The impact of coding region variants on mutant p53 biology
编码区变异对突变 p53 生物学的影响
基本信息
- 批准号:10523512
- 负责人:
- 金额:$ 43.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAfricanAfrican American populationAfrican ancestryAllelesArginineBiochemicalBiologyCancer BiologyCancer Institute of New JerseyChromatin Remodeling FactorClinical TrialsCodeCodon NucleotidesDNA Binding DomainDataETS2 geneFox Chase Cancer CenterGene CombinationsGene ExpressionGenesGenetic PolymorphismGenetic TranscriptionGrowthHumanImpairmentIn VitroInvestigationKnowledgeLearningMalignant NeoplasmsMediatingMediatorMetabolismMinorMissense MutationMolecularMolecular ConformationMutateMutationNeoplasm MetastasisOncogenesOncogenicPTEN genePathogenicityPathway interactionsPharmaceutical PreparationsPopulationPrognosisProlineProtein Degradation InductionProteinsPublishingReportingResearchResearch PersonnelRoleSamplingSingle Nucleotide PolymorphismStructureTP53 geneTestingThe Cancer Genome AtlasTherapeuticTransactivationTumor BiologyTumor SuppressionTumor Suppressor GenesTumor Suppressor ProteinsTumor-DerivedUnderrepresented PopulationsVariantWomanWorkcancer riskcancer therapycaucasian Americanclinically relevantcytotoxicitydesignethnic biasfollow-upfrontierfunctional improvementgain of functiongain of function mutationin vivomalignant breast neoplasmminority health disparitymouse modelmutantmutant mouse modelneoplastic cellnovelpersonalized medicineprotein functionprotein protein interactionrecruittooltreatment responsetumortumor growthtumor metabolismtumor progression
项目摘要
Project Summary
It is now well accepted that tumor-derived mutant forms of p53 are potently oncogenic. Silencing mutant
p53, or inducing the degradation of this protein, can markedly impair tumor growth in vitro and tumor
progression in vivo. The ability of mutant p53 to drive tumor progression is frequently mediated by protein-
protein interaction, and this is often referred to as the “gain of function” (GOF) activity of mutant p53. One
of our gaps in knowledge has been the identification of key GOF activities of mutant p53. Another has
been investigation into how coding region SNPs (single nucleotide polymorphisms) in p53 influence the
mutant p53 GOF. One of the Holy Grails of cancer biology has been the identification of compounds that
can reactivate the p53 pathway in tumors containing mutant p53, by refolding mutant forms of p53 into wild
type conformation and activity. Several groups have reported the identification of compounds that act in
these ways. Another key gap in our knowledge has been how coding region SNPs (single nucleotide
polymorphisms) in p53 impact the folding of mutant p53, and the efficacy of compounds that refold mutant
p53.
In this application, we take aim at two coding region SNPs in p53: Pro72Arg and Tyr107His. We recently
published that the codon 72 variation is a potent intragenic modifier of mutant p53 GOF. Specifically, the
Arg (R72) variant of mutant p53 is a superior mediator of tumor cell invasiveness and is associated with
poor prognosis in women with breast cancer. We will delve into an investigation of the influence of this
SNP on mutant p53 GOF, using novel mouse models for the R175H mutation, containing either P72 or
R72. We will learn their impact on p53 structure using NMR, and on their influence on the efficacy of p53-
refolding compounds. This aim constitutes a structural, molecular and in vivo analysis of the codon 72
SNP of mutant p53.
We have obtained data that the Y017H variant of p53 alters the structure and activity of this protein. We
will explore the effect of this African-specific SNP on p53 function in a novel mouse model. We have
identified genes with impaired transactivation by Y107H, including the chromatin modifier PADI4;; we will
explore its impact on p53 function and tumor suppression. In sum, for both aims we employ a combination
of gene expression, protein-protein interaction, cytotoxicity and novel mouse models. We have recruited
expert collaborators like Donna George (Penn), John Karanicolas (Fox Chase Cancer Center) and
Darren Carpizo (Rutgers-Cancer Institute of New Jersey). These Investigators bring to bear their
complimentary expertise to address an important and clinically-relevant question: how can we better
harness p53 to eradicate cancer.
项目摘要
现在公认的是,肿瘤细胞衍生的p53突变形式具有潜在的致癌性。
p53或诱导该蛋白降解可显著损害体外肿瘤生长,
突变型p53驱动肿瘤进展的能力通常是由蛋白质表达介导的。
蛋白质相互作用,并且这通常被称为突变体p53的“功能获得”(GOF)活性。
我们知识上的一个空白是突变型p53的关键GOF活性的鉴定。 另一个有
研究了p53基因编码区的单核苷酸多态性(single nucleotide polymorphism,SNPs)如何影响
癌症生物学的圣杯之一是鉴定出
通过将突变形式的p53重折叠成野生型,
型构象和活性。 几个小组已经报道了鉴定出的化合物,
这些方式。 我们知识中的另一个关键空白是编码区SNP(单核苷酸)
p53中的多态性)影响突变型p53的折叠以及重新折叠突变型p53的化合物的功效
第53页。
在本申请中,我们针对p53中的两个编码区SNP:Pro72 Arg和Tyr 107 His。
已经公开了密码子72变异是突变型p53 GOF的有效基因内修饰剂。
突变型p53的Arg(R72)变体是肿瘤细胞侵袭性的上级介导物,并且与
乳腺癌患者的预后差。 我们将深入调查这一影响,
突变型p53 GOF上的SNP,使用R175 H突变的新型小鼠模型,含有P72或
我们将使用NMR来了解它们对p53结构的影响,以及它们对p53-R72的功效的影响。
重折叠化合物 这一目标构成了密码子72的结构、分子和体内分析
突变型p53的SNP。
我们已经获得了p53的Y 017 H变体改变该蛋白质的结构和活性的数据。
将在一种新的小鼠模型中探索这种非洲人特有的SNP对p53功能的影响。 我们有
确定了Y107 H反式激活受损的基因,包括染色质修饰剂PADI 4;
探索其对p53功能和肿瘤抑制的影响。总而言之,为了这两个目标,我们采用了组合
基因表达,蛋白质-蛋白质相互作用,细胞毒性和新的小鼠模型。
专家合作者,如唐娜乔治(宾夕法尼亚大学),约翰卡拉尼科拉斯(福克斯大通癌症中心)和
Darren Carpizo(Rutgers-Cancer Institute of新泽西). 这些调查人员将承担他们的
免费的专业知识,以解决一个重要的和临床相关的问题:我们如何才能更好地
利用p53来根除癌症
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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Maureen E. Murphy其他文献
RETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance
撤回文章:IspH 抑制剂杀死革兰氏阴性菌并动员免疫清除
- DOI:
10.1038/s41586-020-03074-x - 发表时间:
2020-12-23 - 期刊:
- 影响因子:48.500
- 作者:
Kumar Sachin Singh;Rishabh Sharma;Poli Adi Narayana Reddy;Prashanthi Vonteddu;Madeline Good;Anjana Sundarrajan;Hyeree Choi;Kar Muthumani;Andrew Kossenkov;Aaron R. Goldman;Hsin-Yao Tang;Maxim Totrov;Joel Cassel;Maureen E. Murphy;Rajasekharan Somasundaram;Meenhard Herlyn;Joseph M. Salvino;Farokh Dotiwala - 通讯作者:
Farokh Dotiwala
Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex
线粒体 p53 激活 Bak 并导致 Bak-Mcl1 复合物的破坏
- DOI:
10.1038/ncb1123 - 发表时间:
2004-04-11 - 期刊:
- 影响因子:19.100
- 作者:
J. I-Ju Leu;Patrick Dumont;Michael Hafey;Maureen E. Murphy;Donna L. George - 通讯作者:
Donna L. George
Kaposi’s sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production
卡波西肉瘤相关疱疹病毒诱导线粒体分裂以逃避宿主免疫反应并促进病毒产生
- DOI:
10.1038/s41564-025-02018-3 - 发表时间:
2025-05-22 - 期刊:
- 影响因子:19.400
- 作者:
Qing Zhu;Robert McElroy;Janvhi Suresh Machhar;Joel Cassel;Zihan Zheng;Behzad Mansoori;Hongrui Guo;Sen Guo;Christian Pangilinan;Jinghui Liang;Dongliang Shen;Lu Zhang;Qin Liu;Andrew V. Kossenkov;Dario C. Altieri;Paul M. Lieberman;Shou-Jiang Gao;Pinghui Feng;Maureen E. Murphy;Jikui Song;Joseph M. Salvino;Qiming Liang;Jae U. Jung;Chengyu Liang - 通讯作者:
Chengyu Liang
Maureen E. Murphy的其他文献
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{{ truncateString('Maureen E. Murphy', 18)}}的其他基金
Functional Analysis of p53 Polymorphic Variants - Diversity Supplement
p53 多态性变体的功能分析 - Diversity Supplement
- 批准号:
10818904 - 财政年份:2023
- 资助金额:
$ 43.6万 - 项目类别:
Purchase of a SARRP 200 Platform for Irradiation
购买 SARRP 200 辐照平台
- 批准号:
10430904 - 财政年份:2022
- 资助金额:
$ 43.6万 - 项目类别:
The impact of coding region variants on mutant p53 biology
编码区变异对突变 p53 生物学的影响
- 批准号:
10304135 - 财政年份:2019
- 资助金额:
$ 43.6万 - 项目类别:
The impact of coding region variants on mutant p53 biology
编码区变异对突变 p53 生物学的影响
- 批准号:
9914543 - 财政年份:2019
- 资助金额:
$ 43.6万 - 项目类别:
The impact of coding region variants on mutant p53 biology
编码区变异对突变 p53 生物学的影响
- 批准号:
10063505 - 财政年份:2019
- 资助金额:
$ 43.6万 - 项目类别:
Tuberculosis Surveillance, Prevention and Control, and Laboratory Upgrade
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8009855 - 财政年份:2010
- 资助金额:
$ 43.6万 - 项目类别:
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