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)

Tumor growth is dependent on new blood vessel formation. Inhibition of vascular endothelial growth factor (VEGF), an endothelial cell mitogen and angiogenic factor secreted by a variety of tumors and tumor cell lines, is sufficient to inhibit primary tumor growth. In the present study, we examined the effect of inhibiting VEGF on tumor cell micrometastasis. A transfectant of A431 (a human epidermoid carcinoma cell line) expressing chloramphenicol acetyltransferase (CAT) was injected s.c. into severe combined immunodeficiency (scid) mice, which were then sacrificed after 6 weeks. The presence of A431 metastases at distant sites was demonstrated by detection of CAT activity in whole-organ lysates. Treatment of animals with VEGF-neutralizing antibodies not only inhibited primary tumor growth but also suppressed metastases, as determined by CAT activity in organ lysates. In experiments to determine the mechanism by which anti-VEGF antibody inhibited metastasis, control animals were sacrificed when their tumors had reached the same size as tumors in VEGF antibody-treated animals. Metastases were uniformly present in these control animals. These findings show that inhibition of VEGF alone is sufficient to prevent tumor growth and dissemination in vivo. The inhibitory effect on metastases appears to be distinct from that on primary tumor growth.
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PMID:Vascular endothelial growth factor promotes tumor dissemination by a mechanism distinct from its effect on primary tumor growth. 863 Oct 34

The expression of vascular endothelial growth factor (VEGF) has been implicated in brain tumor angiogenesis, and the promoter region for the VEGF gene contains several SP-1 and AP-1 (c-Fos and c-Jun) binding motifs. Among eight human glioma cell lines, cellular mRNA levels of transcription factors SP-1 and AP-1 (c-Fos and c-Jun) were found to be closely correlated with those of VEGF. VEGF expression appears to be highly susceptible to hypoxia or exogenous cytokines and growth factors. Of various cytokines and growth factors, basic fibroblast growth factor (bFGF), tumor necrosis factor alpha (TNF-alpha), and interleukin 1 most potently enhanced VEGF mRNA levels of a glioma cell line, U251. Incubation of the glioma cells with bFGF or TNF-alpha increased both VEGF and SP-1 mRNA at 30 min and c-Fos mRNA at 1-3 h, over 5-fold. Nuclear run-on assays showed an apparent increase of the transcription of the VEGF gene as well as the SP-1 gene by bFGF or TNF-alpha. Gel mobility shift assays demonstrated that only SP-1 binding activity was increased 1 h after exposure to bFGF or TNF-alpha, and also that AP-1, but not SP-1, activity was significantly activated by hypoxia. Mithramycin, an inhibitor of SP-1, at 1-10 nM inhibited activation of the VEGF gene by bFGF or TNF-alpha but not that by hypoxia. Western blot analysis also demonstrated an increase in cellular amounts of VEGF by TNF-alpha and a decrease by co-administration with mithramycin. The promoter activity of the VEGF gene, which contains five SP-1 binding sites and one AP-1 binding site but not hypoxia regulatory elements, was enhanced by bFGF or TNF-alpha but not by hypoxia. The chloramphenicol acetyltransferase assay with VEGF promoter deletion constructs demonstrated that four clusterized SP-1 binding sites in the proximal promoter were essential for the basal transcription and the TNF-alpha-dependent activation. These data indicated that the expression of the VEGF gene enhanced by bFGF or TNF-alpha appeared to be mediated in part through the transcription factor SP-1, suggesting a different mechanism from that for hypoxia-induced activation of the VEGF gene.
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PMID:Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1. 891 Apr 39

The flt-1 gene encodes a transmembrane tyrosine kinase, Flt-1, a receptor for vascular endothelial growth factor. The expression of flt-1 gene is restricted to endothelial cells in vivo. To understand the molecular mechanism underlying endothelial-specific expression of this gene, we studied the functional significance of transcriptional motifs in the 200-base pair region of the human flt-1 gene promoter, which has been identified to confer cell type specificity. By point mutation analysis using chloramphenicol acetyltransferase plasmids in 293E1 cells, which express significant levels of flt-1 mRNA, we found that an Ets motif, E4, at -54 to -51 and a cAMP response element (CRE) at -83 to -76 are involved in the transcriptional regulation of this gene. Disruption of either this CRE or E4 within the promoter sequence of 90 base pairs resulted in a decrease in chloramphenicol acetyltransferase activity of 90%, indicating that co-existence of both of CRE and Ets motif E4 is necessary for transcription of the flt-1 gene. Co-transfection of an expression vector containing c-ets-1, c-ets-2, or c-erg cDNA with this 90-base pair sequence yielded a 5-8-fold elevation of chloramphenicol acetyltransferase activity, further supporting the idea that Ets family protein(s) participates in the regulation of the flt-1 gene. Gel shift assays using nuclear extracts of 293E1 and endothelial cells demonstrated the existence of protein factor(s) that specifically binds to CRE and Ets motif E4, respectively. Taken together, our results strongly suggest cooperation of a CRE and an Ets motif for the function of the flt-1 gene promoter.
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PMID:A cAMP response element and an Ets motif are involved in the transcriptional regulation of flt-1 tyrosine kinase (vascular endothelial growth factor receptor 1) gene. 894 64

Type IV collagen is present ubiquitously in basement membranes. A bifunctional promoter regulates the expression of the alpha1/alpha2 genes, and the alpha3/alpha4 and the alpha5/alpha6 genes are also considered to be regulated by putative bifunctional promoters. Unlike the other type IV collagen chains, the alpha5(IV) and alpha6(IV) chains do not always co-localize and are present in distinct basement membranes. To address such dichotomy in the alpha5(IV) and alpha6(IV) gene regulation, we cloned a mouse genomic DNA fragment containing the promoter region between the two transcription start sites of these genes and we then placed this putative promoter sequence between the chloramphenicol acetyltransferase and Luciferase reporter genes, so that these genes would be transcribed in opposite directions in this unique construct. Glomerular endothelial cells and mesangial cells generate the kidney glomerular basement membrane, which always contains the alpha5(IV) chain but not the alpha6(IV) chain. In contrast, the basement membranes of Bowman's capsule and distal tubuli (produced by the tubular epithelial cells) contain the alpha6(IV) chain. We demonstrate that, in response to TGF-beta (transforming growth factor beta), epidermal growth factor, vascular endothelial growth factor and platelet-derived growth factor, expression from the alpha5(IV) gene is significantly enhanced in the glomerular endothelial cells and mesangial cells, but not expression from the alpha6(IV) gene. In contrast, the expression from the alpha6(IV) gene, and not that from the alpha5(IV) gene, was significantly enhanced in response to growth factors in the tubular epithelial cells. Our results demonstrate that the proximal bifunctional promoter regulates the expression of the alpha5(IV) and alpha6(IV) genes in a cell-specific manner and offers the first demonstration of the promoter plasticity in growth factor regulation of type IV collagen genes in different tissues of the body.
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PMID:Bifunctional promoter of type IV collagen COL4A5 and COL4A6 genes regulates the expression of alpha5 and alpha6 chains in a distinct cell-specific fashion. 1559 79

Acetazolamide has been recognized as an effective treatment for acute mountain sickness. The efficacy of acetazolamide is related to metabolic acidosis, which promotes chemoreceptors to respond to hypoxic stimuli at altitude. In this study, adult male Sprague-Dawley rats were treated with acetazolamide (100mg/kg or 50mg/kg, I.P.) for 3 days. Primary cultured cortical neurons and PC12 cell lines were exposed to acidosis-permissive (pH 6.5) or standard (pH 7.2) media for 20h. HIF-1alpha and its target genes were assayed by Western blot, real-time PCR, HIF-1 DNA-binding assay and chloramphenicol acetyltransferase reporter gene assay. HIF-1alpha protein level and HIF-1 DNA-binding activities were increased in cerebral cortices of rats treated with acetazolamide. Moreover, the mRNA levels of erythropoietin, vascular endothelial growth factor, and glucose transporter-1 also increased. The HIF-1alpha protein level and activity of HIF-driven chloramphenicol acetyltransferase reporters of cortical neurons and PC12 cells treated with acidosis media were significantly enhanced. We conclude that the normoxic induction of HIF-1alpha and HIF-1 mediated genes by acetazolamide may mediate the effect of acetazolamide in the reduction of symptoms of acute mountain sickness.
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PMID:Normoxic induction of cerebral HIF-1alpha by acetazolamide in rats: role of acidosis. 1915 Apr 86