Tsichlis P N, Shepherd B M, Bear S E
Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111.
Proc Natl Acad Sci U S A. 1989 Jul;86(14):5487-91. doi: 10.1073/pnas.86.14.5487.
The Mlvi-1/mis-1/pvt-1 locus, located approximately 270 kilobase pairs 3' of the c-myc protooncogene, was originally discovered as a common region of provirus integration in Moloney murine leukemia virus-induced rat T-cell lymphomas. The same locus was shown subsequently to be coamplified with c-myc and to be involved in chromosomal translocations in a variety of human and animal neoplasms. Provirus integration in Mlvi-1 in Moloney murine leukemia virus-induced rat T-cell lymphomas activates the c-myc protooncogene. The studies reported here were aimed to determine whether, in addition to the activation of c-myc, provirus integration affected the expression of other neighboring genes. Provirus integration was shown to occur in three clusters separated by regions of uninterrupted DNA. The proviruses in all three clusters had integrated in a single-transcriptional orientation, and they appeared intact. Systematic hybridization of Mlvi-1 clones to rat, mouse, and human genomic DNA revealed three patches of evolutionarily conserved sequences. Two of them were mapped in regions targeted by the provirus, and the third was mapped immediately 5' to the provirus clusters. A probe derived from the conserved sequences 5' of the integrated proviruses detected a tumor-specific RNA transcript in tumors carrying a provirus in Mlvi-1 or in the neighboring Mlvi-4 and c-myc loci. The highest level of RNA transcript expression, however, was seen in a CD4+ CD8+ tumor cell line that was not carrying a provirus in this region. We conclude that provirus insertion in this region activates both c-myc and another gene that is located in the immediate vicinity of the integrated Mlvi-1 proviruses and may be developmentally regulated in T cells.
Mlvi-1/mis-1/pvt-1基因座位于原癌基因c-myc下游约270千碱基对处，最初是在莫洛尼鼠白血病病毒诱导的大鼠T细胞淋巴瘤中作为前病毒整合的常见区域被发现的。随后发现该基因座与c-myc共同扩增，并参与多种人类和动物肿瘤的染色体易位。莫洛尼鼠白血病病毒诱导的大鼠T细胞淋巴瘤中Mlvi-1的前病毒整合激活了c-myc原癌基因。本文报道的研究旨在确定除了激活c-myc外，前病毒整合是否会影响其他邻近基因的表达。结果显示前病毒整合发生在三个由不间断DNA区域隔开的簇中。所有三个簇中的前病毒都以单一转录方向整合，且看起来是完整的。用Mlvi-1克隆与大鼠、小鼠和人类基因组DNA进行系统杂交，发现了三个进化保守序列区域。其中两个位于前病毒靶向的区域，第三个位于前病毒簇的紧邻5'端。来自整合前病毒5'端保守序列的探针在携带Mlvi-1或邻近的Mlvi-4和c-myc基因座中前病毒的肿瘤中检测到一种肿瘤特异性RNA转录本。然而，在该区域未携带前病毒的CD4+ CD8+肿瘤细胞系中观察到最高水平的RNA转录本表达。我们得出结论，该区域的前病毒插入激活了c-myc和另一个位于整合的Mlvi-1前病毒紧邻区域的基因，该基因可能在T细胞中受到发育调控。
