In vivo regulation of p53 by MDM2 and MDMX
MDM2 和 MDMX 对 p53 的体内调节
基本信息
- 批准号:9384492
- 负责人:
- 金额:$ 38.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAnimal ModelApoptosisBindingCell Cycle ArrestCell NucleusCytoplasmCytoplasmic ProteinDNA DamageDataDevelopmentEmployee StrikesEnzymesGenesGenetic TranscriptionGenotoxic StressGoalsGrowth and Development functionHeterodimerizationHomologous GeneHomologous ProteinHumanIn VitroIndividualKnock-in MouseMDM2 geneMalignant NeoplasmsMediatingMetabolismMolecularMusMutant Strains MiceMutateMutationOncoproteinsPathway interactionsPhysiologicalPlayPolyubiquitinationPublic HealthRegulationReproductionRing Finger DomainRoleSignaling ProteinSiteTP53 geneTechnologyTestingTherapeuticTransactivationTranslationsTumor Suppressor GenesTumor Suppressor ProteinsUbiquitinationWorkdesigndrug developmentexperimental studyfunctional genomicsin vivoin vivo Modelinnovationinsightmouse modelmutantmutant mouse modelnew therapeutic targetnovelp53 Signaling Pathwaysenescencetranscription factortumor initiationubiquitin-protein ligase
项目摘要
ABSTRACT
The tumor suppressor gene TP53 is the most commonly mutated gene in human cancers. Understanding
the full breadth of p53 function and regulation is crucial to our understanding of tumor initiation and
development. The MDM2 proto-oncoprotein is a primary negative regulator for p53 by promoting p53
polyubiquitination and proteosomal degradation. The MDM2 homologous protein MDMX also functions as a
negative regulator for p53. While many questions remain, a focus on the use of in vivo models is allowing
for a closer view of how this MDM2/MDMX-p53 pathway is regulated, with a newfound emphasis on how
this pathway can be better manipulated for therapeutic gains.
During the last few years, our experiments have been focused on generating and examining MDM2
mutation knock-in mice that are deficient in MDM2 E3 ligase function or MDM2-MDMX binding. We have
generated MDM2C462A and MDM2Y487A mutant mice, both lacking MDM2 E3 ligase function. Studies with the
MDM2C462A mice, which also lack MDM2-MDMX interaction, and the MDM2Y487A mice, which retain MDM2-
MDMX interaction, have generated new insight into the in vivo regulation of p53 by MDM2 E3 ligase and the
MDM2-MDMX heterooligomer.
Recently, we have generated a number of new mouse models expressing an inducible p53 under various
MDM2 and MDMX backgrounds. Our preliminary data generated with these inducible p53 mice have
revealed several surprising findings. We found that MDMX can suppress p53 expression independent of
MDM2 E3 ligase function; we found that in vivo MDMX is required for MDM2 mediated p53 degradation;
and we found that the MDM2C462A mutant has gained a neomorphic function for stimulating p53
transcriptional activity.
Experiments proposed in this application are designed to study (1) whether MDMX regulates p53
expression through modulating its translation; (2) what is the mechanism by which MDMX impacts on
MDM2 mediated p53 degradation; (3) how the RING finger mutant MDM2 gained a function to activate p53.
These experiments provide proof-of-principle evidence for exploring inhibition of MDM2 RING E3 ligase
function and disruption of MDM2-MDMX interaction as potential drug development strategies targeting
cancers expressing high levels of MDM2 and MDMX and WT p53.
摘要
肿瘤抑制基因TP53是人类癌症中最常见的突变基因。理解
P53功能和调控的全部范围对于我们理解肿瘤的发生和发展至关重要。
发展。MDM2原癌蛋白是促进P53的主要负调控因子
多泛素化和蛋白酶体降解。MDM2同源蛋白MDMX也具有
P53的负调控因子。尽管许多问题仍然存在,但对活体模型的使用的关注正在允许
更详细地了解MDM2/MDMX-p53通路是如何调控的,新的重点是如何
这一途径可以被更好地操纵以获得治疗收益。
在过去的几年里,我们的实验一直集中在生成和检查MDM2上
MDM2 E3连接酶功能或MDM2-MDMX结合缺陷的突变敲入小鼠。我们有
获得了MDM2C462A和MDM2Y487A突变小鼠,它们都缺乏MDM2 E3连接酶功能。学习与研究
同样缺乏MDM2-MDMX相互作用的MDM2C462A小鼠和保留MDM2-MDMX-的MDM2Y487A小鼠。
MDMX的相互作用,为MDM2 E3连接酶和MDM2 E3连接酶对p53的体内调控提供了新的见解
MDM2-MDMX杂寡体。
最近,我们已经建立了一些新的小鼠模型,在不同的不同条件下表达可诱导的p53
MDM2和MDMX背景。我们用这些可诱导的p53小鼠产生的初步数据
揭示了几个令人惊讶的发现。我们发现MDMX可以抑制P53的表达,而不是依赖于
MDM2 E3连接酶功能:我们发现在体内,MDM2介导的P53降解需要MDMX;
我们发现MDM2C462a突变体获得了刺激P53的新功能
转录活性。
本申请中提出的实验旨在研究(1)MDMX是否调节P53
MDMX通过调节其翻译来表达;(2)MDMX通过什么机制影响
MDM2介导的P53降解;(3)环指突变体MDM2如何获得激活P53的功能。
这些实验为探索MDM2环E3连接酶的抑制提供了原则证据
MDM2-MDMX相互作用作为潜在靶向药物开发策略的功能和破坏
高表达MDM2、MDMX和WT P53的肿瘤。
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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YANPING ZHANG其他文献
YANPING ZHANG的其他文献
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{{ truncateString('YANPING ZHANG', 18)}}的其他基金
In vivo regulation of p53 by MDM2 and MDMX
MDM2 和 MDMX 对 p53 的体内调节
- 批准号:
10225456 - 财政年份:2017
- 资助金额:
$ 38.47万 - 项目类别:
In vivo regulation of p53 by MDM2 and MDMX
MDM2 和 MDMX 对 p53 的体内调节
- 批准号:
9976986 - 财政年份:2017
- 资助金额:
$ 38.47万 - 项目类别:
Mitochondrial p32 regulation of the Mdm2-p53 tumor suppression signaling and apop
线粒体 p32 对 Mdm2-p53 肿瘤抑制信号和 apop 的调节
- 批准号:
8186498 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
The in vivo role of the Mdm2-MdmX interaction in p53 regulation
Mdm2-MdmX 相互作用在 p53 调节中的体内作用
- 批准号:
8468671 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
Mitochondrial p32 regulation of the Mdm2-p53 tumor suppression signaling and apop
线粒体 p32 对 Mdm2-p53 肿瘤抑制信号和 apop 的调节
- 批准号:
8657900 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
The in vivo role of the Mdm2-MdmX interaction in p53 regulation
Mdm2-MdmX 相互作用在 p53 调节中的体内作用
- 批准号:
8299227 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
Mitochondrial p32 regulation of the Mdm2-p53 tumor suppression signaling and apop
线粒体 p32 对 Mdm2-p53 肿瘤抑制信号和 apop 的调节
- 批准号:
8446316 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
The in vivo role of the Mdm2-MdmX interaction in p53 regulation
Mdm2-MdmX 相互作用在 p53 调节中的体内作用
- 批准号:
8680038 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
Mitochondrial p32 regulation of the Mdm2-p53 tumor suppression signaling and apop
线粒体 p32 对 Mdm2-p53 肿瘤抑制信号和 apop 的调节
- 批准号:
9060280 - 财政年份:2012
- 资助金额:
$ 38.47万 - 项目类别:
In vivo function of Mdm2 E3 ubiquitin ligase
Mdm2 E3 泛素连接酶的体内功能
- 批准号:
7667721 - 财政年份:2008
- 资助金额:
$ 38.47万 - 项目类别:
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