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 plasmid containing the K-fgf proto-oncogene linked to the dihydrofolate reductase gene has been constructed, and used in transfection experiments to investigate the effects of K-fgf expression on the tumorigenic and metastatic properties of NIH-3T3 fibroblasts. Analysis of cells transfected with K-fgf revealed that expression of the K-fgf proto-oncogene can, in a single step, induce both tumorigenic and metastatic characteristics, as determined in soft agar cloning experiments, and in tumorigenicity and experimental lung metastasis assays with BALB/c nu/nu mice. Selection for resistance to increasing concentrations of methotrexate lead to the isolation of a series of cell lines containing amplifications of both the dihydrofolate reductase gene and the linked K-fgf gene, which synthesized elevated levels of growth factor message and protein. The most highly resistant and gene amplified cell lines exhibited lower than expected levels of K-fgf mRNA, and also appeared to have down-regulated cell surface growth factor receptors. Further support for the concept that altered K-fgf expression can induce fully malignant and metastatic cells was obtained in experimental metastasis assays, where K-fgf transfected and gene amplified cell lines were highly aggressive.
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PMID:Transformation and amplification of the K-fgf proto-oncogene in NIH-3T3 cells, and induction of metastatic potential. 191 83

We have investigated the drug resistance and gene amplification potential of NIH3T3 cells transfected with sequences coding for K-FGF, a known oncogene product, or bFGF, a non-oncogene member of the fibroblast growth factor family. Resistance to methotrexate, N-(phosphonacetyl)-L-aspartate and hydroxyurea was observed with K-fgf transfectants, due to amplification of dihydrofolate reductase, CAD or ribonucleotide reductase R2 genes, respectively. In keeping with the increase in gene amplification frequency, cells transfected with the K-fgf gene also exhibited a marked increase in CAD gene amplification rate, as determined by fluctuation analysis in the presence of N-(phosphonacetyl)-L-aspartate. Cells transfected with bFGF encoding cDNA also exhibited a significant elevation in N-(phosphonacetyl)-L-aspartate resistance, and CAD gene amplification. Treatment with suramin, which interferes with the interaction of fibroblast growth factors with their cell surface receptors, did not decrease the drug resistance properties of K-fgf transfected cells. These observations with suramin and the findings with bFGF, which lacks a conventional signal sequence for secretion, suggests that the growth factor-mediated effects on drug resistance and gene amplification occur through an intracellular as opposed to autocrine mode of action. The finding that aberrant growth factor expression regulates gene amplification opens up new possibilities for investigating intracellular mechanisms relevant to this process and also describes new functions for the altered expression of K-FGF and bFGF, which are relevant to mechanisms of malignant progression.
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PMID:Fibroblast growth factor mediated alterations in drug resistance, and evidence of gene amplification. 790 43

Newly synthesized proteins are usually exported through the endoplasmic reticulum (ER) and Golgi due to the presence in their primary sequence of a hydrophobic signal peptide that is recognized by the ER translocation system. However, some secreted proteins lack a signal peptide and are exported independently of ER-Golgi. Fibroblast growth factor (FGF)1 is included in this group of polypeptides, as well as S100A13 that is a small calcium-binding protein critical for FGF1 export. Classically secreted proteins are transported into ER in their unfolded states. To determine the role of protein tertiary structure in FGF1 export through the cell membrane, we produced the chimeras of FGF1 and S100A13 with dihydrofolate reductase (DHFR). The specific DHFR inhibitor, aminopterin, prevents its unfolding. We found that aminopterin did not inhibit the release of FGF1:DHFR and S100A13:DHFR. Thus, FGF1 and S100A13 can be exported in folded conformation.
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PMID:Protein folding does not prevent the nonclassical export of FGF1 and S100A13. 1923 22