Moloney murine leukemia virus (Mo-MuLV) is a thymotropic and leukemogenic retrovirus which causes T lymphomas. The long terminal repeat (LTR) of Mo-MuLV affects the regulation of a number of cellular genes, including collagenase IV, monocyte chemoattractant protein-1, and c-jun genes, all of which contain 12-O-tetradecanoylphorbol-13-acetate-responsive element consensus sites within their promoters. We report here that Mo-MuLV stimulates the collagenase IV gene through transcription factor AP-1, and that the expression of a subgenomic portion of Mo-MuLV LTR alone is sufficient for this effect. Transient or stable expression of the viral LTR increases cellular AP-1 DNA binding activity. The collagenase IV 12-O-tetradecanoylphorbol-13-acetate-responsive element consensus sequence was shown to be required for this trans-activation. Deletions or mutations of this consensus site which abolished AP-1 binding also abolished trans-activation by the LTR. Transient or stable transfection of the viral LTR into cells stimulated c-jun gene expression, suggesting one mechanism whereby the viral LTR may induce cellular AP-1 activity. Thus, the Mo-MuLV LTR, through activation of the transcription factor AP-1, is capable of regulating cellular gene expression, including the induction of proto-oncogenes. This activity may be relevant to the mechanisms whereby retroviruses which do not contain oncogenes induce neoplasia.
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.
Moloney murine leukemia virus (Mo-MuLV) is a thymotropic and leukemogenic retrovirus which causes T lymphomas and leukemias, yet does not contain a transforming gene product. Mo-MuLV has been shown to trans-activate cellular genes via a polymerase III-generated transcript, designated let, from the long terminal repeat (LTR). Here we demonstrate that introduction of the Mo-MuLV LTR stably, or transiently, into murine or human cultured cells resulted in an 8- to 15-fold increase in collagenase IV (92-kDa gelatinase, gelatinase B, matrix metalloproteinase-9) gene expression. Collagenase IV protein expression was induced 9-fold by stable integration of MuLV LTR, as measured by immunoblot analysis using an anti-collagenase IV polyclonal antibody. The MuLV LTR coordinately stimulated the proteolytic activity of collagenase IV by 14-fold. The AP-1-binding site in the collagenase IV promoter was required for transactivation by the LTR. Collagenase type IV degrades type IV collagen, a major component of basement membrane, which constitutes the first step of the metastatic cascade. The activation of proteolytic enzymes by the MuLV LTR may thus play a contributory role in the development or spread of virus-induced lymphomas or leukemias.
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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