Hypoxia controls nitric oxide-regulated proteins

缺氧控制一氧化氮调节蛋白

• 批准号: 7501330
• 负责人: DOUGLAS D. THOMAS
• 金额: $ 16.21万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7501330
• 关键词: Adverse effects; Affect; Antineoplastic Agents; Behavior; Cell Density; Cell Respiration; Cells; Condition; Data; Event; Functional disorder; Goals; Half-Life; Hypoxia; In Vitro; Lead; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic Pathway; Metabolism; Modeling; Molecular; Neoplasm Metastasis; Nitric Oxide; Oxidation-Reduction; Pathway interactions; Personal Satisfaction; Phosphorylation; Physiology; Pilot Projects; Post-Translational Regulation; Proteins; Radiation therapy; Radio; Rate; Regulation; Research Personnel; Resistance; Signal Pathway; Signal Transduction; Signaling Molecule; TP53 gene; Therapeutic; Therapeutic Agents; Time; Translational Regulation; Tumor Biology; Up-Regulation; Variant; Vascularization; angiogenesis; base; cell behavior; cell motility; design; driving force; in vivo; inhibitor/antagonist; mimetics; neoplastic cell; programs; response; tumor

DESCRIPTION (provided by applicant): It is well-established that tumor hypoxia (low O2) significantly contributes to chemo- and radio-therapy resistance. Under hypoxic conditions, ERK, HIF-1a (Hypoxic inducible factor), and p53 enhance tumor survival by increasing neo-vascularization, cell migration, metastasis, proliferation, and metabolism. Nitric oxide (NO) is an important signaling molecule, synthesized in and around many tumors. We have shown that like hypoxia, NO can post-translationally upregulate and increase the function of ERK, HIF-1a, and p53 in tumor cells. Small amounts of NO upregulate ERK, while incrementally larger amounts are necessary for the upregulation of HIF-1a and p53, respectively. Furthermore, we have shown that cellular metabolism of NO is inversely related to the O2 concentration. The goal of this proposal is to determine how hypoxia regulates NO-driven tumor cell migration via the post-translational regulation of ERK, HIF-1a, and p53. Based on our preliminary data, we hypothesize that the concentration of O2 in the tumor microenvironment is the ultimate upstream determinant of NO-driven tumor cell migration through ERK, HIF-1a, and p53 post-translational regulation. In support of this hypothesis we propose two specific aims: 1) Establish the O2-dependent mechanism of ERK, HIF-1a, and p53 regulation by NO. 2) Demonstrate that NO-driven tumor cell migration is a function of O2 concentration. These data will serve as a template model for predicting and understanding the behavior of tumors in vivo where NO is suspected to be a major driving force. These studies should lead to understanding, for the first time, the crucial yet unknown interrelationship between NO, O2, and protein regulation so that chemotherapeutic design may be specifically directed to target these important aspects of tumor physiology.

描述（由申请人提供）：良好的肿瘤缺氧（低O2）显着有助于化学和放射治疗的耐药性。在低氧条件下，ERK，HIF-1A（低氧诱导因子）和p53通过增加新的血管化，细胞迁移，转移，增殖和代谢来增强肿瘤存活。一氧化氮（NO）是在许多肿瘤周围及其周围合成的重要信号分子。我们已经表明，像缺氧一样，译后可以在肿瘤细胞中上调ERK，HIF-1A和p53的功能。少量的无上调ERK，而HIF-1A和p53的上调分别是逐渐增加的。此外，我们已经表明，NO的细胞代谢与O2浓度成反比。该提案的目的是确定缺氧如何通过ERK，HIF-1A和p53的翻译后调节来调节无驱动的肿瘤细胞迁移。 根据我们的初步数据，我们假设肿瘤微环境中的O2浓度是通过ERK，HIF-1A和P53过渡后调节的无驱动肿瘤细胞迁移的最终上游决定因素。为了支持这一假设，我们提出了两个具体目的：1）建立ERK，HIF-1A和p53调节的O2依赖机制。 2）证明无驱动的肿瘤细胞迁移是O2浓度的函数。这些数据将用作模板模型，以预测和理解体内肿瘤的行为，而无疑是主要驱动力。这些研究应首次理解NO，O2和蛋白质调节之间的关键但未知的相互关系，以便可以专门针对针对肿瘤生理学的这些重要方面的化学治疗设计。