Carcinogen-induced trans activation of gene expression.

Kleinberger, Tamar; Flint, Y B; Blank, Marissa C.; Etkin, Sara; Lavi, Sara

doi:10.1128/mcb.8.3.1366

Cited by 24 publications

(12 citation statements)

References 36 publications

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“…Clone 13 cells were induced by doxycycline or with ethanol vehicle as a control, and nuclei were harvested 6 h later and subjected to run-on analysis as described previously (18). The intensity of hybridization of the 32 P-labeled RNA products to a filter carrying DNA sequences of E4orf4, MYC, ␤-ACTIN, and an empty plasmid was quantified using a PhosphorImager.…”

Section: Resultsmentioning

confidence: 99%

“…Extraction of nuclei, transcription reactions, and the hybridization procedure were carried out as described previously (18) but have been modified in several ways. T-REX and clone 13 cells were induced with 1 g/ml doxycycline for 6 h. Cells were harvested (2 ϫ 10 7 cells per sample), and nuclei were prepared in 1 ml NP-40 lysis buffer ( P]UTP stock [GE Healthcare]) to the thawed nuclei followed by 30 min of incubation at room temperature.…”

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Adenovirus E4orf4 Protein DownregulatesMYCExpression through Interaction with the PP2A-B55 Subunit

Ben-Israel

Sharf

Rechavi

et al. 2008

J Virol

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The adenovirus E4 open reading frame 4 (E4orf4) protein is a multifunctional viral regulator that is involved in the temporal regulation of viral gene expression by modulating cellular and viral genes at the transcription and translation levels and by controlling alternative splicing of adenoviral late mRNAs. When expressed individually, E4orf4 induces apoptosis in transformed cells. Using oligonucleotide microarray analysis, validated by quantitative real time PCR, we found that MYC (also known as c-Myc) is downregulated early after the induction of E4orf4 expression. As a result, Myc protein levels are reduced in E4orf4-expressing cells. MYC downregulation is observed both when E4orf4 is expressed individually and within the context of viral infection. E4orf4 reduces MYC transcription but does not affect transcriptional elongation or RNA stability. An interaction with the PP2A-B55 subunit is required for the downregulation of MYC by E4orf4. Since Myc overexpression was previously shown to inhibit adenovirus replication, the downregulation of Myc by E4orf4 would contribute to efficient virus infection.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Adenovirus E4orf4 Protein DownregulatesMYCExpression through Interaction with the PP2A-B55 Subunit

Ben-Israel

Sharf

Rechavi

et al. 2008

J Virol

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“…The amplified DNA is heterogeneous in size and is enriched for sequences spanning the 2-kilobase-pair (kb) region around the origin of DNA replication (26). SV40 overreplication is bidirectional (26) and is aphidicolin sensitive (14,20), suggesting the involvement of the cellular DNA replication machinery in this process. Similar activation of polyomavirus in drug-treated virally transformed rat cells was reported by several groups (11,23,29,34).…”

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“…Similar activation of polyomavirus in drug-treated virally transformed rat cells was reported by several groups (11,23,29,34). Cell fusion experiments demonstrated that the induction of SV40 and polyomavirus DNA synthesis is mediated by carcinogen-induced transacting factors (4,23,31) involved in another carcinogen-induced process: enhanced gene expression (20,22). It was previously demonstrated that exposure of various cell lines to environmental agents results in elevated expression of several viral and cellular genes (15,17,20,22,35,45 (4).…”

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“…Cytosolic extracts from N-methyl-N'-nitro-N-nitrosoguanidine-treated cells supported de novo DNA synthesis in the presence of excess exogenous T antigen and the SV40-containing plasmid pSVK,. (15,17,20,22,35,45). This process is regulated by cellular factors, is not dependent on DNA replication, and is controlled at the levels of transcription and posttranscription (20, 22; T. Kleinberger, manuscript in preparation).…”

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Carcinogen-induced DNA amplification in vitro: overreplication of the simian virus 40 origin region in extracts from carcinogen-treated CO60 cells.

Berko-Flint¹,

Karby²,

Hassin³

et al. 1990

Mol. Cell. Biol.

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An in vitro system to study carcinogen-induced amplification in simian virus 40 (SV40)-transformed Chinese hamster (C060) cells is described. SV40 amplification in this system resembled in many aspects the viral overreplication observed in drug-treated C060 cells. Cytosolic extracts from N-methyl-N'-nitro-N-nitrosoguanidine-treated cells supported de novo DNA synthesis in the presence of excess exogenous T antigen and the SV40-containing plasmid pSVK,. (15,17,20,22,35,45). This process is regulated by cellular factors, is not dependent on DNA replication, and is controlled at the levels of transcription and posttranscription (20, 22; T. Kleinberger, manuscript in preparation). The nature of the factors involved in the enhanced expression and their possible role in the overreplication phenomenon is not yet known.To facilitate analysis of the trans-acting factors responsible for viral overreplication, an in vitro system for DNA amplification was established in our laboratory (4). This system is based on the in vitro system for SV40 replication developed recently by Li and Kelly (27). By using the in vitro system for SV40 replication, it was demonstrated by several laboratories that cytosolic extracts from permissive cells supplemented with purified T antigen efficiently replicate exogenous SV40 DNA templates containing a functional origin of replication, yielding complete closed circular DNA molecules (16,18,27,43,49). Cytosolic extracts from Chinese hamster and other nonpermissive cell lines failed to support significant viral DNA replication (28).The in vitro amplification system described here consists of cytosolic extracts from drug-treated SV40-transformed Chinese hamster (C060) cells (24), template SV40 DNA molecules, and exogenous T antigen. This system provides an excellent tool for analysis of the mode of DNA amplification, characterization of the amplified DNA, and purification of the cellular factors responsible for the amplification process. The availability of this system will facilitate studies on the molecular mechanisms of gene amplification, on the control of cellular permissivity to viral replication, and on the putative existence of carcinogen-induced SOS-like responses.

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Inhibition of N‐methyl‐N′'‐nitro‐n‐nitrosoguanidine‐induced methotrexate and adriamycin resistance in CHO cells by adeno‐associated virus type 2

Yalkinoglu

Schlehofer

Hausen

1990

Intl Journal of Cancer

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We studied the effects of helper-dependent parvovirus AAV [adeno-associated virus] type 2 on carcinogen-inducible resistance to methotrexate (MTX) and adriamycin (ADR) in Chinese hamster ovary cells. Both types of drug resistance were monitored by determination of the number of drug-resistant colonies normalized for the respective value of plating efficiency under non-selective conditions. Treatment of cells with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) drastically enhanced the frequency of resistance to MTX and ADR. By contrast, infection of cells with AAV-2 prior to treatment with MNNG markedly inhibited carcinogen-induced drug resistance. Infection by AAV alone did not exert any effect. Analysis of the dihydrofolate reductase (dhfr) gene copy numbers of individual MTX-resistant clones derived from MNNG-treated and non-treated cultures revealed similar frequencies (60-80%) and amplitudes of dhfr gene amplification (2- to 8-fold) irrespective of prior AAV treatment. Hence, carcinogen-induced enhancement of MTX-resistance could reflect an increase in the frequency of dhfr gene amplification among the survivors of MNNG treatment. On the other hand, inhibition of carcinogen-inducible drug resistance by AAV suggests an interference of the virus with cellular responses to genotoxic stress, thus leading to enhanced cell killing under altered growth conditions. Possible mechanisms responsible for the inhibitory effect of AAV and its relevance in relation to tumor chemotherapy are discussed.

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Carcinogen-induced trans activation of gene expression.

Cited by 24 publications

References 36 publications

Adenovirus E4orf4 Protein DownregulatesMYCExpression through Interaction with the PP2A-B55 Subunit

Adenovirus E4orf4 Protein DownregulatesMYCExpression through Interaction with the PP2A-B55 Subunit

Carcinogen-induced DNA amplification in vitro: overreplication of the simian virus 40 origin region in extracts from carcinogen-treated CO60 cells.

Inhibition of N‐methyl‐N′'‐nitro‐n‐nitrosoguanidine‐induced methotrexate and adriamycin resistance in CHO cells by adeno‐associated virus type 2

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