GENETIC ASPECTS OF VIRAL ONCOGENESIS IN WILD MOUSE SPECIES

近交系小鼠和野生小鼠物种在它们的 对逆转录病毒和逆转录病毒引起的疾病的易感性。 这些 差异归因于各种小鼠染色体基因， 这些基因包括内源性逆转录病毒序列、小鼠细胞 促进或限制病毒复制的基因，以及 被病毒插入破坏的原癌基因。 我们一直在使用 识别和染色体定位小鼠基因的各种方法 参与这种耐药性，并表征病毒的目标， 阻力 在一系列实验中，我们使用了特定地点的 诱变以改变病毒gag的CA基因中的病毒序列 它以前曾被确定为目标的产品的 细胞抗性基因Fv 1。 我们发现，一个单一的改变， 氨基酸将改变抗性表型，我们在 至少一种具有新耐药模式的病毒（通过氨基酸 在这个位置上进行替换。 在其他实验中，我们 与其他小组合作， 代表肿瘤组织中前病毒整合的常见位点。 我们 发现莫洛尼病毒感染了c-myc基因转基因小鼠， 在MMTV控制下的长终端重复包含高 整合导致表达改变的肿瘤比例 Notch 1是一种控制细胞命运的基因， 在几种组织中的测定。 这表明， myc和Notch 1在疾病过程中的作用。 我们还检查了常见的 Friend亲嗜性病毒诱导的红白血病整合位点 并将一个这样的位点定位到远端Chr 9。 精细绘图显示， 位点位于或非常靠近抗性基因Fv 2。 这种集成是 用于进一步表征该区域并识别表达的 这些基因可能代表Fv 2的候选基因。

Inbred strains of mice and wild mouse species differ in their susceptibility to retroviruses and retrovirus-induced diseases. These differences have been attributed to various mouse chromosomal genes, and these genes include endogenous retroviral sequences, mouse cellular genes which facilitate or restrict virus replication, and proto-oncogenes disrupted by viral insertion. We have been using various approaches to identify and chromosomally map mouse genes involved in this resistance, and to characterize the viral targets of resistance. In one series of experiments, we used site-specific mutagenesis to alter the viral sequences in the CA gene of viral gag which had been previously identified as the target of the product of the cellular resistance gene, Fv1. We found that alteration of a single amino acid will change the resistance phenotype, and we produced at least one virus with a novel resistance pattern by amino acid substitution at this site. In other experiments, we have been collaborating with other groups to characterize chromosomal sites which represent common sites of proviral integration in tumor tissue. We found that Moloney virus infected mice transgenic for the c-myc gene under the control of the MMTV long terminal repeat contained a high proportion of tumors in which integrations produced altered expression of the mouse homolog of Notch1, a gene which controls cell fate determination in several tissues. This suggests a collaboration between myc and Notch1 in the disease process. We also examined common integration sites in erythroleukemias induced by Friend ecotropic virus and mapped one such site to distal Chr 9. Fine mapping showed that this site is at or very near the resistance gene Fv2. This integration is being used to further characterize this region and identify expressed genes which may represent candidates for Fv2.