Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals
Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals
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DOI：
10.1038/sj.onc.1202278
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发表时间：
1999-01-07
期刊：
影响因子：
8
通讯作者：
Croul, S
中科院分区：
文献类型：
--
作者：
Krynska, B;Otte, J;Croul, S
JCV是一种在人类人群中广泛传播的乳头状病毒。JCV的原型Mad-1变异体在免疫抑制的个体中诱导一种致命的中枢神经系统脱髓鞘疾病，称为进行性多灶性白质脑病(PML)。JCV(Mad-L)对中枢神经系统的独特嗜性归因于病毒早期启动子的组织特异性调控，该启动子负责产生病毒调节蛋白T抗原，该病毒的原型JCV(CY)已多次从PML和非PML患者的尿液中分离出来，在调节序列的结构组织上与JCV(Mad-1)不同。为了研究JCV(CY)的组织特异性表达及其致病作用，建立了含有JCV(CY)早期区域的转基因小鼠。其中一些9-13个月大的小鼠表现出疾病的迹象，表现为后肢瘫痪、驼背姿势和打扮不佳。神经病理学检查未发现脑髓鞘过少的迹象，但令人惊讶的是，发现存在起源于小脑和周围脑干的原始肿瘤。肿瘤肿块还渗入周围组织。RNA和蛋白质研究结果显示，在临床正常和受影响的转基因小鼠的后脑中，T抗原mRNA表达水平很高。然而，在表现出严重疾病的动物的大脑中检测到更高水平的T抗原RNA和蛋白质。JCV(CY)诱导的转基因小鼠肿瘤与人髓母细胞瘤/原始神经外胚层肿瘤(PNETs)在定位、组织学形态和标记蛋白表达等方面非常相似，这一新的动物模型在人脑肿瘤研究中具有重要的应用价值。
JCV is a papovavirus which is widespread in the human population. The prototype Mad-1 variant of JCV induces a fatal demyelinating disease of the central nervous system (CNS) called Progressive Multifocal Leukoencephalopathy (PML) in immunosuppressed individuals. The unique tropism of JCV (Mad-l) to the CNS is attributed to the tissue-specific regulation of the viral early promoter which is responsible for the production of the viral regulatory protein, T-antigen, The archetype form of this virus, JCV(CY), which has been repeatedly isolated from the urine of PML and non-PML individuals, is distinct from JCV(Mad-1) in the structural organization of the regulatory sequence. To characterize the tissue specific expression of JCV(CY) and to investigate its potential in inducing disease, transgenic mice containing the early region of JCV(CY) were generated. Some of these mice between 9-13 months of age exhibited signs of illness as manifested by paralysis of rear limbs, hunched posture, and poor grooming. Neuropathological examination indicated no sign of hypomyelination of the brain, but surprisingly, revealed the presence of primitive tumors originating from the cerebellum and the surrounding brain stem. The tumor masses also infiltrated the surrounding tissue. Results from RNA and protein studies revealed a high level of T-antigen mRNA expression in hindbrains of clinically normal and affected transgenic mice. However, higher levels of T-antigen RNA and protein were detected in brains of the animals exhibiting severe illness. The close resemblance of JCV(CY) induced tumor in transgenic mice to the human medulloblastoma/primitive neuroectodermal tumor (PNETs) in location, histologic appearance, and expression of marker proteins strongly suggests the utility of this novel animal model for the study of human brain tumors.