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

基本信息

批准号：
10399408
负责人：
Xiaolu Yang
金额：
$ 44.47万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10399408
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

项目摘要

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.

项目描述该应用的总体目标是表征哺乳动物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正常细胞获得一组特征，以克服控制其增殖的各种约束。我们会在这里测试以下观点：提高去除错误折叠蛋白的能力可能是肿瘤细胞的新特征。蛋白质折叠是正常无重理细胞中的一个具有挑战性的过程，甚至在初期和建立中更是如此肿瘤细胞经常遇到损害蛋白质的高氧化应激。但是，PQC 去除哺乳动物细胞中错误折叠蛋白以及这些系统在肿瘤发生中的作用的系统是不太了解。我们的实验室最近发现，许多哺乳动物三方基序（TRIM）蛋白可以专门识别错误折叠的蛋白质并将其标记为蛋白酶体降解，并且某些修剪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的能力明显由于修剪的上调，癌细胞的增加。这种较高的降解功率可减轻氧化能力与致癌生长和允许致癌生长有关的应力。这些发现表明修剪为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剂防御联系起来，并将其连接起来提出了先前未认识到肿瘤细胞的特征。我们的中心假设是修剪蛋白构成哺乳动物细胞中的主要PQC系统，对于抗氧化剂防御和致癌性至关重要转型。我们提出了三个具体目标。首先，大量的修剪蛋白包括超过70 在人类中。为了全面了解装饰系统，我们将系统地研究所有人的作用人体修剪错误折叠蛋白的蛋白酶体降解，并定义了它们不同的分子基础效力。其次，我们将研究错误折叠蛋白的积累如何引起高氧化应激，即以及如何通过清除错误折叠的蛋白质来改善这种压力。第三，我们将确定使用细胞和动物模型，修剪系统在癌症进展中的作用。此外，我们的结果表明去除错误折叠蛋白对蛋白酶体抑制高度敏感，这可能提供解释用于基于蛋白酶体的癌症疗法。我们将测试增加产量的观念错误折叠的蛋白质，结合蛋白酶体阻塞，可能在杀死癌细胞方面非常有效。总的来说，这些目标将解决与蛋白质稳态和致癌有关的关键问题转型，可能会为开发有效疗法提供有价值的信息。