A novel protein quality control system and its role in tumorigenesis

一种新型蛋白质质量控​​制系统及其在肿瘤发生中的作用

• 批准号: 10088426
• 负责人: Eric J Brown
• 金额: $ 45.32万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10088426
• 关键词: Address; Amino Acid Motifs; Animal Model; Animals; Antioxidants; Binding; Caenorhabditis elegans; Cell Death; Cell model; Cells; Characteristics; Clinical; Crowding; Development; Environment; Evolution; Excision; Goals; Growth; Hand; Human; Impairment; Knowledge; Life; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammalian Cell; Mediating; Molecular; Molecular Conformation; Mus; Normal Cell; Oncogenic; Oxidative Stress; PML gene; Process; Production; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Proteolysis; Quality Control; Role; Signal Transduction; Stress; Sumoylation Pathway; System; TRIM Motif; TRIM11 gene; Testing; Ubiquitination; Up-Regulation; base; cancer cell; cancer initiation; cancer therapy; effective therapy; macromolecule; malignant phenotype; member; misfolded protein; multicatalytic endopeptidase complex; neoplastic cell; novel; protein degradation; protein folding; protein misfolding; proteostasis; trait; tumor; tumor progression; tumorigenesis; ubiquitin ligase; virtual

PROJECT DESCRIPTION The overall goal of this application is to characterize a novel protein quality control (PQC) system in mammalian cells and to elucidate its role in tumorigenesis. Oncogenic transformation is a progressive process during which normal cells acquire a set of traits to overcome various constraints that govern their proliferation. Here we will test the notion that a heightened ability to remove misfolded proteins may be a new characteristic of tumor cells. Protein folding is a challenging process in normal unstressed cells, and even more so in incipient and established neoplastic cells, which frequently encounter high oxidative stresses that damage proteins. However, PQC systems that remove misfolded proteins in mammalian cells and the role of these systems in tumorigenesis are not well understood. Our lab recently found that many mammalian tripartite motif (TRIM) proteins can specifically recognize misfolded proteins and mark them for proteasomal degradation, and that certain TRIM can also directly activate the proteasome. Moreover, we observed that the capacity to remove misfolded proteins is markedly increased in cancer cells due to the up-regulation of TRIMs. This higher degradation power mitigates oxidative stress associated with oncogenic growth and permits oncogenic growth. These findings indicate TRIMs as versatile regulators of protein quality, connect the clearance of misfolded proteins to antioxidant defense, and suggest a previously unrecognized characteristic of tumor cells. Our central hypothesis is that TRIM proteins constitute a major PQC system in mammalian cells that are critical for antioxidant defense and oncogenic transformation. We propose three specific aims. First, TRIM proteins exist in a large number including over 70 in humans. To gain a comprehensive view of the TRIM system, we will systematically investigate the role of all human TRIMs in proteasomal degradation of misfolded proteins and define the molecular basis for their different potency. Second, we will investigate how the accumulation of misfolded proteins causes high oxidative stress, and how TRIMs ameliorate this stress through the clearance of misfolded proteins. Third, we will determine the role of the TRIM system in cancer progression using cell and animal models. Moreover, our results suggest that the removal of misfolded protein is highly sensitive to proteasome inhibition, which may provide an explanation for proteasome-inhibitor-based therapies for cancer. We will test the notion that increasing production of misfolded proteins, combined with proteasome blockage, may be highly effective in killing cancer cells. Collectively, these aims will address critical issues pertaining to protein homeostasis and oncogenic transformation, and will likely provide valuable information for the development of effective therapies.

项目描述 本申请的总体目标是表征哺乳动物中的新型蛋白质质量控制（PQC）系统。 细胞，并阐明其在肿瘤发生中的作用。致癌转化是一个渐进的过程，在此过程中， 正常细胞获得一组特性以克服控制其增殖的各种限制。这里我们将 测试的概念，提高能力，以消除错误折叠的蛋白质可能是一个新的特点，肿瘤细胞。 蛋白质折叠在正常的无应激细胞中是一个具有挑战性的过程，在早期和成熟的细胞中更是如此。 肿瘤细胞经常遇到破坏蛋白质的高氧化应激。然而，PQC 去除哺乳动物细胞中错误折叠蛋白的系统以及这些系统在肿瘤发生中的作用， 没有很好地理解。本实验室最近发现，许多哺乳动物三重基序（TRIM）蛋白可以特异性地 识别错误折叠的蛋白质，并标记它们的蛋白酶体降解，某些TRIM也可以直接 激活蛋白酶体。此外，我们观察到，去除错误折叠蛋白质的能力明显增强。 在癌细胞中由于TRIM的上调而增加。这种更高的降解能力减轻了氧化 与致癌生长相关的应激并允许致癌生长。这些研究结果表明， 蛋白质质量的多功能调节剂，将错误折叠蛋白质的清除与抗氧化防御联系起来， 提示了肿瘤细胞一个以前未被认识的特征。我们的中心假设是TRIM蛋白 在哺乳动物细胞中构成了一个主要的PQC系统，对于抗氧化防御和致癌至关重要。 转型我们提出三个具体目标。首先，TRIM蛋白大量存在，包括超过70种 在人类身上。为了全面了解TRIM系统，我们将系统地调查所有 人TRIMs在蛋白酶体降解错误折叠蛋白质中的作用，并确定了它们不同的分子基础。 力量其次，我们将研究错误折叠蛋白质的积累如何导致高氧化应激， 以及TRIMs如何通过清除错误折叠的蛋白质来缓解这种压力。第三，我们将确定 使用细胞和动物模型研究TRIM系统在癌症进展中的作用。此外，我们的研究结果表明， 错误折叠蛋白质的去除对蛋白酶体抑制高度敏感，这可以提供一种解释 用于基于蛋白酶体抑制剂的癌症治疗。我们将测试增加生产的概念， 错误折叠的蛋白质与蛋白酶体阻断相结合，可以非常有效地杀死癌细胞。 总的来说，这些目标将解决与蛋白质稳态和致癌相关的关键问题。 转化，并可能为开发有效的治疗方法提供有价值的信息。