Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Redox regulation of DNA-binding proteins through the reversible oxidation of key cysteine sulfhydryl groups has been demonstrated to occur in vitro for a range of transcription factors. The direct redox regulation of DNA binding has not been described in vivo, possibly because most protein thiol groups are strongly buffered against oxidation by the highly reduced intracellular environment mediated by glutathione, thioredoxin, and associated pathways. For this reason, only accessible protein thiol groups with high thiol-disulfide oxidation potentials are likely to be responsive to intracellular redox changes. In this article, we demonstrate that zinc finger DNA-binding proteins, in particular members of the Sp-1 family, appear to contain such redox-sensitive -SH groups. These proteins displayed a higher sensitivity to redox regulation than other redox-responsive factors both in vitro and in vivo. This effect was reflected in the hyperoxidative repression of transcription from promoters with essential Sp-1 binding sites, including the simian virus 40 early region, glycolytic enzyme, and dihydrofolate reductase genes. Promoter analyses implicated the Sp-1 sites in this repression. Non-Sp-1-dependent redox-regulated genes including metallothionein and heme oxygenase were induced by the same hyperoxic stress. The studies demonstrate that cellular redox changes can directly regulate gene expression in vivo by determining the level of occupancy of strategically positioned GC-binding sites.
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PMID:Physical and functional sensitivity of zinc finger transcription factors to redox change. 862 48

Ten T-cell acute lymphoblastic (T-ALL) CEM cell lines selected for resistance toward methotrexate (CEM/MTX60PGA, CEM/MTX140LV, CEM/MTX1500LV, CEM/MTX5000PGA, CEM/MTXR1, CEM/MTXR2, and CEM/MTXR3), doxorubicin (CEM/ADR5000), vincristine (CEM/VCR1000), or hydroxyurea (CEM/HUR90), respectively, and parental drug-sensitive CCRF-CEM cells were analyzed using comparative genomic hybridization. Most genomic imbalances were not specific for drug resistance, as they were found in both parental and drug-resistant lines. Three aberrations were common to all or most cell lines analyzed: dim(5q35), dim(9p21p24), and enh(20q). We were concerned on those imbalances which were specifically present in drug-resistant but not in drug-sensitive cells. All methotrexate-resistant cell lines were characterized by an enhancement or an amplification of 5q13. The methotrexate resistance-conferring dihydrofolate reductase (DHFR) gene is located at this locus. Gain of DHFR was verified by PCR analyses. CEM/MTX60PGA, CEM/MTX140LV, CEM/MTX1500LV, and CEM/MTX5000PGA showed enh(14q21qter) and CEM/MTX5000PGA amp(5p13p15.2). These two loci harbor the methylenetetrahydrofolate dehydrogenase (MTHFD1) and 5'-methyltetrahdrofolate-homocysteine methyltransferase reductase (MTRR) genes, both of which are involved in folate metabolism. Their gain indicates a role in methotrexate resistance. A loss of 4q35 was found in CEM/MTXR2, CEM/MTXR3, and CEM/ADR5000 where the proapoptotic caspase-3 gene is located. The thioredoxin (TXN) locus 9q31 was enhanced in CEM/ADR5000 and CEM/MTX5000PGA cells. 2p22pter was increased in hydroxyurea-resistant CEM/HUR90 cells. Ribonucleotide reductase polypeptide M2 (RRM2), which confers resistance to hydroxyurea, resides at this locus. Other specific genomic imbalances in drug-resistant cell lines were dim(1p36.5), enh(4p), dim(8p22pter), enh(12p13), dim(17p), enh(18q12), enh(21q22.2), dim(21q22.2), and dim(22q13). All genomic imbalances were subjected to hierarchical cluster analysis and clustered image mapping to identify profiles of chromosomal aberrations in the cell lines. The obtained dendrograms allowed separation of imbalances common to all or most cell lines from other more individual aberrations. Furthermore, methotrexate-resistant cell lines clustered together. Our future efforts will be directed toward those imbalances which implicate still unknown candidate drug resistance genes.
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PMID:Genomic imbalances in drug-resistant T-cell acute lymphoblastic CEM leukemia cell lines. 1248 98

In addition to their well-known anti-malarial activity, artemisinin and its derivatives (1,2,4-trioxanes) possess potent activity against tumor cells in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. These genes are from classes with different biological function; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Anti-oxidant stress genes (thioredoxin, catalase, gamma-glutamyl-cysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines over-expressing genes that confer resistance to established anti-tumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that this drug has a different target and is not subject to multidrug resistance. The Plasmodium translationally controlled tumor protein (TCTP) represents a known target protein of artemisinin and its derivatives in the malaria parasite. The microarray-based mRNA expression of human TCTP correlated with sensitivity to artesunate in tumor cells, suggesting that human TCTP contributes to response of tumor cells to the drug. The multi-factorial nature of cellular response to artemisinin and its derivatives may be beneficial to treat otherwise drug-resistant tumors and may explain why resistance development has not been observed in either cancer or malaria.
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PMID:Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. 1587 3

Secondary metabolites from plants serve as defense against herbivores, microbes, viruses, or competing plants. Many medicinal plants have pharmacological activities and may, thus, be a source for novel treatment strategies. During the past 10 years, we have systematically analyzed medicinal plants used in traditional Chinese medicine and focused our interest on Artemisia annua L. (qinhao, sweet wormwood). We found that the active principle of Artemisia annua L., artemisinin, exerts not only antimalarial activity but also profound cytotoxicity against tumor cells. The inhibitory activity of artemisinin and its derivatives towards cancer cells is in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. The identified genes are from classes with diverse biological functions; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX, NF-kappaB). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Antioxidant stress genes (thioredoxin, catalase, gamma-glutamylcysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines overexpressing genes that confer resistance to established antitumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that artesunate is not involved in multidrug resistance. The anticancer activity of artesunate has also been shown in human xenograft tumors in mice. First encouraging experience in the clinical treatment of patients suffering from uveal melanoma calls for comprehensive clinical trials with artesunate for cancer treatment in the near future.
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PMID:Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin--from bench to bedside. 1735 63