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.
项目总结
项目成果
期刊论文数量(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
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
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
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
结核病监测、预防和控制以及实验室升级
- 批准号:
8009855 - 财政年份:2010
- 资助金额:
$ 43.6万 - 项目类别:
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