The mechanism of interferon effect on cell transformation by murine sarcoma virus

Huleihel, Mahmoud; Marvit, J.; Aboud, Mordechai

doi:10.1002/ijc.2910310611

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…If among its other actions, interferon coordinately inhibits formation of circular DNA, integration, and growth of oncogenic retroviruses (25), its effects on visna predictably would be minimal, and the exogenous life cycle of visna in vitro provides a ready explanation for our failure to detect homology between lentivirus DNA and cellular genes (5).…”

Section: Discussionmentioning

confidence: 99%

Slow virus visna: reproduction in vitro of virus from extrachromosomal DNA.

Harris¹,

Blum²,

Scott³

et al. 1984

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

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Under permissive conditions of growth in tissue culture, the retrovirus visna multiplies over the course of a few days to high titer and kills the host cell. We show that in this lytic life cycle, viral DNA is tightly associated with, but not covalently linked to, chromosomal DNA. This finding provides explanations for a number of the unusual properties of the lentivirus subfamily of retroviruses, and suggests potential mechanisms for the block in virus gene expression in vivo responsible for the slow infection in nature.Visna virus is the prototype of the subfamily of retroviruses that cause slow infections in sheep characterized by pathological changes in the lungs and central nervous system (1,2). Both the persistence of virus in the face of the immune response mounted by the host and the slow evolution of disease can be explained by restriction in virus gene expression imposed at the transcriptional level (3, 4). Most of the cells that harbor virus genomes have insufficient antigen to be detected and destroyed by immune surveillance, and limitation in synthesis of virus gene products allows the host cell to survive for the extended periods characteristic of slow infections.The mechanism of the block in transcription is unknown but has generally been assumed to be related to a lysogenic state, since visna virus is a retrovirus, and viral DNA is associated with high molecular weight host DNA (5-7). However, we recently found that transcription in vitro is governed by the extent of early DNA synthesis and suggested that extrachromosomal DNA might be the template for viral RNA (8). Moreover, Panganiban and Temin (9) have shown that production of spleen necrosis virus, an avian C-type retrovirus, can occur from unintegrated viral DNA. For these reasons, we reexamined the role of integration in the visna life cycle in vitro and found that in the vast majority of cells unintegrated DNA must serve as the template for transcription and for virus production. MATERIALS AND METHODSInfection of Cells and Isolation of DNA. Confluent cultures of sheep choroid plexus (SCP) cells were infected at a multiplicity of 3 plaque-forming units per cell as described (8,10). At 60-70 hr after infection, cells were removed by trypsinization and either replated under agarose for infectious center assay or separated into nuclear and cytoplasmic fractions (11). High molecular weight DNA was isolated by the Hirt fractionation procedure (12). In some experiments, high molecular weight DNA was purified further by electrophoresis in 0.5% low-gelling temperature agarose; the portion of the gel containing DNA 20 kilobase pairs (kbp) or greater in size was excised and melted, and DNA was isolated by phenol/chloroform extraction.Cloning of Visna DNA. Viral DNA for probes and for reconstruction experiments was obtained by cloning. The relevant restriction enzyme sites in visna DNA (9) are shown in Fig. 1. DNA from the Hirt supernatant fraction from SCP cells infected for 60 hr was digested with Sst I, and the fragments were inserted into ...

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Section: Discussionmentioning

confidence: 99%

Slow virus visna: reproduction in vitro of virus from extrachromosomal DNA.

Harris¹,

Blum²,

Scott³

et al. 1984

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

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“…In sensitive cells, IFN treatment causes marked changes in the expression of genes involved in the regulation of cell proliferation, differentiation, and cell surface antigen expression (4). In several tumor cells, alpha/beta interferon (IFN-a/p) treatment leads to a reversal of the transformed and tumorigenic phenotype (1, 2, 14,32,33,35,36). So far, the respective molecular mechanisms are not fully understood.…”

mentioning

confidence: 99%

Murine gamma interferon inhibits v-mos-induced fibroblast transformation via down regulation of retroviral gene expression

Seliger¹,

Kruppa²,

Pfizenmaier³

1987

J Virol

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Expression of the retroviral vector Neor myeloproliferative sarcoma virus (MPSV), which contains the v-mos oncogene and the neomycin resistance gene, leads to neoplastic transformation of mouse fibroblasts. Murine recombinant gamma interferon (IFN-y) could revert the neoplastic properties of established Neor MPSVtransformed cell lines to an apparently untransformed phenotype. In the presence of IFN-y, the Neor MPSV transformants showed a greater than 97% reduction of cloning efficiency in soft agar, strongly reduced proliferative capacity, and morphological changes. The IFN-y-induced phenotypic reversion was preceded by a rapid and selective reduction of all retroviral RNA species, apparently due to IFN-y action on the long terminal repeat of Neor MPSV. The mRNA levels of cellular genes either remained unaffected (,I-actin) or were even enhanced (H-2) in IFN-y-treated Neor MPSV-transformed cells. Upon removal of IFN-y, retroviral gene expression was fully recovered and a gradual reappearance of the transformed phenotype of these cells within 3 weeks was noted. These data show that IFN-'y can cause a virtually complete, but reversible, inhibition of v-mos-induced neoplastic properties in transformed fibroblasts by selective down regulation of retroviral RNA levels.

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“…When sensitive cells are treated with interferon (IFN) prior to infection with retroviruses, the integration of the viral genome into cellular DNA is inhibited (6)(7)(8). After integration, the viral expression can still be reversibly modified by short-term treatments with IFN (9-13).…”

mentioning

confidence: 99%

Persistent expression of v-mos oncogene in transformed cells that revert to nonmalignancy after prolonged treatment with interferon.

Sergiescu¹,

Gerfaux²,

Joret³

et al. 1986

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

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BALB/c embryonic fibroblasts productively transformed by Moloney sarcoma virus and cultivated for over 600 generations in the presence of mouse alpha/beta interferon reverted to an apparently normal phenotype and were unable to produce tumors in nude mice. Nevertheless, the presence of an integrated Moloney sarcoma virus genome in the nonmalignant Moloney sarcoma virus-transformed interferon-treated cell DNA could be shown by focus formation upon transfection and by hybridization with a v-mos probe. After digestion with various restriction endonucleases, similar hybridization patterns of v-mos sequences were obtained with DNAs from both reverted and transformed cells. However, additional integration sites and at least twice as many copies of the oncogene were found in the nonmalignant Moloney sarcoma virus-transformed interferon-treated cell DNA. Polyadenylylated RNA extracted from reverted and control cells contained two mos-specific transcripts. Interestingly, the nonmalignant Moloney sarcoma virus-transformed interferon-treated cells produced helper virus, but no detectable mos-containing virions, suggesting that a posttranscriptional block in the v-mos gene expression had occurred in these cells. It should be stressed that, after up to 100 additional passages, cells cultured in the absence of interferon maintained their nontumorigenic character in spite of the persistent transcription of the mos oncogene.

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The mechanism of interferon effect on cell transformation by murine sarcoma virus

Cited by 4 publications

References 33 publications

Slow virus visna: reproduction in vitro of virus from extrachromosomal DNA.

Slow virus visna: reproduction in vitro of virus from extrachromosomal DNA.

Murine gamma interferon inhibits v-mos-induced fibroblast transformation via down regulation of retroviral gene expression

Persistent expression of v-mos oncogene in transformed cells that revert to nonmalignancy after prolonged treatment with interferon.

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