REGULATION OF TRANSGENE EXPRESSION

Tg.AC转基因小鼠携带的转基因基因由致癌的v-Ha-ras编码区组成，5个侧翼是小鼠zetaglobin启动子，3个侧翼是SV-40多聚腺苷化序列。该转基因位于11号染色体着丝粒的近端，在被全层创伤、紫外线或化学致癌物激活之前，在转录上是沉默的。当Tg.AC小鼠用结构相似的非致癌化学物质治疗时，这种区别的致癌反应不会发生。转基因的表达是一个必需的早期事件，它驱动细胞增殖，导致克隆性扩张和肿瘤形成。遗传和表观遗传机制可能有助于这种诱导反应。在用致癌物治疗后，需要一个非常独特和特殊的顺式区域和转录因子的组合来激活转基因，这是肿瘤形成过程中固有的。我们实验室有兴趣阐明Tg.AC v-Ha-ras转基因小鼠的诱导致瘤反应。我们的方法是利用分子、遗传和生化技术来识别转录控制区和相关因素。

Genetically initiated Tg.AC transgenic mice carry a transgene consisting of an oncogenic v-Ha-ras coding region flanked 5 by a mouse zetaglobin promoter and 3 by an SV-40 polyadenylation sequence. Located proximal to the centromere on chromosome 11, the transgene is transcriptionally silent until activated by full thickness wounding, UV light, or chemical carcinogens. This discriminating tumorigenic response does not occur when Tg.AC mice are treated with structurally similar non-carcinogenic chemicals. Expression of the transgene is a required early event that drives cellular proliferation resulting in clonal expansion and tumor formation. Genetic and epigenetic mechanism may contribute to this induced response. A very unique and specific assemblage of cis regions and transcription factors intrinsic to the tumorigenic process are required to activate the transgene following treatments with carcinogens. Our laboratory is interested in elucidating the induced tumorigenic response in Tg.AC v-Ha-ras transgenic mice. Our approach is to utilize molecular, genetic and biochemical techniques to identify the transcriptional control regions and the associated factors.