DNA amplification in multidrug, cross-resistant Chinese hamster ovary cells: molecular characterization and cytogenetic localization of the amplified DNA.

Teeter, Larry D.; Atsumi, Saoko; Sen, Subrata; Kuo, Tien

doi:10.1083/jcb.103.4.1159

Cited by 25 publications

(10 citation statements)

References 25 publications

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“…Southern blot hybridizations have shown that both P-gp (35,42) and gene class 5 sequences (unpublished data) are coamplified 30-to 40- Indeed, we found that the Z7 marker chromosome (M) gained an additional segment with a size approximating that of the missing part in chromosome lq. Furthermore, the Giemsabanding pattern in the Z7 addition matched that of the distal portion of chromosome lq.…”

Section: Materuils and Methodsmentioning

confidence: 70%

“…Furthermore, the Giemsabanding pattern in the Z7 addition matched that of the distal portion of chromosome lq. No loss or gain of other chromosome segments was evident in these two MDR cells (35,42).…”

Section: Materuils and Methodsmentioning

confidence: 98%

“…The cell lines VCR15, VBR1.5, and ADR10 were originally established by stepwise selection protocols involving progressively increasing concentrations of vincristine (VC), vinblastine (VB), and adriamycin to final concentrations of 15, 1.5, and 10 ,ug/ml, respectively (35,42 14,1994 on of the long arm) in most of these metaphases ( Fig. 2A and B, arrowheads) (2,35).…”

Section: Materuils and Methodsmentioning

confidence: 99%

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Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells.

Kuo¹,

Vyas²,

Jiang³

et al. 1994

Mol. Cell. Biol.

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Recent studies of several drug-resistant Chinese hamster cell lines suggested that a breakage-fusion-bridge mechanism is frequently involved in the amplification of drug resistance genes. These observations underscore the importance of chromosome breakage in the initiation of DNA amplification in mammalian cells. However, the mechanism of this breakage is unknown. Here, we propose that the site of chromosome breakage consistent with the initial event of P-glycoprotein (P-gp) gene amplification via the breakage-fusion-bridge cycle in three independently established multidrug-resistant CHO cells was located at 1q31. This site is a major chromosome fragile site that can be induced by methotrexate and aphidicolin treatments. Pretreatments of CHO cells with methotrexate or aphidicolin enhanced the frequencies of resistance to vinca alkaloid and amplification of the P-gp gene. These observations suggest that chromosome fragile sites play a pivotal role in DNA amplification in mammalian cells. Our data are also consistent with the hypothesis that gene amplification can be initiated by stress-induced chromosome breakage that is independent of modes of action of cytotoxic agents. Drug-resistant variants may arise by their growth advantage due to overproduction of cellular target molecules via gene amplification.

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Section: Materuils and Methodsmentioning

confidence: 70%

Section: Materuils and Methodsmentioning

confidence: 98%

Section: Materuils and Methodsmentioning

confidence: 99%

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Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells.

Kuo¹,

Vyas²,

Jiang³

et al. 1994

Mol. Cell. Biol.

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“…Why do human and murine cells usually maintain amplicons in DMs, whereas CHO cells with rare exceptions (26,47,48) display HSRs? We have observed in both CHO and human cells that chromosomes carrying HSRs often are involved in bridgebreakage-fusion cycles, as evidenced by the presence of sister chromatid fusions, dicentrics, and chromosome fragments (this study; refs.…”

Section: Discussionmentioning

confidence: 99%

Amplification of the human dihydrofolate reductase gene via double minutes is initiated by chromosome breaks

Singer

Mesner

Friedman

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

121

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DNA sequence amplification is one of the most frequent manifestations of genomic instability in human tumors. We have shown previously that amplification of the dihydrofolate reductase (DHFR) gene in Chinese hamster cells is initiated by chromosome breaks, followed by bridge-breakage-fusion cycles that generate large intrachromosomal repeats; these are ultimately trimmed by an unknown process to smaller, more homogenous units manifested as homogenously staining chromosome regions (HSRs). However, in most human tumor cells, amplified DNA sequences are borne on unstable, extrachromosomal double minutes (DMs), which suggests the operation of a different amplification mechanism. In this study, we have isolated a large number of independent methotrexate-resistant human cell lines, all of which contained DHFR-bearing DMs. Surprisingly, all but one of these also had suffered partial or complete loss of one of the parental DHFR-bearing chromosomes. Cells in a few populations displayed what could be transient intermediates in the amplification process, including an initial HSR, its subsequent breakage, the appearance of DHFR-containing fragments, and, finally, DMs. Our studies suggest that HSRs and DMs both are initiated by chromosome breaks, but that cell types differ in how the extra sequences ultimately are processed and͞or maintained.

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“…Two partial mdr cDNAs were isolated from a mouse lymphocyte cDNA library by using a hamster mdr DNA sequence (45) as a probe. Bidirectional sequencing of inserts revealed that one cDNA, designated XmcDR3.9, contains a 3.9-kilobase insert spanning from 350 nucleotides (nt) downstream of the translation start site to the 3' end of the mdrl cDNA described earlier (25).…”

Section: Methodsmentioning

confidence: 99%

Overexpression of the multidrug resistance gene mdr3 in spontaneous and chemically induced mouse hepatocellular carcinomas.

Teeter¹,

Becker²,

Chisari³

et al. 1990

Mol. Cell. Biol.

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Overexpression of a family of plasma membrane glycoproteins, known as P-glycoproteins, is commonly associated with multidrug resistance in animal cells. In rodents, three multidrug resistance (mdr or pgp) genes have been identified, but only two can confer the multidrug resistance phenotype upon transfection into animal cells. Using the RNase protection method, we demonstrated that the levels of three mdr gene transcripts differ among mouse tissues, confirming a previous report that the expression of these genes is tissue specific (J. M. Croop, M. Raymond, D. Huber, A. DeVault, R. J. Arceci, P. Gros, and D. E Housman, Mol. Cell. Biol. 9:1346Biol. 9: -1350Biol. 9: , 1989. The levels of mdr transcripts were determined for mouse liver tumors spontaneously arising in both C3H/HeN and transgenic animals containing the hepatitis B virus envelope gene and for tumors induced by two different carcinogenic regimens in C57BL/6N and B6C3-F1 mice. The mdr3 gene was overexpressed in all 22 tumors tested. Our results demonstrate that overexpression of the mdr3 gene in mouse liver tumors does not require exposure of the animals to carcinogenic agents and suggest that its overexpression is associated with a general pathway of hepatic tumor development. The overexpression of the mdr3 gene, which is the homolog of human mdrl gene, in hepatocellular carcinomas may be responsible for the poor response of these tumors to cancer chemotherapeutic agents.The involvement of multidrug resistance (mdr, also known as P-glycoprotein, pgp) genes in the development of resistance to a variety of hydrophobic antineoplastic compounds in animal cells and in human tumors has been established in recent years (for reviews, see references 11, 14, 22, and 30). Three mdr genes have been reported in rodents, while only two have been identified in humans. In the mouse, the full-length cDNAs for mdrl (25) Predicted structural features of P-glycoprotein (5, 25) derived from the amino acid sequences deduced from cloned cDNAs, as well as photoaffinity cross-linking studies (9, 41), have led to a proposal suggesting that these proteins function in MDR cells by forming pores in the membrane through which they actively expel intracellular antineoplastic compounds. Consistent with this idea, it has been suggested that P-glycoproteins play an important role in the excretory systems of normal animals. In situ hybridization (36) and immunocytochemical analyses (18,46)

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DNA amplification in multidrug, cross-resistant Chinese hamster ovary cells: molecular characterization and cytogenetic localization of the amplified DNA.

Abstract: Abstract. Vincristine-resistant

Cited by 25 publications

References 25 publications

Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells.

Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells.

Amplification of the human dihydrofolate reductase gene via double minutes is initiated by chromosome breaks

Overexpression of the multidrug resistance gene mdr3 in spontaneous and chemically induced mouse hepatocellular carcinomas.

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