Radiation-induced translational control of gene expression

辐射诱导的基因表达翻译控制

基本信息

批准号：
7368652
负责人：
Philip Tofilon
金额：
$ 34.45万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-11 至 2012-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The genome-wide evaluation of radiation-induced changes in gene expression has typically been evaluated using microarray analysis of total cellular mRNA, which reflects modifications in a gene's transcription. However, gene expression is dependent not only on transcriptional activity, but on a variety of post-transcriptional events that ultimately control mRNA translation. Our recent data generated using the microarray analyses of polysome bound mRNA indicate that gene translation is considerably more susceptible to radiation induced modifications than is transcription. Importantly, this study showed that there is a correlation between the genes whose translational activity was affected and the expression of their corresponding proteins. The overall goal of this proposal is to delineate the significance of radiation-induced translational control of gene expression in cellular radioresponse. Towards this end, radiation-induced translational gene expression profiles will be generated as a function of cell type. These studies will involve microarray analysis of polysome-bound mRNA isolated from tumor cell lines originating from histologies relevant to radiotherapy as well as from a variety of normal cells. This genome wide interrogation will test the hypotheses that radiation induced translational control of gene expression is a fundamental characteristic of cellular radioresponse and that there is tumor type and/or lineage specificity in the genes subject to radiation-induced translational control. In addition, to define the molecules and processes that mediate radiation-induced translational control will be delineated. The studies will define the contribution of the general translational machinery as well as selected RNA binding proteins that have been shown to regulate the translation of specific mRNA subpopulations. Finally, the molecules mediating the process of radiation-induced translational control and the proteins corresponding to the mRNAs whose translation is affected by radiation will be tested for their role in cell survival after irradiation. These analyses, in addition to identifying fundamental determinants of radiosensitivity, will determine whether radiation-induced translational control of gene expression provides a novel source of targets for radiation modifiers. Whereas the radiobiological significance of modifying constitutively expressed proteins has been clearly established, the proposed studies offer an opportunity to investigate and potentially exploit radiation-induced translational control of gene expression, a previously unexplored component of cellular radioresponse.

描述（由申请人提供）：辐射诱导的基因表达变化的全基因组评估通常使用总细胞mRNA的微阵列分析来评估，其反映了基因转录的修饰。然而，基因表达不仅取决于转录活性，还取决于最终控制 mRNA 翻译的各种转录后事件。我们最近使用多核糖体结合 mRNA 的微阵列分析生成的数据表明，基因翻译比转录更容易受到辐射诱导的修饰的影响。重要的是，这项研究表明，翻译活性受到影响的基因与其相应蛋白质的表达之间存在相关性。该提案的总体目标是阐明辐射诱导的基因表达翻译控制在细胞放射反应中的重要性。为此，将生成辐射诱导的翻译基因表达谱作为细胞类型的函数。这些研究将涉及对多核糖体结合的 mRNA 进行微阵列分析，这些 mRNA 是从源自与放射治疗相关的组织学的肿瘤细胞系以及多种正常细胞中分离出来的。这种全基因组询问将检验以下假设：辐射诱导的基因表达翻译控制是细胞放射反应的基本特征，并且受辐射诱导翻译控制的基因存在肿瘤类型和/或谱系特异性。此外，还将描述介导辐射诱导平移控制的分子和过程。这些研究将确定一般翻译机制的贡献以及已被证明可以调节特定 mRNA 亚群翻译的选定 RNA 结合蛋白的贡献。最后，将测试介导辐射诱导翻译控制过程的分子以及与翻译受辐射影响的mRNA相对应的蛋白质在辐射后细胞存活中的作用。这些分析除了确定辐射敏感性的基本决定因素外，还将确定辐射诱导的基因表达翻译控制是否为辐射调节剂提供了新的靶标来源。尽管修饰组成型表达蛋白的放射生物学意义已经明确，但拟议的研究提供了一个研究和潜在利用辐射诱导的基因表达翻译控制的机会，这是细胞放射反应中先前未探索的组成部分。