RETROVIRUS REGULATION IN VITRO AND DURING DEVELOPMENT

逆转录病毒的一个有据可查的特征是大多数病毒分离株， 尽管能够在感染的多种组织中复制， 在动物中，仅在一种或少数细胞类型中诱导肿瘤。为 非急性转化性禽和鼠逆转录病毒，根据定义， 不含病毒相关癌基因，肿瘤的特异性 诱导以及病毒引起疾病的频率， 分离主要与长末端重复序列（LTR），其中包含 病毒增强子和启动子。在此应用中提出了实验 利用禽非急性转化病毒研究 定义（a）频率和（B）特异性的不同病毒LTR 和（c）用于破坏表达的机制 在肿瘤中前病毒整合位点的细胞基因。这些领域 通过定义野生型的转录特性来研究， 来自高度和弱致癌病毒的突变体和重组LTR， 通过复制能力病毒的体内致瘤性测试， 包括这些土地登记册。实验也包括表征一个新的 在禽逆转录病毒中定义的共同整合位点（bravo） 诱导的B细胞淋巴瘤，并确定前病毒的作用 整合在这个位置上。这项应用研究将有助于 我们对病毒成分的身份和调控的理解 在肿瘤诱导中的作用以及细胞转录因子和 细胞癌基因也参与了这一过程。此外，拟议的 对bravo基因座的研究可能会产生重要的信息， 鉴于许多先前表征的常见前病毒 肿瘤中的整合位点识别出有助于正常 细胞生长、分化或发育，以及在它们的异常形式中， 到细胞转化。

A well documented feature of retroviruses is that most virus isolates, although able to replicate in a wide variety of tissues in infected animals, induce tumors in only one or a small number of cell types. For non-acute transforming avian and murine retroviruses, which by definition do not contain viral-associated oncogenes, the specificity of tumor induction as well as the frequency with which a virus causes disease, segregate primarily with the long terminal repeat (LTR) that contains the viral enhancer and promoter. Experiments are proposed in this application to use avian non-acute transforming viruses to investigate properties of different viral LTRs that define (a) the frequency and (b) the specificity of tumor induction and (c) the mechanism(s) employed to disrupt expression of cellular genes at sites of provirus integration in tumors. These areas are investigated by defining the transcriptional properties of wild type, mutant, and recombinant LTRs from highly and weakly oncogenic viruses and by in vivo oncogenicity testing of replication competent viruses that include these LTRs. Experiments are also included to characterize a novel common integration site (bravo) that has been defined in avian retrovirus induced B cell lymphomas and to determine the effects of provirus integration at this locus. Studies in this application will contribute to our understanding of the identity and regulation of viral elements involved in tumor induction and of the role that cellular transcription factors and cellular oncogenes play in this process as well. In addition, the proposed studies on the bravo locus are likely to yield important information in light of the fact that many of the previously characterized common provirus integration sites in tumors identify genes that contribute to both normal cell growth, differentiation or development and, in their abnormal form, to cellular transformation.