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)

The main manifestation of systemic sclerosis (SSc) is the overproduction of extracellular matrix, predominantly type I collagen. This study was undertaken to evaluate the effects of noncytotoxic doses of the topoisomerase I inhibitor camptothecin (CPT) on collagen production in the activated dermal fibroblasts from patients with SSc and healthy donors. The fibroblasts were cultured in the presence or absence of CPT. Production of collagenous proteins by fibroblasts was determined in cell and matrix layers by ELISA and in conditioned media by [(3)H]proline incorporation, gel electrophoresis, and autoradiography. Expression of alpha2(I) collagen (COL1A2) mRNA was measured by northern blot, and the activity of COL1A2 promoter was determined by a chloramphenicol acetyltransferase assay. CPT (10(-7) M) decreased the deposition of type I collagen by 68%, of type III by 38%, and of type VI by 21% in SSc fibroblasts and to a lesser degree in healthy controls. Similarly, CPT (10(-8) M to 10(-6) M) significantly inhibited secretion of newly synthesized collagenous proteins into conditioned media by 50%. CPT (10(-8) M to 10(-6) M) caused a significant dose-dependent inhibition of COL1A2 mRNA levels and COL1A2 promoter activity, both by as much as 60%. The inhibitory effect of CPT on collagen production by fibroblasts from patients with SSc suggests that topoisomerase I inhibitors may be effective in limiting fibrosis in such patients.
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PMID:The inhibitory effects of camptothecin, a topoisomerase I inhibitor, on collagen synthesis in fibroblasts from patients with systemic sclerosis. 1154 73

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


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