The Role of XBP1 During Hypoxia and Tumor Growth

XBP1 在缺氧和肿瘤生长过程中的作用

• 批准号: 7425391
• 负责人: ALBERT KOONG
• 金额: $ 22.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-04 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425391
• 关键词: Address; Binding Proteins; Boxing; Cell Survival; Cells; Development; Distant; Endoplasmic Reticulum; Gene Targeting; Growth; Human; Hypoxia; Lead; Mannosidase; Mediating; Mediator of activation protein; Modeling; Mus; Oxygen; Pathway interactions; Physiological; Protein Overexpression; Proteins; RNA Splicing; Recurrence; Reporting; Research Personnel; Role; Severities; Signal Pathway; Solid Neoplasm; Stress; Testing; Tissue Microarray; Tumor Tissue; base; cancer therapy; deprivation; insight; neoplastic cell; novel; protein misfolding; response; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Hypoxia induces a physiologic endoplasmic reticulum (ER) stress in solid tumors. Previous studies have indicated that hypoxia is a major determinant of local, regional, and distant recurrence after anticancer therapy. While many investigators have pursued studies characterizing the hypoxia induced factor (HEF-1 and HIF-2) mediated response to hypoxia, we will investigate the role the unfolded protein response (UPR), a HIF-independent signaling pathway, on tumor growth. The UPR is an evolutionarily conserved pathway that functions to reduce protein accumulation in the ER resulting in an increased capacity to tolerate ER stress. We hypothesize that since the UPR is activated during hypoxia, it may be a critical regulator of cell survival during hypoxia and is necessary for tumor growth. In this proposal, we will analyze the effect of modulating XBP1 expression on tumor growth, determine the effect of hypoxia on ER associated degradation (ERAD), and investigate the role of an XBP1 target gene, EDEM (ER degradation enhancing alpha-manosidase-like protein) on tumor growth. Ultimately, these studies may not only lead to the development of novel anticancer therapies based upon inhibition of XBP1 in tumors, but may also provide fundamental insights into our understanding of tumorigenesis.

描述（由申请人提供）：缺氧诱导实体瘤的生理内质网（ER）应激。 先前的研究表明，缺氧是抗癌治疗后局部，区域和远处复发的主要决定因素。 尽管许多研究者已经进行了表征缺氧诱导因子（HEF-1和HIF-2）介导的反应的研究，但我们将调查未折叠的蛋白质反应（UPR）（UPR）（UPR），一种与HIF无关的信号通路，对肿瘤生长的作用。 UPR是一种进化保守的途径，可在ER中降低蛋白质积累的功能，从而增加耐受性ER应激的能力。 我们假设，由于在缺氧期间激活了UPR，因此它可能是缺氧期间细胞存活的关键调节剂，对于肿瘤生长是必不可少的。 在该提案中，我们将分析调节XBP1表达对肿瘤生长的影响，确定缺氧对ER相关降解（ERAD）的影响，并研究XBP1靶基因EDEM（ER降解增强α-mar剂量酶样蛋白）对肿瘤生长的作用。 最终，这些研究不仅可能导致基于肿瘤中XBP1抑制的新型抗癌疗法的发展，而且还可以提供对我们对肿瘤发生的理解的基本见解。