Determination of the leukaemogenicity of a murine retrovirus by sequences within the long terminal repeat

Lenz, Jack; Celander, Daniel W.; Crowther, R.; Patarca, Roberto; Perkins, Dennis; Haseltine, William A.

doi:10.1038/308467a0

Cited by 314 publications

(254 citation statements)

References 54 publications

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“…Enhancers have been identified in the U3 region of the long terminal repeats (LTRs) of retroviruses (17,19,20). More recently, the LTRs of murine leukemia viruses (MLVs) have been implicated in the specific type of neoplasia caused by these viruses (5,9,22,28), and it is possible that the sequences resembling enhancers are responsible for this specificity (4).…”

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confidence: 99%

Murine leukemia virus long terminal repeat sequences can enhance gene activity in a cell-type-specific manner.

Yoshimura¹,

Davison²,

Chaffin³

1985

Mol. Cell. Biol.

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We tested the ability of sequences in the long terminal repeat (LTR) of a mink cell focus-forming (MCF) murine leukemia virus to function as an enhancer in a cell-type-specific manner. In a stable transformation assay, the MCF or Akv LTR and the simian virus 40 enhancer had similar activities in murine fibroblasts. In contrast, the MCF LTR had a significantly greater activity in murine T lymphoid cells than did either the simian virus 40 enhancer or the Akv LTR.One of the regulatory signals for transcription of eucaryotic genes is cis-acting enhancer elements that can augment the transcriptional activity of different genes (for review, see references 14 and 18). Enhancer elements were first identified in the simian virus 40 (SV40) genome but have subsequently been found in other viruses, including retroviruses (17,23,24), and have recently been identified for cellular genes (1,13,29). Unique characteristics of these enhancer elements include their ability to function in an orientationindependent manner and over relatively long distances (2,12,25). Enhancer activity can also occur in a tissue-or species-specific manner (10, 21). Enhancers have been identified in the U3 region of the long terminal repeats (LTRs) of retroviruses (17,19,20). More recently, the LTRs of murine leukemia viruses (MLVs) have been implicated in the specific type of neoplasia caused by these viruses (5, 9, 22, 28), and it is possible that the sequences resembling enhancers are responsible for this specificity (4).We have examined the LTR of a mink cell focus-forming (MCF) MLV ) to study the role that these terminal repeated sequences play in the specificity of tumor formation by MCF viruses. Lymphomagenic MCF MLVs have been implicated in the development of thymic lymphomas in strain AKR mice because of their ability to accelerate the onset of tumorigenesis (6,27 (Fig. 1, in brackets) in the U3 region. From a comparison of the nucleotide sequence of the LTRs of MCF-13 and Akv (Fig. 1), it seems clear that the greatest differences are present in the U3 region. This is a region in the LTR where duplicated sequences resembling enhancer elements have been identified for other retroviruses, and these sequences also appear to be present in the case of MCF-13 and Akv (Fig. 1). We wished to determine whether the repeated sequences for MCF-13 and Akv could also * Corresponding author. function as enhancer elements and whether this activity could occur in a cell-type-specific manner. Tissue-specific differences in the activities of these enhancerlike elements could help to account for the different pathogenic properties of these two viruses.To test this idea, we compared the LTRs of MCF-13 and Akv, along with the prototypical SV40 enhancer, in plasmid constructs containing each enhancer and the selectable gene conferring neomycin resistance (Neor) in murine cells in culture. A clone generated by Southern and Berg (33) which contains the SV40 origin of replication was used to test the SV40 enhancer (Fig. 2). The SV40 sequences that are present in thi...

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confidence: 99%

Murine leukemia virus long terminal repeat sequences can enhance gene activity in a cell-type-specific manner.

Yoshimura¹,

Davison²,

Chaffin³

1985

Mol. Cell. Biol.

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“…In a previous study, we demonstrated that Mlvi-2, a second common domain for provirus integration in MoMuLV-induced rat thymic lymphomas, also maps to mouse chromosome 15 (36). However, in contrast to Mlvi-1, Mlvi-2 could not be detected in hybrid HM25, suggesting that Mlvi-2 maps to the centromeric end of chromosome 15. Thus, the separation of Mlvi-J and Mlvi-2 in a hybrid apparently carrying a chromosome 15 The genetic mapping of Mlvi-J to chromosome 15 raised the possibility that this region of integration could contain the cellular oncogenes c-myc or c-sis.…”

Section: S Ppepementioning

confidence: 88%

“…2). These enzymes generated Mlvi-) specific fragments of 20 kb (KpnI) and 10 DNA contained mouse c-myc sequences, indicating that this hybrid line contains at least a fragment of the distal end of chromosome 15 (13). Thus, it can be concluded that the murine Mlvi-J homolog is present on chromosome 15 and probably maps to the distal end of this chromosome.…”

mentioning

confidence: 95%

“…However, in contrast to Mlvi-1, Mlvi-2 could not be detected in hybrid HM25, suggesting that Mlvi-2 maps to the centromeric end of chromosome 15. Thus, the separation of Mlvi-J and Mlvi-2 in a hybrid apparently carrying a chromosome 15 The genetic mapping of Mlvi-J to chromosome 15 raised the possibility that this region of integration could contain the cellular oncogenes c-myc or c-sis. Both of these oncogenes have been mapped to chromosome 15 (5,13,19), and several recent studies have suggested that aberrations involving c-myc are involved in some rat and mouse viral leukemias (4,28).…”

Section: S Ppepementioning

confidence: 99%

“…The major retroviral sequences necessary for transformation in avian leukosis virus have been localized to the U3 region of retroviral long terminal repeats (LTRs) (21,22,(31)(32)(33). Recent studies with murine nontransforming retroviruses also argue for the importance of the proviral LTR sequences in determining oncogenicity (3,6,15). These viral sequences can alter the transcriptional activity of nearby cellular oncogenes since LTRs contain promoter sequences as well as cis-active enhancers (14,30; L. A. Laimins, P. Tsichlis, and G. Khoury, Nucleic Acids Res., in press).…”

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Genetic mapping of a cellular DNA region involved in induction of thymic lymphomas (Mlvi-1) to mouse chromosome 15.

Ca¹,

Strauss²,

Tsichlis³

1985

Mol. Cell. Biol.

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Mlvi-1 defines a genetic locus representing a common domain for proviral DNA integration in Moloney murine leukemia virus-induced rat thymic lymphomas. Cellular sequences homologous to Mlvi-1 are present in mouse DNA, and we have used hamster-mouse somatic cell hybrids to chromosomally map Mlvi-1 in the mouse genome. Results demonstrated that Mlvi-1 maps to mouse chromosome 15 and that it is distinct from the Mlvi-2 integration region and from the cellular oncogenes c-myc and c-sis, which also map to this chromosome. Therefore, Mlvi-1 may contain novel sequences involved in the establishment and maintenance of virus-induced murine tumors, many of which contain abnormalities of chromosome 15.

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Moloney murine leukemia virus long terminal repeat activates monocyte chemotactic protein-1 protein expression and chemotactic activity

Faller

Weng

Graves³

et al. 1997

J. Cell. Physiol.

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Moloney murine leukemia virus (Mo-MuLV) is a thymotropic and leukemogenic retrovirus which causes T lymphomas. Recently, Mo-MuLV has been shown to trans-activate cellular genes. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine which can promote the migration and diapedesis of monocytes and lymphocytes, as well as inducing metastasis of lymphomas. Here we demonstrate that introduction of Mo-MuLV or the MuLV LTR alone, transiently or stably, into Balb/c-3T3 cells or HeLa cells resulted in 9-11 fold increases in MCP-1 transcripts. This trans-activation of the MCP-1 gene by the Mo-MuLV LTR is independent of the physical location of the MCP-1 gene or of the LTR, occurring whether the LTR or the MCP-1 gene is integrated in the genome or transiently expressed. Immunoblot analysis using an anti-MCP-1 polyclonal antibody showed that the expression of the MuLV LTR in HeLa cells also induced the appearance of the MCP-1 protein. Boyden Chamber analysis demonstrated that the MCP-1 chemotactic activity produced by HeLa cells with an integrated MuLV LTR was elevated by 11 fold and that neutralizing antibody to human MCP-1 abrogated monocyte migration in response to MuLV LTR expression. Promoter deletional analysis showed the LTR responsive cis-acting element in the MCP-1 promoter is located between -141 and -88. Deletion of this region abolished the trans-activation of MCP-1 by the LTR. These LTR-mediated activations of a chemotactic and inflammatory cytokine may be relevant as mechanisms whereby retroviruses which do not contain oncogenes can induce neoplasia.

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Determination of the leukaemogenicity of a murine retrovirus by sequences within the long terminal repeat

Cited by 314 publications

References 54 publications

Murine leukemia virus long terminal repeat sequences can enhance gene activity in a cell-type-specific manner.

Murine leukemia virus long terminal repeat sequences can enhance gene activity in a cell-type-specific manner.

Genetic mapping of a cellular DNA region involved in induction of thymic lymphomas (Mlvi-1) to mouse chromosome 15.

Moloney murine leukemia virus long terminal repeat activates monocyte chemotactic protein-1 protein expression and chemotactic activity

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