Transformation of Cells by the REL Oncogene

描述（由申请人提供）：转录因子Rel/NF-kappaB家族在许多人类癌症中被错误调控，本提案侧重于在癌症中模拟该信号通路的系统。特别是，人类REL基因（编码c-Rel或REL）在几种相当常见的人类淋巴样细胞癌中被扩增或突变，特别是弥漫性b细胞淋巴瘤和霍奇金淋巴瘤。然而，REL诱导的淋巴瘤发生的体外模型很少，也没有特异性的REL蛋白功能抑制剂。因此，本研究的一个主要重点是利用本实验室开发的模型系统，通过鉴定转化活性改变的REL突变体和可以与转化所需REL转激活序列相互作用的蛋白质，进一步了解人类REL恶性转化鸡淋巴细胞的机制。此外，利用融合蛋白和共表达系统，将研究人类雌激素受体对REL诱导转化的抑制作用，并鉴定REL靶基因。在两个相关的目标中，将尝试开发REL诱导肿瘤发生的小鼠模型系统，并且在与John A Porco博士（波士顿大学化学系和化学方法与图书馆开发中心）的合作研究中，将使用酵母为基础开发REL蛋白质功能的第一阶段化学抑制剂

DESCRIPTION (provided by applicant): The Rel/NF-kappaB family of transcription factors is mis-regulated in a number of human cancers, and this proposal focuses on systems that model this signaling pathway in cancer. In particular, the human REL gene (encoding c-Rel or REL) is amplified or mutated in several rather common human lymphoid cell cancers, especially diffuse B-cell lymphomas and Hodgkin's lymphoma. Nevertheless, there are few in vitro models for REL-induced lymphomagenesis, and there are no specific inhibitors of REL protein function. Thus, one primary focus of this proposal is to use a model system developed in this laboratory to further understand the mechanism by which human REL malignantly transforms chicken lymphoid cells by identifying REL mutants with altered transforming activity and proteins that can interact with REL transactivation sequences required for transformation. Furthermore, using fusion proteins and co-expression systems, the inhibition of REL-induced transformation by the human estrogen receptor will be investigated and REL target genes will be identified. In two related Aims, attempts will be made to develop mouse model systems for REL-induced oncogenesis, and in collaborative studies with Dr John A Porco (Chemistry Department and Center for Chemical Methodology & Library Development at Boston University), first-stage chemical inhibitors of REL protein function will be developed using a yeast-based reporter gene assay. Finally, mouse cell lines in which the absence of RelA is associated with the transformed state will be further characterized. As such, this proposal describes exploratory research that seeks to develop models to validate the REL transcription factor as a therapeutic target in certain human lymphoid cell cancers, and, as such, the information derived from this work may have prognostic or therapeutic significance for the treatment of specific human diseases.