TRANSFORMATION OF CELLS BY THE V REL ONCOGENE

描述：（改编自研究者摘要） 转录因子控制着许多参与关键细胞调控的基因。 过程，如增殖、免疫和炎症反应，以及 凋亡突变型Rel转录因子的表达也已被证实。 与几种动物和人类癌症有关。此应用程序探讨了 一种禽类逆转录病毒恶性转化和永生的机制 禽淋巴样细胞，作为某些人的分子基础的模型， 由突变的Rel转录因子引起的淋巴癌。具体 v-Rel的功能对于其转化细胞的能力很重要， 追究这些包括突变的包膜氨基酸的能力， 赋予v-Rel一个N-末端反式激活结构域， 磷酸化对v-Rel转运的影响，以及C 0末端序列的影响 c-Rel的胞质定位。抗凋亡蛋白的能力， 将研究Bcl-2家族在v-Rel诱导肿瘤发生中的协同作用 通过创建用于表达弱致癌性Rel蛋白的载体， Bcl-2家族成员在第三个项目中，Trip 6蛋白， 在具有v-Rel的双杂交筛选中，将被表征。具体地说， Trip 6的反式激活和亚细胞定位的要求将是 通过创建Trip 6敲除小鼠和细胞系来探索。最后，细胞系 将表征特异性Rel/NF-κ B家族成员的缺陷，和 这些细胞系将用于分析特定的 Rel/NJ-kappaB复合物与不同的生理过程，如粘附， 生长控制和凋亡。该项目的长期目标是 开发哺乳动物模型系统用于研究Rel介导的肿瘤发生， 为了更接近地模拟涉及Rel改变的人类癌症， 转录因子功能

DESCRIPTION: (Adapted from investigator's abstract) The Rel/NF-kB family of transcription factors controls a number of genes involved in key cellular processes, such as proliferation, immune and inflammatory responses, and apoptosis. Expression of mutant Rel transcription factors has also been associated with several animal and human cancers. This application explores the mechanism by which an avian retrovirus malignantly transforms and immortalizes avian lymphoid cells, as a model for the molecular basis of certain human lymphoid cancers that are caused by mutant Rel transcription factors. Specific functions of v-Rel that are important for its ability to transform cells will be investigated. These include the ability of mutant Envelope amino acids to endow v-Rel with an N-terminal transactivation domain, the effect of phosphorylation on transaction by v-Rel, and the effect of C0terminal sequences on cytoplasmic localization of c-Rel. the ability of anti-apoptosis proteins in the Bcl-2 family to cooperate in v-Rel-induced oncogenesis will be investigated by creating vectors for the expression of weakly oncogenic Rel proteins and Bcl-2 family members. In a third project, the protein Trip6, which was isolated in a two-hybrid screen with v-Rel, will be characterized. Specifically, requirements for transactivation and subcellular localization of Trip6 will be explored by creating Trip6 knockout mice and cell lines. Finally, cell lines deficient in specific Rel/NF-kappaB family members will be characterized, and these cell lines will be used to analyze the contribution of specific Rel/NJ-kappaB complexes to distinct physiological processes, such as adhesion, growth control, and apoptosis. A long-term goal of this project will be to develop mammalian model systems for studying Rel-mediated oncogenesis, in order to more closely mimic human cancers that involve alterations in Rel transcription factor function.