Differential effects of retroviral long terminal repeats on interleukin-3 gene expression and autocrine transformation.
Previously we documented the transposition of an intracisternal A particle (IAP) provirus to the interleukin 3 (IL-3) locus which resulted in autocrine transformation. In the present study, the effects of different long terminal repeats (LTRs) on IL-3 gene expression and autocrine transformation were investigated. LTRs from defective IAPs, and replication competent Moloney murine leukemia virus (MoMuLV), human T cell leukemia (HTLV), and immunodeficiency (HIV) viruses, were inserted 5' of the IL-3 promoter region, and their transforming abilities determined. Addition of the lymphocyte specific (LS) IAP-LTR to the germline IL-3 (gIL3) gene, the IAP-LTR present in the previously described transposition, resulted in a modified IL-3 gene that only infrequently transformed IL-3-dependent cells. In contrast, addition of plasmacytoma (PC) IAP-LTRs to the gIL3 gene, which were isolated from IAPs expressed in plasmacytomas, resulted in modified IL-3 genes that transformed IL-3-dependent cells more readily. The MoMuLV-LTR and the TCRdelta enhancer also stimulated high levels of IL-3 expression and autocrine transformation. In contrast, the HTLV-I, HTLV-II and HIV LTRs did not induce significant IL-3 synthesis or autocrine transformation. Consistent with these results, higher levels of CAT expression were observed in cells transiently transfected with PC-IAP-LTR or a TCR enhancer compared with LS-IAP and HTLV LTRs. In summary, the rank order for the effects of different LTRs on IL-3 expression and cell transformation is: TCRdelta-enhancer approximately MoMuLV-LTR > PC-IAP-LTRs >> LS-IAP-LTR >> HTLV-LTRs approximately HIV-LTR. These results indicate that the LS-IAP-LTR is very weak at inducing IL-3 gene transcription and additional genetic mutations may be necessary for LS-IAPs to induce autocrine transformation of hematopoietic cells. In contrast, the enhancers contained in PC-IAP-LTRs and TCR enhancers may be more effective in inducing abnormal gene expression and malignant transformation.
Wang
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Department of Microbiology and Immunology, East Carolina University School of Medicine, Greenville, North Carolina 27858, USA.
McCubrey
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JA
D000818:Animals; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D017977:Deltaretrovirus / Q000235:genetics; D015870:Gene Expression; D015967:Gene Expression Regulation, Viral; D006133:Growth Substances / Q000378:metabolism / Q000502:physiology; D016325:HIV Long Terminal Repeat; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D006801:Humans; D007377:Interleukin-3 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics; D016254:Mutagenesis, Insertional; D010954:Plasmacytoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D012190:Retroviridae / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection
D006133:Growth Substances; D007377:Interleukin-3; D012333:RNA, Messenger