Control of Protein Synthesis by the UPS Under Stress
应激状态下 UPS 对蛋白质合成的控制
基本信息
- 批准号:9512865
- 负责人:
- 金额:$ 43.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:AreaAttenuatedBreast Cancer CellBreast Cancer cell lineCancer BiologyCancer Cell GrowthCellular StressCellular Stress ResponseCollaborationsComplementComplexCullin 2 ProteinCullin ProteinsDataData SetDevelopmentERBB2 geneGrowthIndividualLinkMediatingMiningN-terminalNeoplasm MetastasisPhosphorylationPhosphotransferasesPhysiologicalPolyribosomesProgesterone ReceptorsProtein BiosynthesisProteinsProteomeRegulationResearchResolutionRibosomesRoleStressSystemTechnologyThe Cancer Genome AtlasTimeTranslatingUbiquitinUbiquitinationXenograft procedurearmbasecohorterbB-2 Receptorexperimental studygenetic regulatory proteinimprovedinhibitor/antagonistmalignant breast neoplasmmulticatalytic endopeptidase complexnanoporenanosensorsnovelprotein degradationreceptor expressionrecruitresponsesensor technologytreatment responseultraviolet irradiation
项目摘要
PROJECT SUMMARY
This proposal is based on a newly discovered regulatory arm of the cellular stress response, whereby Jun N-
terminal kinase (JNK) is recruited to translating ribosomes (polysomes) to mediate degradation of newly
synthesized proteins (NSPs). We established the significance of this novel regulatory module to breast cancer
(BCa) biology, and identify ubiquitin proteasome system (UPS) components that—for the first time—are linked
with the surveillance of NSPs. They include Cullin 2, Nedd8, and ubiquilin1 (UBQLN1), which we demonstrate
to impact protein synthesis in BCa cells. Dysregulated expression of these UPS components in BCa underlies
the rationale for studying their role in BCa development and response to therapy.
Our preliminary results support the hypothesis that control of NSP stability constitutes a novel layer of
regulation of protein synthesis/availability, which in turn governs cellular responses to stress. We
further hypothesize that such regulation has direct implications for BCa development and response to
therapy. We focus on several complementary but hitherto unappreciated mechanisms that may underlie NSP
surveillance under stress.
The productive and long-standing collaborations between Drs. Topisirovic, Sonenberg, Mills and Ronai are
now extended to include Dr. Meller, thereby enabling extensive and complementary expertise in the areas of
protein synthesis and cancer biology to also include nanopore-sensing technology, enabling the resolution of
ubiquitin chain topologies. Together, we will assess specific, newly identified NSP regulatory factors that
function individually or in concert to regulate the cellular stress response, particularly in the context of BCa
development and response to therapy. The proposed research will: (1) Establish the physiological
significance of the RACK1–JNK–eEF1A2 regulatory axis to the cellular stress response, growth and
therapeutic response of breast cancer. (2) Assess the role of stress-induced polysomal recruitment of
Nedd8–Cullin machinery in regulating the decay of NSPs in BCa. (3) Determine the importance of
UBQLN1 recruitment to polysomes in regulating newly synthesized proteins under stress conditions
and in modulating the response of BCa to therapy.
Our proposed studies will establish the importance and significance of select UPS components in a novel
regulatory network that controls protein synthesis during cellular stress, and establish its role in BCa using a
combination of BCa cultures and xenografts, RPPA technology, and TCGA dataset mining.
项目总结
这一建议是基于新发现的细胞应激反应的调节臂,由此Jun N-
末端激酶(JNK)被招募来翻译核糖体(多聚体),以介导新的
合成蛋白质(NSP)。我们确定了这个新的调控模块对乳腺癌的意义。
(BCA)生物学,并识别首次连接的泛素蛋白酶体系统(UPS)组件
在国家体育总局的监督下。它们包括cullin 2、Nedd8和ubiquilin1(UBQLN1),我们演示了它们
影响BCA细胞的蛋白质合成。这些UPS成分在BCA中的异常表达
研究它们在BCA发展和治疗反应中的作用的理论基础。
我们的初步结果支持这样的假设,即对NSP稳定性的控制构成了一层新的
调节蛋白质的合成/可获得性,进而控制细胞对应激的反应。我们
进一步假设,这种监管对BCA的发展和应对具有直接影响
心理治疗。我们的重点是几个互补的,但到目前为止还没有得到认可的机制,它们可能是NSP的基础
处于压力下的监视。
Topisirovic博士、Sonenberg博士、Mills博士和Ronai博士之间富有成效的长期合作是
现已扩展到包括Meller博士,从而在以下领域实现了广泛和互补的专业知识
蛋白质合成和癌症生物学还包括纳米孔传感技术,使解决
泛素链拓扑。我们将共同评估具体的、新确定的NSP监管因素
单独或共同发挥调节细胞应激反应的功能,特别是在BCA的背景下
发展和对治疗的反应。建议的研究将:(1)建立生理学
RACK1-JNK-eEF1A2调节轴在细胞应激反应、生长和发育中的意义
乳腺癌的治疗反应。(2)评估应激诱导的多核体招募的作用。
NEDD8-cullin机制在调节BCA中NSP衰变中的作用(三)确定工作重点
UBQLN1在应激条件下调节新合成蛋白质的多聚体募集
以及调节BCA对治疗的反应。
我们提出的研究将确定在一部小说中选择UPS组件的重要性和意义
在细胞应激期间控制蛋白质合成的调控网络,并通过使用
BCA培养和异种移植的结合、RPPA技术和TCGA数据集挖掘。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ze'ev A Ronai其他文献
Ze'ev A Ronai的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Ze'ev A Ronai', 18)}}的其他基金
Control of Protein Synthesis by the UPS Under Stress
应激状态下 UPS 对蛋白质合成的控制
- 批准号:
9177401 - 财政年份:2016
- 资助金额:
$ 43.87万 - 项目类别:
Control of Protein Synthesis by the UPS Under Stress
应激状态下 UPS 对蛋白质合成的控制
- 批准号:
9301496 - 财政年份:2016
- 资助金额:
$ 43.87万 - 项目类别:
Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance
黑色素瘤转移和耐药性之间的信号重新连接
- 批准号:
10080714 - 财政年份:2016
- 资助金额:
$ 43.87万 - 项目类别:
Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance
黑色素瘤转移和耐药性之间的信号重新连接
- 批准号:
8955610 - 财政年份:2016
- 资助金额:
$ 43.87万 - 项目类别:
Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance
黑色素瘤转移和耐药性之间的信号重新连接
- 批准号:
9213360 - 财政年份:2016
- 资助金额:
$ 43.87万 - 项目类别:
相似海外基金
A platform for rapidly generating live attenuated enterovirus vaccines
快速生成减毒肠道病毒活疫苗的平台
- 批准号:
24K02286 - 财政年份:2024
- 资助金额:
$ 43.87万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
I-Corps: Translation potential of an efficient method to generate live-attenuated and replication-defective DNA viruses for vaccine development
I-Corps:一种有效方法的转化潜力,可生成用于疫苗开发的减毒活病毒和复制缺陷型 DNA 病毒
- 批准号:
2420924 - 财政年份:2024
- 资助金额:
$ 43.87万 - 项目类别:
Standard Grant
Developing a robust native extracellular matrix to improve islet function with attenuated immunogenicity for transplantation
开发强大的天然细胞外基质,以改善胰岛功能,并减弱移植的免疫原性
- 批准号:
10596047 - 财政年份:2023
- 资助金额:
$ 43.87万 - 项目类别:
Live attenuated non-transmissible (LANT) Klebsiella pneumoniae vaccines
肺炎克雷伯氏菌减毒非传染性 (LANT) 活疫苗
- 批准号:
10742028 - 财政年份:2023
- 资助金额:
$ 43.87万 - 项目类别:
Protecting Pigs From Enzootic Pneumonia: Rational Design Of Safe Attenuated Vaccines.
保护猪免受地方性肺炎:安全减毒疫苗的合理设计。
- 批准号:
BB/X017540/1 - 财政年份:2023
- 资助金额:
$ 43.87万 - 项目类别:
Research Grant
A “Goldilocks” live attenuated poultry vaccine for Infectious Coryza
用于传染性鼻炎的“Goldilocks”家禽减毒活疫苗
- 批准号:
LP210301365 - 财政年份:2023
- 资助金额:
$ 43.87万 - 项目类别:
Linkage Projects
A novel live-attenuated Zika vaccine with a modified 5'UTR
一种带有改良 5UTR 的新型寨卡减毒活疫苗
- 批准号:
10730832 - 财政年份:2023
- 资助金额:
$ 43.87万 - 项目类别:
Combating melanoma with an attenuated bacterial therapeutic
用减毒细菌疗法对抗黑色素瘤
- 批准号:
10659841 - 财政年份:2023
- 资助金额:
$ 43.87万 - 项目类别:
Investigating Host and Viral Factors for Improved Design of Future Live Attenuated Vaccines for IBV
研究宿主和病毒因素以改进未来 IBV 减毒活疫苗的设计
- 批准号:
BB/V016067/1 - 财政年份:2022
- 资助金额:
$ 43.87万 - 项目类别:
Research Grant
L2M NSERC-Bioengineering attenuated Sclerotinia sclerotiorum strains as bioherbicide for cereal production and lawn management
L2M NSERC-生物工程减毒核盘菌菌株作为谷物生产和草坪管理的生物除草剂
- 批准号:
576545-2022 - 财政年份:2022
- 资助金额:
$ 43.87万 - 项目类别:
Idea to Innovation