Induction of endogenous avian tumor virus gene expression by pyrrolizidine alkaloids

Pearson, Margot; Karchesy, Joseph J.; Deeney, A.O'c.; Deinzer, Max L.; Beaudreau, G. S.

doi:10.1016/0009-2797(84)90107-8

Cited by 10 publications

(2 citation statements)

References 39 publications

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“…A retroviral long terminal repeat (LTR) was chosen as the sensor for signals arising from DNA damage. Previous work by others had demonstrated the induction of avian tumor virus production by carcinogens (3), the induction of avian tumor virus transcription by pyrrolizidine alkaloids (4), and the induction of endogenous murine retroviruses by aflatoxin B1 and 2-acetylaminofluorene (5). Also in transformed C3H/10T1/2 murine fibroblasts, transcription of Moloney murine sarcoma virus (Mo-MuSV) LTR sequences was observed that was absent or present at a very low level in untransformed cells (6).…”

mentioning

confidence: 86%

Induction of transcription from the long terminal repeat of Moloney murine sarcoma provirus by UV-irradiation, x-irradiation, and phorbol ester.

Lin

Goldthwait

Samols³

1990

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

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The long terminal repeat (LTR) of Moloney murme sarcoma virus (Mo-MuSV) was used as a model system to study the stress response of mammalian cells to physical carcinogens. The chloramphenicol acetyltransferase (CAT) gene was inserted between two Mo-MuSV LTRs, and the LTR-CAT-LTR construct was used for virus production and was integrated into the genome of NIH 3T3 cells in the proviral form. This construct was used to assure that the integrated CAT gene was driven by the promoter of the LTR. Expression of the CAT gene was stimulated 4-fold by UV irradiation, and the peak of activity was observed at 18 hr. In contrast, stimulation of the CAT expression after x-irradiation was 2-fold and occurred at -6 hr. Phorbol myristate acetate also stimulated CAT-activity 4-fold with a peak at 6 hr. Downregulation of protein kinase C blocked totally the response to x-irradiation brut only partially the response to UV. The protein kinase inhibitor-H7 blocked the response to treatment by UV, x-ray, and phorbol ester.Prokaryotic? cells respond to DNA damage by the induction ofa series of enzymes. This is known as the SOS response (1). In mammalian cells, the "stress response" is in a general sense similar in that a series of genes are activated under various conditions. Herrlich et al. (2) demonstrated that y-irradiation,'UV-irradiation, other agents that damage DNA or block DNA replication, and phorbol ester increased the levels of a series of mRNAs and proteins.The goals of this study were to establish a reporter system for stress response, to determine whether x-ray-and UVirradiation could trigger that response, and to investigate some aspects of the internal signaling system for that response. A retroviral long terminal repeat (LTR) was chosen as the sensor for signals arising from DNA damage. Previous work by others had demonstrated the induction of avian tumor virus production by carcinogens (3), the induction of avian tumor virus transcription by pyrrolizidine alkaloids (4), and the induction of endogenous murine retroviruses by aflatoxin B1 and 2-acetylaminofluorene (5). Also in transformed C3H/10T1/2 murine fibroblasts, transcription of Moloney murine sarcoma virus (Mo-MuSV) LTR sequences was observed that was absent or present at a very low level in untransformed cells (6). Thus, there was considerable evidence that an LTR might be transcriptionally activated due to a stress response from carcinogens.For experiments reported here, the chloramphenicol acetyltransferase (CAT) gene was inserted into a Mo-MuSV vector and stably integrated into the genome of NIH 3T3 cells in the proviral form. Increased CAT expression was observed following UV-irradiation, x-irradiation, and phorbol ester addition. Differences in the kinetics of expression were observed. Down-regulation of protein kinase C affected the response of the CAT gene to both x-ray-and UV-irradiation. The response to both these challenges was blocked by the protein kinase inhibitor H7. MATERIALS AND METHODSPlasmids. The retroviral-derived vector poly-pMV was...

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confidence: 86%

Induction of transcription from the long terminal repeat of Moloney murine sarcoma provirus by UV-irradiation, x-irradiation, and phorbol ester.

Lin

Goldthwait

Samols³

1990

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

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“…Senecionine has been shown to be mutagenic, cytotoxic, and genotoxic (Williams et al, 1980;Green et al, 1981;Candrian et al, 1984;Pearson et al, 1984;Mori et al, 1985;Griffin and Segall, 1986) with the toxicity attributed to the formation of reactive pyrroles by the action of hepatic microsomal enzyme systems White and Mattocks, 1971;Mattocks, 1986). Recently our laboratory isolated trans-4-OH-2-hexenal (t-4HH) from the hepatic microsomal metabolism of senecionine (Segall et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Lipid peroxidation and cellular damage caused by the pyrrolizidine alkaloid senecionine, the alkenal trans-4-hydroxy-2-hexenal, and related alkenals

Griffin

Segall

1987

Cell Biol Toxicol

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Lipid peroxidation was examined as a possible mechanism for cell injury by trans-4-OH-2-hexenal, the macrocyclic pyrrolizidine alkaloid senecionine and related alkenals in isolated rat hepatocytes. Each compound elicited a positive dose response for peroxidation of cellular lipids as measured by the formation of thiobarbituric acid-reactive products. The addition of the anti-oxidant N,N'-diphenyl-p-phenylenediamine to the hepatocyte suspensions inhibited the production of thiobarbituric acid-reactants. However, the presence of the anti-oxidant had no protective effects on the cell membrane integrity as evidenced by the leakage of lactate dehydrogenase from the cells into the surrounding media. These results suggest that lipid peroxidation which occurs in the presence of senecionine, trans-4-OH-2-hexenal or related alkenals is not entirely responsible for the cellular damage in isolated rat hepatocytes.

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Hepatic Pathological Changes Due to Hydroxyalkenals

Wilson

Segall

Lamé

1986

Biological Reactive Intermediates III

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Induction of endogenous avian tumor virus gene expression by pyrrolizidine alkaloids

Cited by 10 publications

References 39 publications

Induction of transcription from the long terminal repeat of Moloney murine sarcoma provirus by UV-irradiation, x-irradiation, and phorbol ester.

Induction of transcription from the long terminal repeat of Moloney murine sarcoma provirus by UV-irradiation, x-irradiation, and phorbol ester.

Lipid peroxidation and cellular damage caused by the pyrrolizidine alkaloid senecionine, the alkenal trans-4-hydroxy-2-hexenal, and related alkenals

Hepatic Pathological Changes Due to Hydroxyalkenals

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