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:
- 金额:$ 44.47万
- 依托单位:
- 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:
- 关键词:AddressAmino Acid MotifsAnimal ModelAnimalsAntioxidantsBindingCaenorhabditis elegansCell DeathCell modelCellsCharacteristicsClinicalCrowdingDevelopmentEnvironmentEvolutionExcisionGoalsGrowthHandHumanImpairmentKnowledgeLifeMaintenanceMalignant - descriptorMalignant NeoplasmsMammalian CellMediatingMolecularMolecular ConformationMusNormal CellOncogenicOxidative StressPML geneProcessProductionProteasome InhibitionProteasome InhibitorProteinsProteolysisQuality ControlRoleSignal TransductionStressSumoylation PathwaySystemTRIM MotifTRIM11 geneTestingUbiquitinationUp-Regulationbasecancer cellcancer initiationcancer therapyeffective therapymacromoleculemalignant phenotypemembermisfolded proteinmulticatalytic endopeptidase complexneoplastic cellnovelprotein degradationprotein foldingprotein misfoldingproteostasistraittumortumor progressiontumorigenesisubiquitin ligasevirtual
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Xiaolu Yang其他文献
Xiaolu Yang的其他文献
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{{ truncateString('Xiaolu Yang', 18)}}的其他基金
Regulation of the ERK signaling pathway by K63-linked polyubiquitination
K63 连接的多聚泛素化对 ERK 信号通路的调节
- 批准号:
10701811 - 财政年份:2022
- 资助金额:
$ 44.47万 - 项目类别:
Regulation of the ERK signaling pathway by K63-linked polyubiquitination
K63 连接的多聚泛素化对 ERK 信号通路的调节
- 批准号:
10535249 - 财政年份:2022
- 资助金额:
$ 44.47万 - 项目类别:
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:
9917186 - 财政年份:2020
- 资助金额:
$ 44.47万 - 项目类别:
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:
10558619 - 财政年份:2020
- 资助金额:
$ 44.47万 - 项目类别:
Role of Daxx in protein folding and tumorigenesis
Daxx 在蛋白质折叠和肿瘤发生中的作用
- 批准号:
10689110 - 财政年份:2019
- 资助金额:
$ 44.47万 - 项目类别:
Role of Daxx in protein folding and tumorigenesis
Daxx 在蛋白质折叠和肿瘤发生中的作用
- 批准号:
10495196 - 财政年份:2019
- 资助金额:
$ 44.47万 - 项目类别:
Role of the pentose phosphate pathway in tumorigenesis
磷酸戊糖途径在肿瘤发生中的作用
- 批准号:
9236169 - 财政年份:2016
- 资助金额:
$ 44.47万 - 项目类别:
Role of the pentose phosphate pathway in tumorigenesis
磷酸戊糖途径在肿瘤发生中的作用
- 批准号:
9101315 - 财政年份:2016
- 资助金额:
$ 44.47万 - 项目类别:
Role of p53 family proteins in glucose metabolism
p53家族蛋白在葡萄糖代谢中的作用
- 批准号:
8846081 - 财政年份:2014
- 资助金额:
$ 44.47万 - 项目类别:
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