Functional analysis of beta-TRCP in cell cycle control and DNA damage response

β-TRCP 在细胞周期控制和 DNA 损伤反应中的功能分析

基本信息

  • 批准号:
    8792536
  • 负责人:
  • 金额:
    $ 32.84万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-05-01 至 2017-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Aberrant regulation of cell cycle progression results in genomic instability that ultimately leads to cancer development. Proper cell cycle transitions are driven by coordinated waves of ubiquitin-dependent degradation of key cell cycle regulators by APC and SCF, the two major E3 ubiquitin ligase complexes. However, the critical mechanisms mediating ordered SCF and APC activities have not yet been identified. Previously we demonstrated that the APC/Cdh1 complex ubiquitinates and thus targets the SCF component Skp2 for degradation, hence gaining important insight as to why SCF and APC activities are mutually exclusive. More recently, we accumulated evidence suggesting that the F-box protein ß-TRCP can target Cdh1 for degradation, thereby creating a negative feedback loop to repress APC activity. This finding extends our understanding of the underlying mechanisms that tightly orchestrate the activity of the SCF and APC complexes. In Specific Aim #1, we will utilize both genetic and biochemical approaches to explore the underlying molecular mechanisms through which ß-TRCP controls Cdh1 abundance and activity. We will further define how sequential phosphorylation of Cdh1 by Cyclin A/Cdk2 and Plk1 triggers the interaction with, and subsequent ubiquitination, by ß-TRCP. The proposed studies are expected to reveal the important function of ß-TRCP in governing S phase entry via timely destruction of Cdh1. Recent studies indicate that beside its cell cycle regulatory function, ß-TRCP has also emerged as a critical player in S and G2 DNA damage response checkpoints, mainly through destruction of its downstream targets Cdc25A and Claspin. However, further investigation will be necessary to fully understand the function of ß-TRCP in DNA damage response, especially in the regulation of the G1 damage response checkpoint, primarily regulated by the p53 pathway. Mdm2 is the major negative regulator of p53 and frequently overexpressed in tumors, yet the underlying mechanisms are unclear. We recently reported that SCFß-TRCP is a novel E3 ubiquitin ligase targeting Mdm2 for ubiquitination and destruction in a CK1δ-dependent manner. But it remains largely unknown how CK1δ is activated following DNA damage to govern the Mdm2/p53 pathway. In Specific Aim #2, we intend to continue this innovative research by using multi-disciplinary approaches to investigate how ATM modulates Mdm2 stability by regulating CK1δ activity and cellular localization. We will also examine whether Mdm2 is the primary physiological signaling pathway by which ß-TRCP regulates the p53 pathway to govern the DNA damage response, and whether non-degradable Mdm2 (Δp1-23A) displays elevated oncogenic activities. Moreover, we will explore whether clinically, disruption of the components of Mdm2 destruction pathways (ß-TRCP/ATM/CK1δ) facilitates tumorigenesis, which may be responsible for Mdm2 accumulation often seen in tumors. Our proposed studies will provide new insight into the signaling pathways controlling Mdm2 destruction. It also provides the rationale for developing CKI and ATM agonists as anti-cancer agents.
描述(由申请人提供):细胞周期进程的异常调节导致基因组不稳定,最终导致癌症发展。适当的细胞周期转换是由两个主要的E3泛素连接酶复合物APC和SCF对关键细胞周期调节因子的泛素依赖性降解的协调波驱动的。然而,介导有序SCF和APC活动的关键机制尚未确定。以前,我们证明了APC/Cdh 1复合物泛素化,从而靶向SCF组分Skp 2降解,从而获得重要的见解,为什么SCF和APC活动是相互排斥的。最近,我们积累的证据表明,F-box蛋白的CDH-TRCP可以靶向Cdh 1降解,从而创建一个负反馈回路,抑制APC活性。这一发现扩展了我们对紧密协调SCF和APC复合物活性的潜在机制的理解。在具体目标#1中,我们将利用遗传和生物化学方法来探索潜在的分子机制,通过该机制,CDH-TRCP控制Cdh 1丰度和活性。我们将进一步确定如何依次磷酸化Cdh 1的细胞周期蛋白A/Cdk 2和Plk 1触发的相互作用,并随后泛素化,通过β-TRCP。拟议的研究预计将揭示 通过及时销毁Cdh 1,TRCP在管理S阶段进入方面的作用。最近的研究表明,除了其细胞周期调节功能,β-TRCP也已成为S和G2 DNA损伤反应检查点的关键参与者,主要通过破坏其下游靶标Cdc 25 A和Claspin。然而,需要进一步调查,以充分了解 β-TRCP在DNA损伤反应中,尤其是在G1期损伤反应检查点的调控中,主要受p53通路的调控。mdm 2是p53的主要负调控因子,在肿瘤中经常过度表达,但其潜在机制尚不清楚。我们最近报道了SCF-TRCP是一种新的E3泛素连接酶,以CK 1 δ依赖的方式靶向Mdm 2进行泛素化和破坏。但在DNA损伤后,CK 1 δ是如何被激活以控制Mdm 2/p53通路的,这在很大程度上仍然是未知的。在具体目标#2中,我们打算通过使用多学科方法来研究ATM如何通过调节CK 1 δ活性和细胞定位来调节Mdm 2稳定性,从而继续这项创新研究。我们还将研究Mdm 2是否是β-TRCP调节p53通路以控制DNA损伤反应的主要生理信号通路,以及不可降解的Mdm 2(Δp1- 23 A)是否显示出升高的致癌活性。此外,我们将探索在临床上,Mdm 2破坏途径的组分(β-TRCP/ATM/CK 1 δ)的破坏是否促进肿瘤发生,这可能是肿瘤中常见的Mdm 2积累的原因。我们提出的研究将为控制Mdm 2破坏的信号通路提供新的见解。它还提供了开发CKI和ATM激动剂作为抗癌剂的基本原理。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Targeting Cdc20 as a novel cancer therapeutic strategy.
  • DOI:
    10.1016/j.pharmthera.2015.04.002
  • 发表时间:
    2015-07
  • 期刊:
  • 影响因子:
    13.5
  • 作者:
    Wang, Lixia;Zhang, Jinfang;Wan, Lixin;Zhou, Xiuxia;Wang, Zhiwei;Wei, Wenyi
  • 通讯作者:
    Wei, Wenyi
Functional analysis of Cullin 3 E3 ligases in tumorigenesis.
Biochemical Aspects of PD-L1 Regulation in Cancer Immunotherapy.
  • DOI:
    10.1016/j.tibs.2018.09.004
  • 发表时间:
    2018-12
  • 期刊:
  • 影响因子:
    13.8
  • 作者:
    Zhang J;Dang F;Ren J;Wei W
  • 通讯作者:
    Wei W
Ubiquitination-mediated degradation of cell cycle-related proteins by F-box proteins.
SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination.
  • DOI:
    10.18632/oncotarget.1971
  • 发表时间:
    2014-06-30
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Wu X;Fukushima H;North BJ;Nagaoka Y;Nagashima K;Deng F;Okabe K;Inuzuka H;Wei W
  • 通讯作者:
    Wei W
{{ 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 }}

Wenyi Wei其他文献

Wenyi Wei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('Wenyi Wei', 18)}}的其他基金

Deciphering the physiological role and interplay between ubiquitination and phosphorylation pathways to guide targeted cancer therapies
破译泛素化和磷酸化途径之间的生理作用和相互作用,以指导靶向癌症治疗
  • 批准号:
    10240580
  • 财政年份:
    2020
  • 资助金额:
    $ 32.84万
  • 项目类别:
Deciphering the physiological role and interplay between ubiquitination and phosphorylation pathways to guide targeted cancer therapies
破译泛素化和磷酸化途径之间的生理作用和相互作用,以指导靶向癌症治疗
  • 批准号:
    10663923
  • 财政年份:
    2020
  • 资助金额:
    $ 32.84万
  • 项目类别:
Deciphering the physiological role and interplay between ubiquitination and phosphorylation pathways to guide targeted cancer therapies
破译泛素化和磷酸化途径之间的生理作用和相互作用,以指导靶向癌症治疗
  • 批准号:
    10456316
  • 财政年份:
    2020
  • 资助金额:
    $ 32.84万
  • 项目类别:
Integrative Characterization on the function of COPD GWAS gene, HHIP
COPD GWAS 基因 HHIP 功能的综合表征
  • 批准号:
    9886349
  • 财政年份:
    2020
  • 资助金额:
    $ 32.84万
  • 项目类别:
Integrative Characterization on the function of COPD GWAS gene, HHIP
COPD GWAS 基因 HHIP 功能的综合表征
  • 批准号:
    10379283
  • 财政年份:
    2020
  • 资助金额:
    $ 32.84万
  • 项目类别:
Integrative Characterization on the function of COPD GWAS gene, HHIP
COPD GWAS 基因 HHIP 功能的综合表征
  • 批准号:
    10598541
  • 财政年份:
    2020
  • 资助金额:
    $ 32.84万
  • 项目类别:
Targeting the APC/Cdc20 E3 ubiquitin ligase for chemoradiation sensitization
靶向 APC/Cdc20 E3 泛素连接酶进行放化疗增敏
  • 批准号:
    9285774
  • 财政年份:
    2016
  • 资助金额:
    $ 32.84万
  • 项目类别:
Characterizing the signaling pathways that regulate Skp2 oncogenic function
表征调节 Skp2 致癌功能的信号通路
  • 批准号:
    9172846
  • 财政年份:
    2016
  • 资助金额:
    $ 32.84万
  • 项目类别:
Targeting the APC/Cdc20 E3 ubiquitin ligase for chemoradiation sensitization
靶向 APC/Cdc20 E3 泛素连接酶进行放化疗增敏
  • 批准号:
    9922891
  • 财政年份:
    2016
  • 资助金额:
    $ 32.84万
  • 项目类别:
Characterizing the signaling pathways that regulate Skp2 oncogenic function
表征调节 Skp2 致癌功能的信号通路
  • 批准号:
    9918851
  • 财政年份:
    2016
  • 资助金额:
    $ 32.84万
  • 项目类别:

相似海外基金

Delays in Acquisition of Oral Antineoplastic Agents
口服抗肿瘤药物的获取延迟
  • 批准号:
    9975367
  • 财政年份:
    2020
  • 资助金额:
    $ 32.84万
  • 项目类别:
Eliminate the difficulty of venous puncture in patients receiving antineoplastic agents - Development of a new strategy for the prevention of induration-
消除接受抗肿瘤药物的患者静脉穿刺的困难 - 制定预防硬结的新策略 -
  • 批准号:
    16K11932
  • 财政年份:
    2016
  • 资助金额:
    $ 32.84万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanisms of the antineoplastic agents inhibiting DNA replication and their applications to cancer patient treatmen
抗肿瘤药物抑制DNA复制的分子机制及其在癌症患者治疗中的应用
  • 批准号:
    19591274
  • 财政年份:
    2007
  • 资助金额:
    $ 32.84万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
PNET EXPERIMENTAL THERAPEUTICS--ANTINEOPLASTIC AGENTS AND TREATMENT DELIVERY
PNET 实验治疗——抗肿瘤药物和治疗实施
  • 批准号:
    6346309
  • 财政年份:
    2000
  • 资助金额:
    $ 32.84万
  • 项目类别:
TRAINING IN PHARMACOLOGY OF ANTINEOPLASTIC AGENTS
抗肿瘤药物药理学培训
  • 批准号:
    2720213
  • 财政年份:
    1999
  • 资助金额:
    $ 32.84万
  • 项目类别:
TRAINING IN PHARMACOLOGY OF ANTINEOPLASTIC AGENTS
抗肿瘤药物药理学培训
  • 批准号:
    6513197
  • 财政年份:
    1999
  • 资助金额:
    $ 32.84万
  • 项目类别:
Training in Pharmacology of Antineoplastic Agents
抗肿瘤药物药理学培训
  • 批准号:
    7101017
  • 财政年份:
    1999
  • 资助金额:
    $ 32.84万
  • 项目类别:
Training in Pharmacology of Antineoplastic Agents
抗肿瘤药物药理学培训
  • 批准号:
    6894842
  • 财政年份:
    1999
  • 资助金额:
    $ 32.84万
  • 项目类别:
TYROSINE KINASE INHIBITORS AS ANTINEOPLASTIC AGENTS
酪氨酸激酶抑制剂作为抗肿瘤剂
  • 批准号:
    2885074
  • 财政年份:
    1999
  • 资助金额:
    $ 32.84万
  • 项目类别:
TYROSINE KINASE INHIBITORS AS ANTINEOPLASTIC AGENTS
酪氨酸激酶抑制剂作为抗肿瘤剂
  • 批准号:
    6174221
  • 财政年份:
    1999
  • 资助金额:
    $ 32.84万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了