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

Oncogene activation and loss of tumor suppressor genes are known to play a role in tumor initiation as well as its progression. The potential roles of these genes in perturbation of genome stability has become a major interest. To better understand the relationship between expression of an oncogene and genetic instability, we have studied a cell line expressing an activated human Ha-ras under the control of bacterial lactose operon regulatory elements for changes in methotrexate resistance and dihydrofolate reductase (dhfr) gene amplification following mutant Ha-ras induction. In these cells mutant Ha-ras is directed by an inducible SV40 promoter containing a bacterial lac operator sequence which is repressed due to constitutive expression of bacterial lac repressor gene. The expression of this Ha-ras is specifically induced by the addition of isopropyl-1-thio-beta-D-galactopyranoside (IPTG), a lactose analogue, to the culture medium. During single-step methotrexate selection, these cells showed an increased frequency of methotrexate resistance in the presence of IPTG. More than 60% of the methotrexate-resistant colonies showed a 2-6-fold amplification of the dhfr gene. One clone with rearranged dhfr had about 100-fold amplification of the gene. The increased capacity to amplify DNA in response to mutant Ha-ras induction was not locus specific since cells also displayed an increased frequency of resistance to N-(phosphonacetyl)-L-aspartic acid in the presence of ITPG. Four of the methotrexate-resistant clones with amplified dhfr gene were cultured further in the presence or absence of IPTG and subsequently compared for their ability to grow in soft agar as a measure of transformation. In medium containing methotrexate but no IPTG, the clones were unable to grow in soft agar, indicating that methotrexate resistance due to gene amplification is separable from transformation.
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PMID:Increased methotrexate resistance and dhfr gene amplification as a consequence of induced Ha-ras expression in NIH 3T3 cells. 816

Cancer is a disease of uncontrolled cell growth and a major cause of death worldwide. Many molecular events characterize tumor initiation and progression. Global gene expression analyses using next-generation sequencing, proteomics and metabolomics show genomic, epigenetic, and metabolite concentration changes in various tumors. Molecular alterations identified include multiple cancer-driving mutations, gene fusions, amplifications, deletions, and post-translational modifications. Data integration from many high-throughput platforms unraveled dysregulation in many metabolic pathways in cancer. Since cancer cells are fast-growing, their metabolic needs are enhanced, hence the requirement for de novo synthesis of essential metabolites. One critical requirement of fast-growing cells and a historically important pathway in cancer is the nucleotide biosynthetic pathway and its enzymes are valuable targets for small molecule inhibition. Purines and pyrimidines are building blocks of DNA synthesis and due to their excessive growth, cancer cells extensively utilize de novo pathways for nucleotide biosynthesis. Methotrexate, one of the early chemotherapeutic agents, targets dihydrofolate reductase of the folate metabolic pathway that is involved in nucleotide biosynthesis. In this review, we discuss the nucleotide biosynthetic pathways in cancer and targeting opportunities.
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PMID:Dysregulation of de novo nucleotide biosynthetic pathway enzymes in cancer and targeting opportunities. 3173 88