Transformation of Cells by the REL Oncogene

描述(由申请人提供)：REL/NF-kappaB转录因子家族在一些人类癌症中被错误调控，本提案集中在癌症中模拟这一信号途径的系统。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，关于REL诱导的淋巴瘤的体外模型很少，也没有REL蛋白功能的特异性抑制物。因此，这项建议的一个主要焦点是使用本实验室开发的模型系统来进一步了解人REL恶性转化鸡淋巴样细胞的机制，方法是鉴定具有改变转化活性的REL突变体和能够与转化所需的REL反式激活序列相互作用的蛋白质。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，并将识别REL靶基因。在两个相关的目标中，将尝试开发REL诱导的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学与图书馆开发中心)的合作研究中，将使用基于酵母的 报告基因分析。最后，将进一步描述缺乏relA与转化状态相关的小鼠细胞系。因此，这项建议描述了探索性研究，试图开发模型来验证REL转录因子作为某些人类淋巴细胞癌的治疗靶点，因此，从这项工作中获得的信息可能对特定人类疾病的治疗具有预后或治疗意义。

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.