulatory network controlling gene expression during cerebellar granule cell differentiation.
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PMID:Expression of the bHLH gene NSCL-1 suggests a role in regulating cerebellar granule cell growth and differentiation. 1046 48

Brain ischemia is a cause of substantial morbidity and mortality during the later decades of life. In light of this, many studies have used in vitro and in vivo models of acute necrosis to test candidate therapeutic agents. More recently, the existence of a genetically programmed component of ischemic death has become widely accepted. We have used molecular genetic approaches to investigate the potential link between hypoxia-induced gene transcription and the delayed death of ischemic neurons. Hypoxia-induced gene expression is an evolutionarily conserved response comprising both transcriptional activation and posttranscriptional and posttranslational stabilization events. Members of the PER-ARNT-SIM (PAS) family of basic helix-loop-helix transcription factors have been shown to regulate hypoxic transcripts in nonneuronal cultured lines. However, evidence for ischemic activation of PAS proteins within the neuronal compartment or possible involvement in neuronal death is lacking. The tumor-suppressor protein p53 is a known transcriptional activator within the central nervous system that is clearly involved in the pathologic response to ischemia. This article will provide data that implicate the coordinate activities of p53 and the PAS protein HIF-1alpha in driving ischemia-induced delayed neuronal death. Background regarding mechanisms of ischemic neuronal death will also be provided with special attention paid to the role of de novo gene expression in promoting this pathologic sequence. The identification of the HIF-1alpha/p53-mediated signaling pathway in neurons highlights a novel target toward which anti-ischemic neuroprotective drug discovery can be applied.
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PMID:HIF-1alpha and p53 promote hypoxia-induced delayed neuronal death in models of CNS ischemia. 1048 75

Microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix-leucine zipper protein, and plays an important role in the development of various cell types, such as neural-crest-derived melanocytes and optic-cup-derived retinal pigment epithelium. Three isoforms of MITF with distinct amino-termini have been described. These include melanocyte lineage-specific MITF-M, heart-type MITF-H, and the recently identified MITF-A. Here we identify a fourth isoform, MITF-C, with a unique amino-terminus of 34 amino acid residues, which shares about 43% sequence identity with putative transactivation segments of two previously identified leukemogenic factors, ENL and AF-9. Reverse transcription-polymerase chain reaction analysis revealed that MITF-C mRNA is expressed in many cell types, including retinal pigment epithelium, but is undetectable in melanocyte-lineage cells. In contrast, MITF-A and MITF-H mRNAs are coexpressed in all cell types examined. Transient cotransfection assays suggested that MITF-C, like other MITF isoforms, functions as a transcriptional activator of certain target genes, but its transactivation specificity for the target promoters is different from those of other MITF isoforms. Therefore, isoform multiplicity provides MITF with differential expression patterns as well as functional diversity.
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PMID:Molecular cloning of cDNA encoding a novel microphthalmia-associated transcription factor isoform with a distinct amino-terminus. 1057 55


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