Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

A chromosomal origin of DNA replication has been localized within the single-copy rhodopsin gene locus in Chinese hamster (line CHO) cells using two methods. In the first method, single-copy segments were identified at 3 to 15 kb intervals within approximately 75 kb (kb = 10(3) bases) of cloned genomic DNA containing the early-replicating rhodopsin gene near its middle. The cloned single-copy segments were then used as hybridization probes to quantify the replication of their corresponding genomic segments as synchronized cells progressed into S phase. In the second method, genomic DNA synthesized in vivo or in permeabilized early S phase cells was hybridized with slot-blots of the cloned single-copy DNA segments to identify the earliest replicating part of the 75 kb mapped region. The first method indicates that the earliest replicating DNA is located within a 10 kb region beginning 4 kb upstream from and extending 1 kb beyond the rhodopsin gene. The second method confirms the location in the vicinity of the rhodopsin gene and indicates that the earliest replicating region is located within or very near the 4.5 kb rhodopsin gene itself. An extended region of 12 kb that encompasses the entire early-replicating region has been sequenced for analysis and comparison with currently characterized origin regions associated with the CHO dihydrofolate reductase (dhfr) and human c-myc genes. There are several sequence similarities between the dhfr rhodopsin origin regions, including common transcription promoter consensus sequences, rodent Alu repeats with their 3'-A+T rich flanking sequences, A+T-rich yeast ARS and Drosophila SAR consensus sequences, and simple (GA)n repeats, but there are no extended regions of direct similarity. The rhodopsin gene locus is the second sequenced CHO origin region.
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PMID:Localization and DNA sequence of a replication origin in the rhodopsin gene locus of Chinese hamster cells. 156 Apr 57

The murine B-cell hybridoma B9 requires interleukin-6 (IL-6) for its survival and proliferation in vitro. We show here that withdrawal of IL-6 from B9 cultures results in programmed death, concomitant with arrest of the cells in the G1 phase of the cell cycle. Unlike several other systems that undergo programmed cell death, no induction of transcripts corresponding to the testosterone-repressed message-2 or transglutaminase genes is observed during this process. Upon readdition of IL-6 to G1-arrested B9 cells, viability is maintained and entry into S phase occurs after a lag period of 10 to 12 hr. Northern blot analysis showed that the immediate-early mRNAs normally induced shortly after growth factor stimulation in quiescent fibroblasts (c-fos, c-jun, Egr-1, c-myc, JE, and KC), and other growth-related genes (2F1, c-Ha-ras, and p53), are either not induced or remain unchanged during G1 to S phase progression. A correlation was found, however, between the temporal pattern of expression of several G1/S phase genes (dihydrofolate reductase, thymidine kinase, transferrin receptor, and histone H3) and DNA synthesis. These results demonstrate that IL-6-induced viability and growth of hybridoma (and, presumably, plasmacytoma) cells is mediated via novel signal transduction pathways.
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PMID:Suppression of programmed death and G1 arrest in B-cell hybridomas by interleukin-6 is not accompanied by altered expression of immediate early response genes. 170 72

This report describes an unexpected difference in the efficiency of removal of UV-induced DNA damage in the c-myc locus in splenic B lymphoblasts from two inbred strains of mice. In cells from plasmacytoma-resistant DBA/2N mice, 35% of UV-induced damage in the regulatory and 5' flank of c-myc is removed by 12 h. However, in cells from plasmacytoma-susceptible BALB/cAn mice, damage is not removed from this region. In the protein-encoding region and 3' flank of c-myc as well as in two dihydrofolate reductase gene fragments, UV damage is repaired with similar efficiency in B lymphoblasts from both strains of mice. Furthermore, in the protein-encoding portion and 3' flank of c-myc, damage is selectively removed from only the transcribed strand. No repair is detected in the nontranscribed strand. In contrast, DNA repair in the 5' flank of c-myc is not strand specific; in DNA from DBA/2N cells, UV damage is rapidly removed from both the transcribed and nontranscribed strands. In BALB/cAn cells no repair was detected in either strand in the 5'flank, consistent with the results with double-stranded, nick-translated probes to this region of c-myc. In addition to the repair studies, we have detected post-UV-damage formation: in most of the genes studied, we find that additional T4 endonuclease-sensitive sites are formed in the DNA 2 h after irradiation. Our findings provide new insights into the details of gene-specific and strand-specific DNA repair and suggest that there may be close links between DNA repair and B-cell neoplastic development.
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PMID:DNA repair in the c-myc proto-oncogene locus: possible involvement in susceptibility or resistance to plasmacytoma induction in BALB/c mice. 171 24

E2F is a cellular transcription factor that binds to the adenovirus (Ad) E1A enhancer and E2aE promoter regions, to the cellular c-myc P2 and dihydrofolate reductase promoters, and to other viral and cellular regulatory regions. The binding activity of E2F to the Ad E2aE promoter is dramatically increased during an adenovirus infection (termed E2F induction). E2F induction is dependent on the expression of the 150 amino acid E4-ORF6/7 protein which forms a direct, physical complex with E2F to mediate the cooperative and stable binding of E2F to inverted sites in the E2aE promoter. Using in vitro DNA binding assays to measure the formation of the infection-specific complexes, we have defined the minimal domain of the E4-ORF6/7 protein, the C-terminal 70 amino acids, required to complex with E2F and stabilize its binding at the E2aE promoter. The ability of mutant E4-ORF6/7 proteins to form the stable E2F-E2aE promoter complex in vitro correlated well with their ability to trans-activate E2 transcription in vivo. These observations support a model in which the E4-ORF6/7 protein binds to E2F to induce the cooperative binding of two E2F molecules to the E2aE promoter thereby activating E2 transcription.
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PMID:The C-terminal 70 amino acids of the adenovirus E4-ORF6/7 protein are essential and sufficient for E2F complex formation. 183 62

We have hypothesized that the c-myc oncogene might promote DNA amplification. Resistance to methotrexate (MTX), a widely used cancer chemotherapeutic agent, often results from amplification of the gene coding for the target enzyme, dihydrofolate reductase (DHFR). We report here that gratuitously induced expression of c-myc in rat fibroblasts grown in the presence of MTX greatly increases the number of colonies resistant to the drug. This effect is not related to an alteration of cell growth, and it can also be observed to a lesser extent when c-myc is induced prior to selection in MTX. The DHFR gene is amplified in nearly half of the colonies cultured under selection conditions. Given the likely role of the c-myc product in DNA replication, these results strongly suggest that expression of c-myc plays a role in methotrexate resistance by promoting DNA amplification.
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PMID:Stimulation of methotrexate resistance and dihydrofolate reductase gene amplification by c-myc. 188 15

We have used three methods to study the formation and repair of intrastrand adducts and interstrand cross-links in the DNA of Chinese hamster ovary cells induced by the anticancer drug cis-diamminedichloroplatinum II (cisplatin). Using atomic absorption spectroscopy, we found that 21% of the total genomic cisplatin adducts were removed at 8 h and 42% at 24 h. We used ABC excinuclease digestion, coupled with out previously reported methodology to quantify DNA in specific genomic regions. These adducts were removed faster in the transcribed dihydrofolate reductase and c-myc genes compared to a noncoding fragment, a region containing the little or nontranscribed c-fos oncogene, and to the overall genome. Interstrand cross-links in specific sequences were quantified by Southern hybridization of denatured-renatured DNA separated on a neutral gel. We found that cross-links were removed more efficiently from the gene regions than intrastrand adducts and, at high levels of cross-linking, removal was similar from transcribed and from nontranscribed regions.
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PMID:Gene-specific formation and repair of cisplatin intrastrand adducts and interstrand cross-links in Chinese hamster ovary cells. 201 18

We have studied DNA repair after UV damage in the murine c-myc locus. It appears that a region in B cells upstream of the murine c-myc gene is repaired with a different efficiency in plasmacytoma-resistant DBA/2N mice than in plasmacytoma-susceptible BALB/cAn mice. The region just upstream of c-myc is inefficiently repaired in B lymphoblasts derived from BALB/cAn mice. In contrast, this same region of c-myc is efficiently repaired in B lymphoblasts derived from DBA/2N mice. DNA fragments located in the coding region of c-myc and in another gene, dihydrofolate reductase (DHFR), are repaired with equal efficiency in cells from these two strains of mice. It is possible that repair efficiency of the 5' flank of c-myc may be involved in tumor susceptibility of the mouse strain.
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PMID:DNA repair in the c-myc locus. 207 8

Peritoneal cells were derived from a patient (PK) with adenocarcinoma of the colon during the course of cisplatin/5-fluorouracil (5-FUra) treatment. Resistance to cisplatin and 5-FUra, characterized by a lack of response to chemotherapy and continued growth of the tumor, was concomitantly associated with a 2-4-fold increase in DNA copy number for dTMP synthase and dihydrofolate reductase. There was a corresponding amplification in DNA copy number of the c-myc (2X), H-ras (4X), and c-fos (15X) oncogenes. Cytogenetic studies revealed an iso (13q) chromosome, but failed to show any double minutes or homogeneously staining regions. In addition, drug-resistant tumor cells from PK and another patient (HG) displayed enhanced expression of dTMP synthase, c-fos and DNA polymerase beta when compared to normal colon tissue and the HCT8 human colon carcinoma cell line. These results suggest that elevated oncogene DNA and gene expression may be involved in the development of cisplatin resistance.
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PMID:Differential oncogene amplification in tumor cells from a patient treated with cisplatin and 5-fluorouracil. 214 97

Adenovirus E1A dependent trans-activation of transcription involves the utilization of cellular promoter specific transcription factors. One such factor termed E2F is important for the transcription of the viral E2 gene and appears to be a rate limiting component targeted during the trans-activation event. Since E2F is of cellular origin and likely to be involved in cellular gene control, we have identified E2F binding sites in cellular genes. Examples include the c-myc, c-myb and N-myc protoncogenes, the DHFR gene and the EGF receptor gene. The transcription of these genes is regulated by cell proliferation signals and each falls into the so-called immediate early class: genes that are activated independent of new protein synthesis. Because of these common properties of regulation, we have addressed the possible role of E2F in growth factor dependent activation of transcription. Expression of a c-myc promoter driven CAT gene, transfected into quiescent 3T3 cells, is stimulated by serum addition whereas an identical gene containing mutations in the E2F binding sites is not responsive. The DNA binding activity of E2F is increased 4-fold upon serum stimulation and the kinetics of activation parallel activation of c-myc transcription. Furthermore, this increase in E2F activity is independent of new protein synthesis indicating that serum stimulation results in an activation of a pre-existing factor. These results thus provide strong evidence linking E2F and proliferation dependent control of transcription. We also believe that the E2F transcription factor is the first example of a regulator of the class of immediate early genes that is slowly activated by stimulation of cell proliferation.
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PMID:A role for the adenovirus inducible E2F transcription factor in a proliferation dependent signal transduction pathway. 214 65

Fetal liver or bone marrow-derived T lymphocyte precursors undergo extensive, developmentally regulated proliferation in response to inductive signals from the thymic microenvironment. We have used neonatal mouse thymocytes size-separated by centrifugal elutriation to study the cell cycle stage-specific expression of several genes associated with cell proliferation. These include genes involved in the biosynthesis of deoxyribonucleotide precursors, such as dihydrofolate reductase (DHFR), thymidylate synthase (TS), and the M1 and M2 subunits of ribonucleotide reductase, as well as c-myc, a cellular oncogene of unknown function. Using nuclear run-on assays, we observed that the transcription rates for these genes, with the exception of TS, are essentially invariant not only throughout the cell cycle in proliferating cells, but also in noncycling (G0) cells. The TS gene showed a transient increase in transcription rate in cells which bordered between a proliferating and nonproliferating status. Studies of an elutriated T cell line, S49.1, yielded similar results, indicating that the process of immortalization has not affected the transcriptional regulation of these genes. Analysis of steady-state mRNA levels using an RNase protection assay demonstrated that the levels of DHFR and TS mRNA accumulate as thymocytes progress through the cell cycle. In contrast, only the M2 subunit of ribonucleotide reductase showed cyclic regulation. Finally, in contrast to cultured cell models, we observed an abrupt fivefold increase in the steady-state level of c-myc mRNA in the transition from G1 to S-phase. We conclude from these studies that the transcriptional regulation of specific genes necessary for cellular proliferation is a minor component of the developmental modulation of the thymocyte cell cycle.
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PMID:A cell cycle analysis of growth-related genes expressed during T lymphocyte maturation. 227 81


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