Gene amplification: mechanisms and involvement in cancer

2013 ◽  
Vol 4 (6) ◽  
pp. 567-582 ◽  
Author(s):  
Atsuka Matsui ◽  
Tatsuya Ihara ◽  
Hiraku Suda ◽  
Hirofumi Mikami ◽  
Kentaro Semba
Keyword(s):  
Drosophila Melanogaster ◽  
Gene Amplification ◽  
Dihydrofolate Reductase ◽  
Mammalian Cells ◽  
Replication Fork ◽  
Template Switching ◽  
Rolling Circle Replication ◽  
Rolling Circle ◽  
Reductase Gene ◽  
Fork Stalling

AbstractGene amplification was recognized as a physiological process during the development of Drosophila melanogaster. Intriguingly, mammalian cells use this mechanism to overexpress particular genes for survival under stress, such as during exposure to cytotoxic drugs. One well-known example is the amplification of the dihydrofolate reductase gene observed in methotrexate-resistant cells. Four models have been proposed for the generation of amplifications: extrareplication and recombination, the breakage-fusion-bridge cycle, double rolling-circle replication, and replication fork stalling and template switching. Gene amplification is a typical genetic alteration in cancer, and historically many oncogenes have been identified in the amplified regions. In this regard, novel cancer-associated genes may remain to be identified in the amplified regions. Recent comprehensive approaches have further revealed that co-amplified genes also contribute to tumorigenesis in concert with known oncogenes in the same amplicons. Considering that cancer develops through the alteration of multiple genes, gene amplification is an effective acceleration machinery to promote tumorigenesis. Identification of cancer-associated genes could provide novel and effective therapeutic targets.

scholarly journals Novel DNA rearrangements are associated with dihydrofolate reductase gene amplification.

1984 ◽  
Vol 259 (14) ◽  
pp. 9127-9140
Author(s):  
N A Federspiel ◽  
S M Beverley ◽  
J W Schilling ◽  
R T Schimke
Keyword(s):  
Gene Amplification ◽  
Dihydrofolate Reductase ◽  
Dna Rearrangements ◽  
Reductase Gene

Mathematical models of gene amplification with applications to cellular drug resistance and tumorigenicity.

Genetics ◽  
1990 ◽  
Vol 125 (3) ◽  
pp. 633-644
Author(s):  
M Kimmel ◽  
D E Axelrod
Keyword(s):  
Mathematical Models ◽  
Cell Lines ◽  
Gene Amplification ◽  
Dihydrofolate Reductase ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Published Data ◽  
Reductase Gene ◽  
Double Minute ◽  
Double Minute Chromosomes

Abstract An increased number of copies of specific genes may offer an advantage to cells when they grow in restrictive conditions such as in the presence of toxic drugs, or in a tumor. Three mathematical models of gene amplification and deamplification are proposed to describe the kinetics of unstable phenotypes of cells with amplified genes. The models differ in details but all assume probabilistic mechanisms of increase and decrease in gene copy number per cell (gene amplification/deamplification). Analysis of the models indicates that a stable distribution of numbers of copies of genes per cell, observed experimentally, exists only if the probability of deamplification exceeds the probability of amplification. The models are fitted to published data on the loss of methotrexate resistance in cultured cell lines, due to the loss of amplified dihydrofolate reductase gene. For two mouse cell lines unstably resistant to methotrexate the probabilities of amplification and deamplification of the dihydrofolate reductase gene on double minute chromosomes are estimated to be approximately 2% and 10%, respectively. These probabilities are much higher than widely presumed. The models explain the gradual disappearance of the resistant phenotype when selective pressure is withdrawn, by postulating that the rate of deamplification exceeds the rate of amplification. Thus it is not necessary to invoke a growth advantage of nonresistant cells which has been the standard explanation. For another analogous process, the loss of double minute chromosomes containing the myc oncogene from SEWA tumor cells, the growth advantage model does seem to be superior to the amplification and deamplification model. In a more theoretical section of the paper, it is demonstrated that gene amplification/deamplification can result in reduction to homozygosity, such as is observed in some tumors. Other applications are discussed.

Premalignant Cervical Lesions Are Characterized by Dihydrofolate Reductase Gene Amplification and c-Myc Overexpression

2007 ◽  
Vol 11 (4) ◽  
pp. 265-272 ◽  
Author(s):  
Fernando B. Guijon ◽  
KM Greulich-Bode ◽  
Maria Paraskevas ◽  
Patricia Baker ◽  
Sabine Mai
Keyword(s):  
Gene Amplification ◽  
Dihydrofolate Reductase ◽  
Cervical Lesions ◽  
Reductase Gene

scholarly journals Dihydrofolate reductase gene amplification-associated shift of differentiation in methotrexate-adapted HT-29 cells.

1991 ◽  
Vol 115 (5) ◽  
pp. 1409-1418 ◽  
Author(s):  
T Lesuffleur ◽  
A Barbat ◽  
C Luccioni ◽  
J Beaumatin ◽  
M Clair ◽  
...  
Keyword(s):  
Carcinoembryonic Antigen ◽  
Gene Amplification ◽  
Dihydrofolate Reductase ◽  
Brush Border ◽  
Dipeptidylpeptidase Iv ◽  
Gene Coding ◽  
Reductase Gene ◽  
Increased Activity ◽  
Ht 29

Postconfluent cultures of HT-29 cells form a heterogeneous multilayer of which greater than 95% of the cells are undifferentiated. In contrast, when stably adapted to normally lethal concentrations of methotrexate (10(-6)-10(-5) M), they form a monolayer of gobletlike cells (Lesuffleur et al., 1990) which secrete large quantities of mucins and display a discrete brush border with the presence of villin, dipeptidylpeptidase-IV, and carcinoembryonic antigen. When adapted to even higher concentrations of methotrexate (10(-4) and 10(-3) M) there is a shift in the pattern of differentiation from gobletlike to dome-forming absorptive-like cells. These cells still display an apical brush border which expresses villin and dipeptidylpeptidase-IV, but no longer express significant levels of mucins and carcinoembryonic antigen. This shift of differentiation coincides with a sudden amplification of the gene coding for dihydrofolate reductase and an increased activity of the enzyme.

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