Differential effects of retroviral long terminal repeats on interleukin-3 gene expression and autocrine transformation.
Differential effects of retroviral long terminal repeats on interleukin-3 gene expression and autocrine transformation.
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逆转录病毒长末端重复序列对白细胞介素 3 基因表达和自分泌转化的不同影响。
DOI：
10.1038/sj.leu.2400793
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发表时间：
1997
期刊：
影响因子：
11.4
通讯作者：
McCubrey,JA
中科院分区：
文献类型：
--
作者：
Wang,XY;McCubrey,JA
以前，我们记录了脑池内A粒子(IAP)前病毒转位到白介素3(IL-3)基因的转位，这导致了自分泌转化。本研究探讨了不同的长末端重复序列(LTRs)对IL-3基因表达和自分泌转化的影响。将缺陷IAPs和具有复制能力的Moloney鼠白血病病毒(MoMuLV)、人T细胞白血病(HTLV)和免疫缺陷病毒(HIV)的LTRs插入IL-3启动子区域的5‘端，并测定它们的转化能力。将淋巴细胞特异性(LS)IAP-LTR添加到种系IL-3(GIL3)基因中，产生了修改后的IL-3基因，该基因仅罕见地转化IL-3依赖细胞。相反，将浆细胞瘤(PC)IAP-ltrs添加到从浆细胞瘤中表达的IAP分离的gIL3基因中，导致了更容易转化依赖IL-3的细胞的修饰的IL-3基因。MoMuLV-LtR和TcRδ增强子也刺激高水平的IL-3表达和自分泌转化。相反，HTLV-I、HTLV-II和HIV LTRS不能诱导显著的IL-3合成或自分泌转化。与这些结果一致的是，与LS-IAP和HTLV LTRs相比，瞬时转染PC-IAP-LTR或TCR增强子的细胞中CAT表达水平更高。综上所述，不同LTRs对IL-3表达和细胞转化的影响顺序为：TCRδ-Enhancer≈MoMuLV-Ltr>；PC-IAP-Ltrs≫LS-IAP-Ltr≫HTLV-Ltrs≈HIV-Ltr。这些结果表明LS-IAP-LTR在诱导IL-3基因转录方面非常弱，LS-IAP可能需要额外的基因突变才能诱导造血细胞的自分泌转化。相反，PC-IAP-LTRS和TCR增强子中的增强子可能在诱导基因异常表达和恶性转化方面更有效。
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 TCRδ 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: TCRδ-enhancer≈ MoMuLV-LTR> PC-IAP-LTRs≫ LS-IAP-LTR≫ HTLV-LTRs≈ 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.