HIG2 and Hypoxic Regulation of Protein Synthesis

HIG2 和蛋白质合成的缺氧调节

• 批准号: 7194159
• 负责人: Nicholas C. Denko
• 金额: $ 23.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194159
• 关键词: Address; Affinity; Amino Acid Sequence; Amino Acids; Applications Grants; Binding; Biological Assay; Cell Nucleus; Cells; Characteristics; Chemicals; Co-Immunoprecipitations; Condition; Cytoplasm; Cytoplasmic Granules; Gene Proteins; Genetic Transcription; Genetic Translation; Growth; Heat-Shock Response; Human; Hypoxia; Knock-out; Libraries; Localized; Location; Messenger RNA; Modeling; Molecular; Mutagenesis; Normal Cell; Oligonucleotides; Pan Genus; Pathway interactions; Physiological; Play; Post-Translational Protein Processing; Protein Biosynthesis; Protein Overexpression; Proteins; RNA; RNA Binding; RNA-Binding Proteins; Recombinants; Regulation; Repression; Research Personnel; Solid Neoplasm; Stress; Thinking; Transfection; Translations; Tumor Cell Line; Two-Hybrid System Techniques; Vascular Endothelial Growth Factors; Xenograft Model; Yeasts; base; biological adaptation to stress; cell growth; in vivo; inhibitor/antagonist; macromolecule; member; mutant; neoplastic cell; novel; protein expression; research study; response; tumor; tumor growth

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.

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，实验和临床均已证明它会影响肿瘤的侵袭性、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引起的基因和蛋白质表达变化。研究人员已经确定了缺氧应激反应级联的许多组成部分，从缺氧传感到转录变化，再到蛋白质表达变化和翻译后蛋白质修饰。无法启动新的缺氧响应 mRNA 转录的肿瘤细胞在模型肿瘤（HIF 敲除）中生长不良。同样，无法表达缺氧靶蛋白血管内皮生长因子的细胞在模型肿瘤（VEGF 敲除）中也生长不良。因此可以得出结论，研究应激反应级联的其他组成部分是合理的，因为阻断它们可能对肿瘤生长产生类似的深远影响。我们建议研究 HIG2 是否可以影响应激依赖性蛋白质合成，因为我们有证据表明 HIG2 与缺氧期间的翻译机制相关。我们之前已将 HIG2 鉴定为一种新型 63 个氨基酸蛋白，在多种正常细胞和肿瘤细胞系中，缺氧可强烈诱导 HIG2。我们现在表明 HIG2 蛋白与细胞质成员共定位 “应力颗粒”。应激颗粒已被证明可以调节响应热休克的蛋白质翻译，我们认为它们在缺氧期间发挥类似的功能。该资助提案基于这样的假设：HIG2 通过与应激颗粒成分的关联，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 HIG2 靶向应激颗粒的机制，2) 确定缺氧期间 HIG2 的结合伴侣，3) 确定肿瘤形成期间应激颗粒内 HIG2 的功能意义。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，以及这种控制对于人类肿瘤缺氧区域内细胞的存活有多重要。