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)

All-trans-retinoic acid (ATRA) has been shown to be one of the most potent chemical inducers of human neuroblastoma differentiation. The recent discovery that the stereoisomer of ATRA, 9-cis-retinoic acid (9-cis-RA), binds to both the retinoic acid and retinoid X series of receptors prompted us to evaluate the ability of this compound to promote differentiation of this cell type. Using the LA-N-5 cell line, we have now determined that 9-cis-RA can induce the differentiation of human neuroblastoma cells as evidenced by dose-dependent inhibition of cell proliferation, neurite outgrowth, increased acetylcholinesterase activity, and reduction of N-myc mRNA expression. In comparing the effects of 9-cis-RA to ATRA, we found that while both compounds induced qualitatively similar cholinergic (versus adrenergic) features in LA-N-5 cells, 9-cis-RA was 5-to-10-fold more potent than ATRA in its antiproliferative and differentiation activity. These results were supported by transient transfection experiments utilizing chloramphenicol acetyltransferase (CAT) plasmid constructs containing a retinoic acid responsive regulatory element which showed a 2-to-3-fold increase in reporter gene activity induced with 9-cis-RA over that seen with ATRA at pharmacologically relevant retinoid concentrations (> 10(-8) M). Furthermore, we have determined that 9-cis-RA can significantly enhance mRNA levels of the nuclear retinoic acid receptors alpha and beta in LA-N-5 cells. Taken together, these findings have established the ability of 9-cis-RA to induce neuroblastoma differentiation and suggest that this retinoic acid isomer may have better therapeutic characteristics than ATRA.
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PMID:Enhanced potency of 9-cis versus all-trans-retinoic acid to induce the differentiation of human neuroblastoma cells. 758 96

The reduction in levels of the potentially toxic amyloid-beta peptide (Abeta) has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the expression and processing of the Abeta precursor protein (betaAPP). Earlier reports from our laboratory have shown that a novel cholinesterase inhibitor, phenserine, reduces betaAPP levels in vivo. Herein, we studied the mechanism of phenserine's actions to define the regulatory elements in betaAPP processing. Phenserine treatment resulted in decreased secretion of soluble betaAPP and Abeta into the conditioned media of human neuroblastoma cells without cellular toxicity. The regulation of betaAPP protein expression by phenserine was posttranscriptional as it suppressed betaAPP protein expression without altering betaAPP mRNA levels. However, phenserine's action was neither mediated through classical receptor signaling pathways, involving extracellular signal-regulated kinase or phosphatidylinositol 3-kinase activation, nor was it associated with the anticholinesterase activity of the drug. Furthermore, phenserine reduced expression of a chloramphenicol acetyltransferase reporter fused to the 5'-mRNA leader sequence of betaAPP without altering expression of a control chloramphenicol acetyltransferase reporter. These studies suggest that phenserine reduces Abeta levels by regulating betaAPP translation via the recently described iron regulatory element in the 5'-untranslated region of betaAPP mRNA, which has been shown previously to be up-regulated in the presence of interleukin-1. This study identifies an approach for the regulation of betaAPP expression that can result in a substantial reduction in the level of Abeta.
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PMID:Phenserine regulates translation of beta -amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development. 1140 70