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: EC:2.3.1.28 (chloramphenicol acetyltransferase)
5,100 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activated c-myc allele in Burkitt's lymphoma tumor cells is associated with a clustering of somatic mutations within intron I near the exon I boundary. We have identified several discrete protein binding sites within this region of c-myc intron I designated as myc intron factor-1 (MIF-1), MIF-2, and MIF-3. In addition to our previous characterization of a 20-nucleotide binding site for MIF-1, we now have identified adjacent 20-nucleotide and 34-nucleotide binding sites for MIF-2 and MIF-3, respectively. All three elements are protected from exonuclease digestion by nuclear protein extracts, and each gives rise to a distinct migration pattern on mobility shift assays. In addition, MIF-1, 2, and 3 share a 5-nucleotide (TTATG) internal sequence, which may account for cross-competition of these binding sites in the exonuclease protection experiment. Deletion mutant analyses showed that selective removal of the MIF-3 binding site alone was sufficient to enhance chloramphenicol acetyltransferase reporter activity similar to that observed with larger deletions of myc intron I. We have demonstrated that somatic mutations in activated c-myc alleles are frequently clustered in discrete domains that define protein recognition sequences.
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PMID:Somatic mutations in c-myc intron I cluster in discrete domains that define protein binding sequences. 836 2

Activation of the murine c-myc promoter by murine c-Myb protein was examined in several cell lines by using a transient expression system in which Myb expression vectors activate the c-myc promoter linked to a chloramphenicol acetyltransferase reporter gene or a genomic beta-globin gene. S1 nuclease protection analyses confirmed that the induction of c-myc by c-Myb was transcriptional and affected both P1 and P2 start sites in a murine T-cell line, EL4, and a myelomonocytic line, WEHI-3. Mutational analyses of the c-myc promoter revealed that two distinct regions could confer Myb responsiveness in two T-cell lines, a distal site upstream of P1 and a proximal site within the first noncoding exon. In contrast, only the proximal site was required for other cell lineages examined. Five separate Myb-binding sites were located in this proximal site and found to be important for c-Myb trans activation. DNA binding was necessary for c-myc activation, as shown by the loss of function associated with mutation of Myb's DNA-binding domain and by trans-dominant repressor activity of the DNA binding, trans-activation-defective mutant. The involvement of additional protein factors was addressed by inhibiting protein synthesis with cycloheximide in a conditional expression system in which the activity of presynthesized Myb was under the control of estrogen. These experiments indicate that de novo synthesis of additional proteins was not necessary for c-myc trans activation. Together these data reveal two cell lineage-dependent pathways by which c-Myb regulates c-myc; however, both pathways are mechanistically indistinguishable in that direct DNA binding by Myb is required for activating c-myc whereas neither de novo protein synthesis nor other labile proteins are necessary.
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PMID:Mechanism of c-myc regulation by c-Myb in different cell lineages. 847 46

Mammalian c-myc transcripts have long G/C-rich 5' untranslated regions (UTRs) that may fold into secondary structural elements that may impede translation. We have examined the effects of different c-myc first exons, which produce most of the 5' UTR of c-myc transcripts, on translation in Xenopus oocytes and embryos, by placing these structures upstream of a chloramphenicol acetyltransferase (CAT) reporter. Our results demonstrate that the human c-myc first exon inhibits reporter translation in both oocytes and embryos. Unlike their mammalian counterparts, Xenopus c-mycI first exons initiated at either promoter 1 or promoter 2 do not impede translation. We conclude that translation inhibition reported in a previous investigation (Lazarus, 1992. Oncogene, 7:1037) utilizing Xenopus c-mycI 5' non-coding elements was due to the inclusion of nonrelevant non-transcribed sequences. Previous investigators have reported that inhibition of translation in Xenopus oocytes by 5' secondary structure is alleviated after fertilization (Lazarus et al., 1988. Oncogene 3:517; Fu et al., 1991, Science 251:807). We repeated the experiments of Fu et al., examining the effects on translation by a highly stable synthetic hairpin. The hairpin severely [correction of severly] restricted translation in both oocytes and embryos, indicating that highly stable 5' secondary structure is equally inhibitory in oocytes and embryos.
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PMID:Effects of c-myc first exons and 5' synthetic hairpins on RNA translation in oocytes and early embryos of Xenopus laevis. 864 24

A human recombinant cDNA clone that encoded a zinc-finger protein (Myc-associated zinc-finger protein of human islet; MAZi) was cloned by screening a cDNA library prepared from human pancreatic islet cells. The encoded protein showed a high degree of homology to the Myc-associated zinc-finger protein MAZ (ZF87 or Pur-1). However, differences between the cDNAs for MAZi and MAZ were found in the length of the encoded polyalanine stretch and in the sequence of the 5'-end leader. MAZi transcripts were significantly more abundant in rat pancreatic islet carcinoma tissue than in normal rat islet cells. Moreover, MAZi protein bound specifically to the pyrimidine-rich strand of the CT-element of the c-myc gene in vitro and strongly induced the expression of chloramphenicol acetyltransferase (CAT) from a c-myc promoter/ CAT reporter construct in human pancreatic cells. Our results suggest that a distinct member of the MAZ family is expressed in human islet cells and enhances the transcriptional activity of the c-myc gene.
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PMID:Members of the MAZ family: a novel cDNA clone for MAZ from human pancreatic islet cells. 883 93

Contiguous with the 5'-end of the thyroid transcription factor-1 (TTF-1) element upstream of the minimal TSH receptor (TSHR) promoter and within it, there is an element on the noncoding strand with single strand- binding activity. Mutation analyses indicate that it is functionally distinct from the TTF-1 element and is important for the constitutive expression and TSH/cAMP-induced negative autoregulation of the TSHR in thyroid cells but only constitutive expression in nonthyroid cells. In this report we identify a cDNA encoding a single strand-binding protein (SSBP) that forms a specific complex with the noncoding strand of the TSHR, contiguous with the 5'-end of both TTF-1 elements; we term it SSBP-1. SSBP-1 increases promoter activity when contransfected with heterologous SV40 promoter-chloramphenicol acetyltransferase (CAT) chimeras containing the upstream SSBP-binding element from the TSHR promoter or with TSHR promoter-CAT chimeras containing both or only the downstream SSBP element. Mutational analyses reveal that a GXXXXG motif is important for the binding and enhancer function of SSBP-1. TSH/cAMP decreases SSBP-1 RNA levels, as well as SSBP-1/TSHR DNA complex formation, in functioning rat FRTL-5 thyroid cells but not nonfunctioning FRT thyroid or Buffalo rat liver cells that have no TTF-1. SSBP-1 RNA is present ubiquitously; however, its levels are higher in FRTL-5 cells and are increased by overexpression of TTF-1 in cells treated with TSH. This reverses TSH-induced negative regulation of the TSHR. SSBP-1 is, therefore, a positive regulator of TSHR gene expression that contributes to TSHR maximal expression by binding to the SSBP elements. It is a ubiquitous, single-strand transcription factor whose expression in FRTL-5 thyroid cells is, however, regulated by a thyroid-specific gene, TTF-1. TSH/cAMP induces negative autoregulation of the TSHR, in part, by decreasing maximal expression resultant from SSBP-1 binding to the SSBP elements. Like Y-box proteins, which are involved in negative regulation of the TSHR, SSBP-1 also interacts with the major histocompatibility class II promoter S-box; the interaction is single strand-specific. This supports the hypothesis that common transcription factors regulate TSHR and major histocompatibility gene expression. Of additional interest and again like Y-box proteins, SSBP-1 is a member of a family of SSBPs that interact with RNA and are important in RNA processing, can interact with the promoter of retroviruses, and can interact with a gene linked to growth and DNA replication, c-myc.
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PMID:Cloning of the single strand DNA-binding protein important for maximal expression and thyrotropin (TSH)-induced negative regulation of the TSH receptor. 892 67

In Trypanosoma brucei, pre-mRNAs are joined to a 5' 39 nt spliced leader sequence by trans splicing, a process that has not been well characterized. We have asked whether the 3' splice site regions of human and yeast introns are able to substitute in vivo for the 3' spliced leader acceptor regions of trypanosome pre-mRNA sequences. The ability of heterologous sequences to participate in trans splicing in trypanosomes was assayed by chloramphenicol acetyltransferase (CAT) enzyme activity and/or the detection of spliced CAT mRNA. Four out of the six heterologous 3' splice site regions (human beta-globin intervening sequence (IVS)2, human c-myc IVS2, human factor-VIII IVS1, and yeast actin IVS) functioned as 3' spliced leader acceptor regions in T. brucei, while two did not show significant or detectable levels of CAT activity (human beta-globin IVS1 and human c-myc IVS1). In the case of the human beta-globin IVS1 however, lengthening of the polypyrimidine tract as a result of single purine to pyrimidine transversions produced an active acceptor in which the spliced leader addition site coincides with the 3' splice site of the beta-globin exon 2. These studies indicate that some, but not all 3' acceptor regions in humans can function as spliced leader addition sites in trypansomes.
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PMID:Human and fungal 3' splice sites are used by Trypanosoma brucei for trans splicing. 901 Aug 38

Downregulation in expression of the c-myc proto-oncogene is an early molecular event in differentiation of murine C2C12 myoblasts into multinucleated myotubes. During differentiation, levels of c-myc mRNA decrease 3- to 10-fold despite a lack of change in its transcription rate. To identify cis-acting elements that target c-myc mRNA for downregulation during myogenesis, we stably transfected C2C12 cells with mutant myc genes or chimeric genes in which various myc sequences were fused to the human beta-globin gene or to the bacterial chloramphenicol acetyltransferase (CAT) gene. Deletion of coding sequences from myc exon 2 or exon 3 abolished downregulation of myc mRNA during myogenic differentiation, while deletion of introns or sequences in the 5' or 3' untranslated regions (UTRs) did not, demonstrating that coding elements in both exons 2 and 3 are necessary for myc mRNA downregulation. Fusion of coding sequences from either myc exon 2 or 3 to beta-globin mRNA conferred downregulation onto the chimeric mRNA, while fusion of myc 3' UTR sequences or coding sequences from CAT or ribosomal protein L32 did not, demonstrating that coding elements in myc exons 2 and 3 specifically confer downregulation. These results present the apparent paradox that coding elements in either myc exon 2 or myc exon 3 are sufficient to confer downregulation onto beta-globin mRNA, but neither element alone was sufficient for myc mRNA downregulation, suggesting that some feature of beta-globin mRNA may potentiate the regulatory properties of myc exons 2 and 3. A similar regulatory function is not shared by all mRNAs because fusion of either myc exon 2 or myc exon 3 to CAT mRNA did not confer downregulation onto the chimeric mRNA, but fusion of the two elements together did. We conclude from these results that two myc regulatory elements, one exon 2 and one in exon 3, are required for myc mRNA downregulation. Finally, using a highly sensitive and specific PCR-based assay for comparing mRNA levels, we demonstrated that the downregulation mediated by myc exons 2 and 3 results in a decrease in cytoplasmic mRNA levels, but not nuclear mRNA levels, indicating that regulation is a postnuclear event.
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PMID:Coding elements in exons 2 and 3 target c-myc mRNA downregulation during myogenic differentiation. 911 40

Transactivating factor PuF which interacts with a nuclease hypersensitive element locates upstream from the c-myc gene. PuF was recently identified as being encoded by nm23-H2/ NDP kinase gene [Postel, E. H., Berberich, S. J., Flint, S. J., and Ferrone, C. A. (1993) Science 261, 428-429]. Here we have studied the correlation of expression between c-myc and nm23 genes in vitro. By a comparative study of the expression of 2 genes in cell lines, no direct correlation of kinetics was found. A plasmid containing the human c-myc fragment (c-myc CAT) was cloned upstream from the bacterial chloramphenicol acetyltransferase (CAT) gene. When the murine melanoma cell line was cotransfected with a nm23-M2/ NDP kinase expression vector and c-myc CAT, CAT activity was elevated. In addition, cell cycle phases in the murine cell lines transfected with nm23/NDP kinase were estimated; an alteration of the cell cycle, prolonged S-phase was found in the cell lines transfected with nm23-M2/NDP kinase, whereas human nm23-H2/NDP kinase did not play a role in transactivating the c-myc gene or in S-phase prolongation in murine cell lines. From these results we conclude that the murine nm23-M2 gene transactivates the c-myc gene and controls the cell cycle, S-phase, indirectly via a cellular cofactor in the murine cell line, which does not work with the human nm23-H2 gene.
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PMID:Transcription effect of nm23-M2/NDP kinase on c-myc oncogene. 938 43

Expression of messenger RNA (mRNA) in both embryonic and adult cells may be profoundly influenced by untranslated sequences in the 3'-end. Elements in the 3'-untranslated regions (UTRs) of messengers are known to influence messenger stability, polyadenylation, and translation. We have examined the effects of the 3'-UTR of Xenopus laevis c-mycI (either alone or in combination with the 5'-first exon) on the expression of a chloramphenicol acetyltransferase (CAT) reporter in Xenopus embryos. The Xenopus c-mycI 3'-UTR enhanced messenger translation independent of the 5'-UTR. RNase H analysis indicated that the Xenopus c-mycI 3'-UTR can promote the cytoplasmic polyadenylation of CAT mRNA in embryos. The result suggests that the post-fertilization enhancement of translation caused by the c-mycI 3'-UTR may be a consequence of cytoplasmic polyadenylation. A uridine (U)-rich sequence in the Xenopus c-mycI 3'-UTR that may be responsible for polyadenylation is similar to an element that destabilizes mammalian c-myc transcripts. We discuss the possibility that U-rich sequences may play a dual role by destabilizing growth-related transcripts in adult cells and stimulating their polyadenylation during development, and we propose that a switch in the role of such sequences in adult cells could lead to stabilization of these messengers, increased translation, and abnormal growth control.
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PMID:Stimulation of translation and cytoplasmic polyadenylation by the Xenopus c-mycI 3'-untranslated region. 940

We have investigated the effects of 3' noncoding elements in enhancing translation of messengers having translation-inhibiting 5' untranslated regions (UTRs). The translation of transcripts bearing the 5' UTRs of either human c-myc or a synthetic hairpin structure upstream of a chloramphenicol acetyltransferase (CAT) reporter sequence is greatly attenuated in early embryos of Xenopus laevis. Translation of transcripts bearing the human c-myc-5' UTR was markedly stimulated by the presence of 3' poly(A). Transcripts bearing the 5' hairpin element were insensitive to the presence of poly(A), but they were extremely sensitive to the composition of the 3' UTR. A GC-rich distal sequence repressed translation, whereas a proximal GGAAU sequence promoted translation of these transcripts. Our results support the concept that long-range interactions between the 5' and 3' ends of transcripts are important in regulating translation in Xenopus embryos.
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PMID:5'-3' interactions in regulation of translation in Xenopus early embryos. 959 63


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