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Investigating Regulatory Networks that Control Cell Proliferation and Apoptosis

研究控制细胞增殖和凋亡的调控网络

基本信息

批准号：
8937652
负责人：
KURT KOHN
金额：
$ 40.7万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Using gene expression data to enhance our knowledge of control networks relevant to cancer biology and therapy is a challenging but urgent task. Based on the premise that genes that are expressed together in a variety of cell types are likely to functions together, we derived mutually correlated genes that function together in various processes in epithelial-like tumor cells. Expression-correlated genes were derived from data for the NCI-60 human tumor cell lines, as well as data from the Broad Institute's CCLE cell lines. NCI-60 cell lines that selectively expressed a mutually correlated subset of tight junction genes served as a signature for epithelial-like cancer cells. Those signature cell lines served as a seed to derive other correlated genes, many of which had various other epithelial-related functions. Literature survey yielded molecular interaction and function information about those genes, from which molecular interaction maps were assembled. Many of the genes had epithelial functions unrelated to tight junctions, demonstrating that new function categories were elicited. The most highly correlated genes were implicated in the following epithelial functions: interactions at tight junctions (CLDN7, CLDN4, CLDN3, MARVELD3, MARVELD2, TJP3, CGN, CRB3, LLGL2, EPCAM, LNX1); interactions at adherens junctions (CDH1, ADAP1, CAMSAP3); interactions at desmosomes (PPL, PKP3, JUP); transcription regulation of cell-cell junction complexes (GRHL1 and 2); epithelial RNA splicing regulators (ESRP1 and 2); epithelial vesicle traffic (RAB25, EPN3, GRHL2, EHF, ADAP1, MYO5B); epithelial Ca(+2) signaling (ATP2C2, S100A14, BSPRY); terminal differentiation of epithelial cells (OVOL1 and 2, ST14, PRSS8, SPINT1 and 2); maintenance of apico-basal polarity (RAB25, LLGL2, EPN3). The findings provide a foundation for future studies to elucidate the functions of regulatory networks specific to epithelial-like cancer cells and to probe for anti-cancer drug targets. We are now using these methods and findings to investigate the molecular interaction network that controls the switch between epithelial and mesenchymal phenotypes in human cancer cell lines. We are searching databases of large numbers of compounds and human tumor cell lines to find compounds whose cytotoxicity patterns against various cell lines correlate with the expression pattern of genes central to the epithelial-mesenchymal transitions.

使用基因表达数据来增强我们对与癌症生物学和治疗相关的控制网络的了解是一项具有挑战性但紧迫的任务。基于在各种细胞类型中共同表达的基因可能共同发挥功能的前提，我们得出了在上皮样肿瘤细胞中共同发挥作用的相互关联的基因。表达相关基因来自NCI-60人类肿瘤细胞系的数据，以及来自布罗德研究所的CCLE细胞系的数据。NCI-60细胞系选择性地表达一组相互关联的紧密连接基因，作为上皮样癌细胞的标志。这些标志性的细胞系充当了衍生其他相关基因的种子，其中许多基因具有各种其他与上皮相关的功能。文献综述获得了关于这些基因的分子相互作用和功能信息，并根据这些信息组装了分子相互作用图谱。许多基因具有与紧密连接无关的上皮功能，这表明新的功能类别被激发出来。高度相关的基因涉及以下上皮功能：紧密连接的相互作用(CLDN7、CLDN4、CLDN3、MARVELD3、MARVELD2、TJP3、CGN、CRB3、LLGL2、EpCAM、LNX1)；贴壁连接的相互作用(CDH1、ADAP1、CAMSAP3)；桥粒的相互作用(PPL、PKP3、JUP)；细胞-细胞连接复合体的转录调控(GRHL1和2)；上皮RNA剪接调节因子(ESRP1和2)；上皮小泡交通(RAB25、EPN3、GRHL2、EHF、ADAP1、MYO5B)；上皮(Ca+2)信号(ATP2C2、PKP3、JUP)；上皮细胞的终末分化(OVOL1和2，ST14，PRSS8，SPINT1和2)；维持顶基极(RAB25，LLGL2，EPN3)。这些发现为未来的研究提供了基础，以阐明上皮样癌细胞特有的调控网络的功能，并探索抗癌药物靶点。我们现在正在使用这些方法和发现来研究控制人类癌细胞株上皮和间充质表型之间切换的分子相互作用网络。我们正在搜索大量化合物和人类肿瘤细胞系的数据库，以寻找其对各种细胞系的细胞毒模式与上皮-间充质转化中心基因的表达模式相关的化合物。