Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.28 (chloramphenicol acetyltransferase)
 5,100 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LFA-1, Mac-1, and p150,95 comprise a family of cell-surface glycoproteins that mediate adhesive interactions of myeloid and lymphoid cells. These glycoproteins are heterodimers composed of a common beta-subunit and distinct alpha-subunits. The chromosomal gene for the alpha-subunit of p150,95 was isolated to provide a framework from which to study the mechanisms for expression of the gene. The gene spans 30 kb of DNA and contains 31 exons. In agreement with a previous report by Corbi et al. (1990), the exons were found to be divided into five groups separated by large introns. The extracellular domains are encoded in exons 2 through 30 while the transmembrane and cytoplasmic domains are encoded in exons 30 and 31. We have expanded these findings in a number of ways. The first exon contains the 5' untranslated region. The 2,163-bp 5'-flanking sequence contains the first intron and several putative transcriptional initiation sites preceded by two TATA sequences and two GC-like boxes. Additional sequence motifs for a variety of DNA-binding proteins are present and discussed. Fusions of the bacterial chloramphenicol acetyltransferase gene (CAT) to approximately 5.3 kb of 5'-flanking DNA and also to subcloned fragments of this region were constructed and transfected into the human promonocytic cell line, U937. CAT expression was inducible with phorbol-12-myristate-13-acetate (PMA) and full expression was dependent on the presence of intron 1 and sequences upstream from the 2,163-bp flanking DNA. Additionally, intron 1 and a region further upstream contain functional cis-acting sequences.
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PMID:Human p150,95 alpha-subunit: genomic organization and analysis of the 5'-flanking region. 154 18

We and others have shown that some freshly isolated multiple myeloma (MM) cells and derived cell lines express interleukin 6 (IL-6) receptors and proliferate in vitro in response to IL-6; a subset of MM cells also expresses IL-6 mRNA, is intracytoplasmic IL-6 positive and secretes IL-6. We have shown that MM cells express the cell surface adhesion molecules CD29/CDw49d(VLA-4), CD18/CD11a(LFA-1) and CD44, and may localize to marrow via specific adherence to both extracellular matrix proteins and to bone marrow stromal cells (BMSCs). MM cell adhesion triggers IL-6 secretion by normal and MM BMSCs and related IL-6-mediated tumor cell growth. Our attempts to block MM cell adhesion to BMSC-induced IL-6 secretion by using antibodies to CD29/CDw49d, CD18/11a, and/or CD44 demonstrated minimal effects, suggesting that another ligand-receptor interaction triggers IL-6 secretion when MM cells and BMSCs are juxtaposed. Both MM cells and BMSCs express CD40. Triggering of MM cells and BMSCs via CD40 upregulates IL-6 secretion in both MM cells and MM-derived cell lines, as well as BMSCs and BMSC lines, suggesting the possibility of both autocrine and paracrine MM cell growth triggered via CD40. Finally, experiments using the LP 101 BMSC line transiently transfected with IL-6 promoter fragments linked to chloramphenicol acetyltransferase reporter gene demonstrate that adhesion of MM cells induces IL-6 gene transcription in BMSCs, which is conferred via the NF-kappa B binding motif.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of interleukin 6 in multiple myeloma and bone marrow stromal cells. 852 May 9

Cationic lipid-mediated gene transfer to the mouse lung induces a dose-dependent inflammatory response that is characterized by an influx of leukocytes and elevated levels of the cytokines interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma). We have examined the contribution of plasmid DNA (pDNA) to this observed toxicity, specifically the role of unmethylated CpG dinucleotides, which have been previously shown to be immunostimulatory. We report here that complexes of cationic lipid GL-67 and unmethylated pDNA (pCF1-CAT) instilled into the lungs of BALB/c mice induced highly elevated levels of the cytokines TNF-alpha, IFN-gamma, IL-6, and IL-12 in the bronchoalveolar lavage fluids (BALF). In contrast, BALF of animals administered either GL-67 alone or GL-67 complexed with SssI-methylated pDNA contained low levels of these cytokines. Similar results were observed using a plasmid (pCF1-null) that does not express a transgene, demonstrating that expression of chloramphenicol acetyltransferase (CAT) was not responsible for the observed inflammation. The response observed was dose dependent, with animals receiving increasingly higher amounts of unmethylated pDNA exhibiting progressively higher levels of the cytokines. Concomitant with this increase in cytokine levels were also elevated numbers of neutrophils in the BALF, suggesting a possible cause- and-effect relationship between neutrophil influx and generation of cytokines. Consistent with this proposal is the observation that reduction of neutrophils in the lung by administration of antibodies against Mac-1alpha and LFA-1 also diminished cytokine levels. This reduction in cytokine levels in the BALF was accompanied by an increase in transgene expression. In an attempt to abate the inflammatory response, sequences in the pDNA encoding the motif RRCGYY, shown to be most immunostimulatory, were selectively mutagenized. However, instillation of a plasmid in which 14 of the 17 CpG sites were altered into BALF/c mice did not reduce the levels of cytokines in the BALF compared with the unmodified vector. This suggests that other unmethylated motifs, in addition to RRCGYY, may also contribute to the inflammatory response. Together, these findings indicate that unmethylated CpG residues in pDNA are a major contributor to the induction of specific proinflammatory cytokines associated with instillation of cationic lipid:pDNA complexes into the lung. Strategies to abate this response are warranted to improve the efficacy of this nonviral gene delivery vector system for the treatment of chronic diseases.
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PMID:Contribution of plasmid DNA to inflammation in the lung after administration of cationic lipid:pDNA complexes. 1002 47