Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Proper growth and development of multicellular organisms requires precise regulation of developmental genes. One aspect of this regulation is at the level of transcription from the gene promoters. As an initial approach to understanding the regulation of the Pax-6 gene, which plays an important role in eye development and perhaps in other developmental processes, we characterized a promoter region of the quail Pax-6 (Pax-QNR) gene. Sequence analysis of the 5' flanking region revealed a TATA-like box and a CAAT box as well as several putative cis-regulatory elements. A 1.5-kilobase pair fragment, containing 1386 base pairs of 5' flanking sequence, the first exon, and a portion of the first intron, was able to efficiently promote expression of the bacterial CAT gene in quail neuroretina cells. Cotransfection of the Pax-QNR promoter with a vector expressing the 46 kilodalton Pax-QNR protein resulted in an increase in Pax-QNR promoter activity. By electrophoretic migration shift assay and immunoselection experiments, we showed that the Pax-QNR protein can interact directly with the Pax-QNR promoter. By footprinting experiments, we identified the binding sites for the Pax-QNR protein within the promoter region. These results show that Pax-QNR encodes a transcriptional activator and that it potentially trans-activates its own promoter.
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PMID:Quail Pax-6 (Pax-QNR) encodes a transcription factor able to bind and trans-activate its own promoter. 811 18

Cells with divergent mutant alleles of the p53 gene have different biological and biochemical properties in vitro. Increasing evidence indicates that p53 is a transcriptional activator, and recently, high affinity DNA binding sites for p53 have been identified. The purpose of this study was to determine in vivo, the effect that various mutant p53 proteins have on their ability to mediate transactivation and to bind specifically to DNA. Either a p53 responsive or control reporter gene was transfected into 18 human carcinoma cell lines, having various p53 mutations, either with or without a wild-type p53 expression vector. The CAT activity and DNA gel retardation were studied to measure transactivation and DNA binding by these endogenous p53s. As expected, the endogenously produced wild-type p53 binds to DNA binding sequences and can transactivate a reporter construct containing a p53 high affinity DNA binding site. Four of five cell lines with homozygous p53 mutations at codon 273 (273His), contained p53 which had the ability to bind to p53 DNA binding sequences and transactivate. In contrast, all the homozygous, non-codon 273 mutant p53s (156Pro, 175His, 223Leu, 248Gln, 248Trp, 280Lys) present in the other cell lines had no transactivating ability. These findings suggest that the biology of cancers with mutations at codon 273 may be different than those with p53 mutations at other sites. The p53 from WRO, a thyroid carcinoma cell line with p53 mutation at codon 223 (223Leu), was able to bind p53 DNA recognition sequences, but was unable to transactivate. Interestingly, in a vulvar carcinoma cell line (A431) with a p53 mutation at codon 273 (273His), the p53 was unable to transactivate and gave an aberrant band on gel retardation. Both CEM and SK-UT-1, which have compound heterozygous mutations at codons 175/248 (175His/248His), produced p53 which can complex with DNA, as well as transactivate. In contrast, the p53 in cell lines with either homozygous 175His or 248His p53 mutations, were unable either to transactivate or bind to the p53 response element. A cell line (NPA) heterozygous for 266Glu p53 mutation, was able to efficiently transactivate a reporter containing a p53 DNA binding site, therefore showing no evidence of a dominant negative effect of the endogenous p53 mutant allele. In summary, this in vivo study further supports the idea that different p53 mutant alleles have various properties which may affect their function.
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PMID:Transactivational and DNA binding abilities of endogenous p53 in p53 mutant cell lines. 820 36

The murine c-myc gene contains two elements responsive to the rel-oncogene-related family of NF-kappa B factors. Previously we have shown that factor binding to these two NF-kappa B elements mediates induction of transcription of the c-myc promoter upon interleukin-1 treatment of human dermal fibroblasts and human T-cell leukemia virus type I tax gene expression in T cells (D. J. Kessler, M. P. Duyao, D. B. Spicer, and G. E. Sonenshein, J. Exp. Med. 176:787-792, 1992; M. P. Duyao, D. J. Kessler, D. B. Spicer, C. Bartholomew, J. L. Cleveland, M. Siekevitz, and G. E. Sonenshein, J. Biol. Chem. 267:16288-16291, 1992). To begin to delineate the specific roles of the individual members of the NF-kappa B family, here we have tested their effects on activation of a c-myc promoter/exon 1-CAT construct in NIH 3T3 cells. Classical NF-kappa B (p65/p50) was a potent transcriptional activator of the c-myc promoter. Cotransfection with either p65 alone or p65 in combination with p50 mediated significant induction. In contrast, expression of either v-rel or chicken c-rel failed to transactivate, while murine c-rel induced c-myc promoter activity only slightly. Furthermore, induction by classical NF-kappa B was inhibited by coexpression of either v-rel or chicken c-rel. Thus, individual members of the rel family have differential effects of the c-myc promoter, which can modulate overall transcriptional activity and allow for precise regulation of this oncogene under diverse physiologic conditions.
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PMID:Differential regulation of the c-myc oncogene promoter by the NF-kappa B rel family of transcription factors. 828 84

ets oncogene superfamily consists of a family of transcriptional factors that functions as activators and/or repressors. Previously, we have identified a member of this ets superfamily namely erg, ets related gene. erg gene was shown to code for at least two proteins erg-1 and erg-2 because of alternative splicing and alternative usage of initiation codon. In this report we show that erg gene codes for an additional erg variant protein, erg-3 as a result of differential splicing which results in the insertion of 24 amino acids in the coding region of erg-2 protein. RNAase protection analysis revealed that erg-3 transcripts are expressed in a variety of cells. Erg-3 was also found to activate the transcription of the reporter TK-CAT gene linked to erg target sequences suggesting that erg-3 codes for a sequence specific transcriptional activator.
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PMID:Differentially spliced erg-3 product functions as a transcriptional activator. 829 Feb 79

The c-myb protooncogene is preferentially expressed in hematopoietic cells and is required for cell cycle progression at the G1/S boundary. Because c-myb encodes a transcriptional activator that functions via DNA binding, it is likely that c-myb exerts its biological activity by regulating the transcription of genes required for DNA synthesis and cell cycle progression. One such gene, cdc2, encodes a 34-kDa serine-threonine kinase that appears to be required for G1/S transition in normal human T-lymphocytes. To determine whether c-myb is a transcriptional regulator of cdc2 expression, we subcloned a segment of a cdc2 human genomic clone containing extensive 5'-flanking sequences and part of the first exon. Sequence analysis revealed the presence of two closely spaced Myb binding sites that interact with bacterially synthesized Myb protein within a region extending from nucleotides -410 to -392 upstream of the transcription initiation site. A 465-base pair segment of 5'-flanking sequence containing these sites was linked to the CAT gene and had promoter activity in rodent fibroblasts. Cotransfection of this construct with a full-length human c-myb cDNA driven by the early simian virus 40 promoter resulted in a 6-8-fold enhancement of CAT activity that was abrogated by mutations in the Myb binding sites. These data suggest that c-myb participates in the regulation of cell cycle progression by activating the expression of the cdc2 gene.
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PMID:c-myb transactivates cdc2 expression via Myb binding sites in the 5'-flanking region of the human cdc2 gene. 842 Sep 94

Accumulating evidence supports the hypothesis that tumor-suppressor p53 can act as a transcriptional activator. Insertion of high-affinity p53 DNA binding sites upstream of a promoter yields a p53-responsive vector. Chimeric proteins fusing p53 and the GAL4 DNA-binding domain demonstrate the presence of a transcriptional activating domain in the N-terminus of p53. GAL4-p53 chimeras constructed using naturally occurring p53 mutations at either codon 141 (Tyr-141) or 175 (His-175) of p53 had little ability to activate the reporter gene; in contrast, mutations at either codon 248 (Trp-248) or 273 (His-273) produced greater transcriptional activities than did wild-type p53. GAL4 chimeras can be used to analyse interactions between different domains of p53 and between different p53 alleles; a DNA binding site is defined, and a simple measurement can be made of function. We had expected that coexpression of GAL4 chimeras and p53 alleles would squelch transcriptional activation downstream of GAL binding sites. Surprisingly, coexpression of either p53 (Trp-248) or (His-273) with the GALA-p53 (wild-type, His-273, Trp-248, His-175, Tyr-141) effectors conferred an increase in transcriptional activation as compared with the effector alone. Oligomerization of p53 alleles with GAL4-p53 chimeras could underlie this effect, leading to an increase in transcription-activating motifs near the promoter. To test this possibility, we constructed a GAL4-p53 C-terminal chimera with p53 residues 160-393, lacking the transcriptional activating domain but retaining regions believed to be important in p53 oligomerization. Neither GAL4-p53 (C-terminus) nor p53 expression vectors were able to transactivate G5E1B-CAT alone. Both p53 (His-273) and (Trp-248) co-expressed with GAL4-p53 (C-terminus) were able to transactivate the G5E1B-CAT reporter gene; in contrast, p53 (Tyr-141) was not able to activate transcription. p53 (Tyr-141/His-273) behaved as a dominant negative mutant and inhibited the ability of the combination of p53 (His-273) and GAL4-p53 (C-terminus) to stimulate the reporter gene. Double immunoprecipitation by sequentially using GAL4 and p53 antibodies showed that p53 (His-273) and (Tyr-141/His-273), but not p53 (Tyr-141), can efficiently oligomerize in vivo to the C-terminal region of p53. Transcriptional activating function of p53 may be modulated by oligomerization; some mutations, such as His-273 and Trp-248, participate in these functions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mutant p53 proteins have diverse intracellular abilities to oligomerize and activate transcription. 851 Sep 27

The t(8;21) translocation, commonly found in acute myelogenous leukemia (AML), generates a fusion protein containing N-terminal AML1 and C-terminal ETO amino acids. The human AML1 gene encodes several related proteins that specifically bind to the sequence TGT/cGGT, located in the promoter regions of a variety of hematopoietic growth factor genes. To examine the abilities of the AML1B protein (which contains 479 amino acids), a shorter AML1A isoform (which contains amino acids 1-250), and the AML1/ETO fusion protein (which contains AML1A amino acids 1-177) to stimulate transcription from the GM-CSF promoter, we performed co-transfection experiments in T cells using a human GM-CSF promoter-CAT reporter gene plasmid and expression vectors that contain the cDNAs for one of the above proteins. Our data demonstrate that AML1B, but not AML1A or AML1/ETO transactivates the GM-CSF promoter, requiring the TGTGGT sequence contained between base pairs -68 and -53. Furthermore, we show that AML1/ETO, but not AML1A, inhibits the ability of AML1B to stimulate CAT expression. Electrophoretic mobility shift assays demonstrated the specific binding of AML1 proteins to the GM-CSF promoter TGTGGT sequence, which does not require GM-CSF sequences immediately upstream of this binding site. Our data support a role for AML1B as a transcriptional activator and establish that the AML1/ETO fusion protein can act as a dominant negative protein on the human GM-CSF promoter. Although AML1/ETO does not stimulate the transcription of GM-CSF, it may function by inhibiting the normal activity of AML1B in AML cells with the t(8;21) translocation.
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PMID:The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B. 854 24

A short non-coding region (SNR) commonly exists between the E5 and L2 open reading frames of human papillomaviruses (HPVs). Except for the poly(A) signal for early gene transcripts, no biological functions have been discovered for the SNR. To test a possible promoter-like activity of the SNR, we carried out CAT reporter assays using constructs containing the SNRs from HPV-16, -18 and -33 linked to a promoterless CAT gene. We reproducibly observed enhanced expression of CAT gene by the SNRs. Co-expression of a transcriptional activator (LAP/NF-IL6) or deletion of the poly(A) signal augmented the promoter-like activity of the SNRs. RNase protection assays revealed a LAP-inducible CAT mRNA properly initiated from the HPV-16 SNR. These results may suggest that the SNR has a promoter activity that is regulated by keratinocyte differentiation.
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PMID:Evidence for a promoter-like activity in the short non-coding region of human papillomaviruses. 860 81

The visna virus Tat protein is a strong transcriptional activator and is necessary for efficient viral replication. The Tat protein regulates transcription through an AP-1 site proximal to the TATA box within the viral long terminal repeat (LTR). Previous studies from our laboratory using Tat-Gal4 chimeric proteins showed that Tat has a potent acidic activation domain. Furthermore, a region adjacent to the Tat activation domain contains a highly conserved leucine-rich domain which, in the context of the full-length protein, suppressed the activity of the activation domain. To further elucidate the role of this region, four leucine residues within this region of Tat were mutated. In transient-transfection assays using visna virus LTR-CAT as a reporter construct, the activity of this leucine mutant was dramatically reduced. Additionally, domain-swapping experiments using the N-terminal activation domain of VP16 showed that the leucine-rich domain of Tat confers AP-1 responsiveness to the chimeric VP16-Tat protein. A chimeric VP16-Tat construct containing the leucine mutations showed no increased AP-1 responsiveness in comparison with that of the VP16 activation domain alone. Furthermore, in competition experiments, a Gal4-Tat protein containing only the leucine region of Tat (amino acids 34 to 62) was able to inhibit by competition the activity of full-length Tat. These studies strongly suggest that this leucine-rich domain is responsible for targeting the Tat protein to AP-1 sites in the viral LTR. In addition, examination of the amino acid sequence of this region of Tat revealed a highly helical secondary structure and a pattern of residues similar to that in the leucine zippers in the bZIP family of DNA-binding proteins. This has important implications for the interaction of Tat with cellular proteins, specifically Fos and Jun, that contain bZIP domains.
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PMID:The leucine domain of the visna virus Tat protein mediates targeting to an AP-1 site in the viral long terminal repeat. 867 56

NF-kappaB is a pleiotropic transcriptional activator originally identified by its ability to regulate immunoglogulin kappa light chain expression. Purification of this DNA-binding complex demonstrated that NF-kappaB is a heterodimer composed of two subunits, NFKB1 and RelA. Previous studies have shown that truncated versions of these proteins could be expressed and purified from bacterial cells. In the present study, we utilize a baculovirus expression vector system (BEVS) to overexpress each subunit independently to produce homodimers or together to reconstitute functional NF-kappaB. These proteins can be enriched to >70% homogeneity on a kappaB-agarose DNA- affinity column. The purified proteins are active in DNA binding as measured by electrophoretic mobility shift assays. Finally, transcriptional activation of these recombinant proteins can be measured by their ability to activate a kappaB-CAT reporter plasmid in transiently transfected/infected SF-9 cells. Thus, BEVS provides a method for production of full-length, transcriptionally active NF-kappaB proteins.
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PMID:Expression and reconstitution of NF-kappaB from insect cells using a baculovirus vector. 911


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