HIG2 and Hypoxic Regulation of Protein Synthesis

描述（由申请人提供）： 缺氧是实体瘤的一种独特的病理生理应激，实验和临床均显示其影响肿瘤侵袭性、转移潜力和对治疗的反应。这些现象的机制尚未确定，但被认为至少部分依赖于缺氧诱导的基因和蛋白质表达变化。研究人员已经确定了许多组成部分的缺氧应激反应级联开始缺氧传感，转录变化，蛋白质表达的变化和翻译后蛋白质修饰。不能启动新的低氧应答mRNA转录的肿瘤细胞在模型肿瘤中生长不良（HIF敲除）。同样，不能表达低氧靶蛋白血管内皮生长因子的细胞在模型肿瘤中也生长不良（VEGF敲除）。因此，可以得出结论，研究应激反应级联的其他成分是合理的，因为阻断它们可能对肿瘤生长产生类似的深远影响。我们建议调查，如果HIGH 2可以影响应激依赖性蛋白质的合成，因为我们有证据表明，HIGH 2与缺氧期间的翻译机制。我们先前已经鉴定出HIGH 2是一种新的63个氨基酸的蛋白质，其在多种正常细胞和肿瘤细胞系中由缺氧强烈诱导。我们现在表明，HIGH 2蛋白与细胞质中的 压力颗粒应激颗粒已被证明可以调节蛋白质的翻译，以应对热休克，我们认为，他们在缺氧过程中发挥类似的功能。这项拨款建议是基于这样的假设，即HIG2通过与应激颗粒的组分相关联，在缺氧期间调节蛋白质合成中发挥重要作用。为了解决这一假设，我们建议：1）确定机制，通过该机制，HIGH 2是针对应激颗粒，2）确定结合配偶体的HIGH 2在缺氧和3）建立功能的重要性，在应激颗粒中的肿瘤形成过程中。这些实验应该确定HIG2是否是缺氧依赖性翻译控制所必需的，以及这种控制对人类肿瘤缺氧区域内细胞的存活有多重要。

DESCRIPTION (provided by applicant): Hypoxia is a unique patho-physiologic stress of the solid tumor that has been shown both experimentally and clinically to influence tumor aggressiveness, metastatic potential and response to therapy. The mechanisms for these phenomena have not been determined, but are thought to be at least partially dependent upon gene and protein expression changes induced by hypoxia. Investigators have identified many components of the hypoxic stress response cascade starting from hypoxic sensing, to transcriptional changes, to protein expression changes and post-translational protein modifications. Tumor cells that are unable to start new hypoxia-responsive mRNA transcription grow poorly in model tumors (HIF knockouts). Likewise, cells that fail to express the hypoxic target protein vascular endothelial growth factor also grow poorly in model tumors (VEGF knockouts). The conclusion can therefore be made that studying other components of the stress response cascade is reasonable, because blocking them could have similarly profound impact on tumor growth. We propose to investigate if HIG2 can influence stress-dependent protein synthesis because we have evidence that HIG2 is associated with translational machinery during hypoxia. We have previously identified HIG2 as a novel 63 amino acid proteins that is robustly induced by hypoxia in a wide variety of normal cells and tumor cell lines. We now show that the HIG2 protein co-localizes with members of the cytoplasmic "Stress granule". Stress granules have been shown to regulate protein translation in response to heat shock, and we suggest that they serve a similar function during hypoxia. This grant proposal is based upon the hypothesis that HIG2 plays an important function in regulating protein synthesis during hypoxia through its association with components of the stress granule. To address this hypothesis, we propose to 1) Identify the mechanism by which HIG2 is targeted to the stress granule, 2) Determine binding partners for HIG2 during hypoxia and 3) Establish the functional significance of HIG2 within the stress granule during tumor formation. These experiments should determine if HIG2 is necessary for hypoxia-dependent translational control, and how important this control is to the survival of ceils within the hypoxic regions of human tumors.