Mechanism of neurooncogenesis by JC virus -- Relationship to human brain tumors.

一种新的人多瘤病毒JC病毒是我们在日本首次分离到的，已被证明对仓鼠具有高度神经致瘤性，并被命名为JC病毒东京1株（Abb: JCT）。JCT已被证明能在仓鼠体内持续诱导与人类髓母细胞瘤非常相似的中小脑神经外胚层肿瘤。与美国和西德分离株相比，JCT宿主范围广，致瘤性高。为了研究JCT的这种独特性质，我们克隆了JCT- dna，并检测了dna的基因组特征。髓母细胞瘤的起源：克隆JCT- dna的T区，用放射性同位素标记JCT-T区的反构体mRNA，用原位杂交法检测接种后仓鼠小脑中的JCT mRNA。mRNA首先在小脑外颗粒层和内颗粒层之间的分子层细胞以及内颗粒层细胞中检测到。因此，可以说发育中的外颗粒层细胞感染了JCT，携带整合的JCT基因组迁移到内颗粒层，然后在内颗粒层表达表型转化。JCT在限制性内切酶切割模式上的差异：为了与国外的JCT进行比较，我们直接从原PML脑和培养细胞中克隆了JCT DNA。JCT有两个被Hinc II和Pvu II酶切的裂解位点，这在其他菌株中是没有的。这似乎有利于JCT扩大宿主范围。JCT调控基因的差异：我们检测了JCT调控基因的DNA序列，并与其他JC病毒进行了比较。JCT在TATA序列后插入23个碱基对。在另一种插入物中未检测到的插入物具有增强子的潜在核心序列。因此，JCT的高致癌性可能与在其调控基因中插入增强子DNA有关。

A new human polyomavirus, JC virus, first isolated in Japan by us, has been shown to be highly neurooncogenic to hamsters, and was named JC virus Tokyo-1 strain (Abb: JCT). JCT has been shown to induce constantly mid-cerebellar neuroectodermal tumors in hamsters, which are very similar to human medulloblastoma. The host range of JCT was wide, and tumorgeniciy was very high, compared to those isolated from U.S.A. and West Germany. To investigate this unique properties of JCT, we cloned JCT-DNA, and examined the genomic characters of DNA.1. Origin of medulloblastoma: We cloned the T region of JCT-DNA, and labeled the antisence mRNA of JCT-T region with radioisotope, and examined JCT mRNA in the hamster cerebellum after inoculation by in situ hybridization. The mRNA was first detected in the cells of the cerebellar molecular layer between the external granular layer and the internal granular layer, as well as cells in the internal granular layer. Thus, it could be said that the cells in the developing external granular layer were infected with JCT, migrated into the internal granular layer carrying the integrated JCT genome, then express the phenotypic transformation in the internal granular layer.2. Difference of JCT in restriction enzyme cleavaged pattern: To compare the JCT to those from other countries, we cloned JCT DNA directly from the original PML brain as well as cultured cells. JCT has two cleavaged sites by Hinc II and Pvu II digestion, repectively, which were not described in the other strains. This seemed to be adventagious for JCT to widen the host range.3. Differences of regulatory gene of JCT: We examined the DNA sequences of the regulatory genes of JCT, and compared them with other JC viruses. JCT has 23-base pair insertion after TATA sequences. The insertion, which has not detected in the other , has a potential core sequence of the enhancer. Thus, the high oncogenicity of JCT may owe this insertion of enhancer DNA in its regulatory gene.