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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