The Role of p53-R249S’s GOF in HCC development
p53-R249S GOF 在 HCC 发展中的作用
基本信息
- 批准号:10543734
- 负责人:
- 金额:$ 35.4万
- 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:2019-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAflatoxin B1AreaAsiaAutomobile DrivingBindingBiochemicalBiogenesisBiologicalCDK4 geneCell CycleCell Cycle ProgressionCell NucleusCell ProliferationCell SurvivalCellsCentral AfricaChinaClinical TrialsCombined Modality TherapyCyclin D1DevelopmentDiagnosisDisseminated Malignant NeoplasmDominant-Negative MutationDrug resistanceExposure toFBXW7 geneFutureGene ExpressionGenesGeneticGenetic TranscriptionGenomicsGoalsGrowthHBV and AflatoxinHepatitis B InfectionHepatitis B VirusHot SpotHumanInvadedKnock-inKnock-in MouseKnowledgeLightLinkLiverMalignant Epithelial CellMalignant NeoplasmsManuscriptsMediatingMolecularMolecular TargetMusMutateMutationNIMANuclearNuclear ImportOncogenicOncoproteinsPathway interactionsPatientsPeptidylprolyl IsomerasePhosphorylationPhosphotransferasesPlayPrimary carcinoma of the liver cellsProliferatingProtein BiosynthesisPublishingResearchRibosomesRoleSequence AnalysisSignal PathwayTP53 geneTestingTranscriptTumor Suppressor Genesc-myc Genescancer cellcancer stem cellcancer therapycell growthcis-trans-Isomerasescohortcombinatorialdesigndietaryexposed human populationgain of functioninsightloss of functionmutantprogramsrational designstem cell divisiontranscription factortumorigenesis
项目摘要
Project Summary
This application is proposed to determine the biological role of a specific p53 mutant, R249S (p53-RS), whose
Arg 249 is substituted by Ser, in development and progression of hepatocellular carcinoma (HCC) and to
divulge molecular mechanisms underlying its gain of function (GOF) crucial for its oncogenic role. Remarkably,
p53-RS is highly associated with HCC patients who are often exposed to dietary aflatoxin B1 (AFB1) and
infected with Hepatitis Virus B (HBV) in Asia and central Africa, as it is the only hotspot p53 mutation identified
among HCC patients. Since genetic knockin of mouse R246S (equivalent to human R249S) without any
oncogenic challenges only showed its loss of function (LOF) and dominant negative (DN) effect on cancer
development without any GOF activity, it has still remained elusive if p53-RS possesses GOF activity important
for proliferation, invasion and tumorigenesis of HCC. If so, what would be the underlying mechanism for this
GOF activity. Our recent studies uncovered the unique link of a cell cycle-regulated kinase, CDK4, Cyclin
D1(CycD1), a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), and an oncoprotein c-Myc with the
GOF activity of p53-RS. All of these four oncoproteins, CDK4, CycD1, PIN1, and c-Myc play critical roles in the
cell cycle progression and cancer cell proliferation and growth, and are highly expressed in various types of
human cancers, including HCC. Our preliminary and published studies showed that CDK4/CycD1 can
specifically bind to and phosphorylate p53-RS at its HCC-derived Ser249, and this phosphorylation facilitates
p53-RS's PIN1 binding and subsequent nuclear localization. In the nucleus, p53-RS binds to and stabilizes c-
Myc by blocking FBW7-mediated degradation, consequently leading to c-Myc activation and increase of
synthesis of ribosomal proteins-encoded transcripts. Through these actions, p53-RS executes its GOFs activity
crucial for HCC cell proliferation and survival. In light of our preliminary results, we hypothesize a unique
mechanism for this p53 mutant's GOF, i.e., substitution of Arg249 with Ser renders this mutant to a new
phospohorylation substrate for CDK4/CycD1 during the cell cycle, and phosphorylation at this residue makes
p53-RS more accessible for PIN1-binding; As a result, PIN1 facilitates the transport of this mutant p53 to the
nucleus where it promotes HCC proliferation by binding to and activating c-Myc, promoting HCC development
and progression. We will test this hypothesis by addressing two specific aims: 1) To further decipher
biochemical mechanisms underlying the GOF of p53-RS in HCC; 2) To determine if p53-RS's GOF plays
a role in HBV-associated HCC development. Completing these comprehensive studies would gain critical
information for our better understanding of the unique signaling pathway underlying p53-RS's GOF in HCC
development and progression, and also unveil CDK4/CycD1, PIN1 and c-Myc as molecular targets for
developing a more effective combinatorial therapy for HCCs that harbor p53-RS.
项目总结
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Crotonylation at serine 46 impairs p53 activity.
- DOI:10.1016/j.bbrc.2020.01.152
- 发表时间:2020-04-09
- 期刊:
- 影响因子:3.1
- 作者:Liao P;Bhattarai N;Cao B;Zhou X;Jung JH;Damera K;Fuselier TT;Thareja S;Wimley WC;Wang B;Zeng SX;Lu H
- 通讯作者:Lu H
Role of c-Myc in lung cancer: Progress, challenges, and prospects.
- DOI:10.1016/j.pccm.2023.07.001
- 发表时间:2023-09
- 期刊:
- 影响因子:0
- 作者:Wallbillich, Nicholas J;Lu, Hua
- 通讯作者:Lu, Hua
{{
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 }}
Hua Lu其他文献
Hua Lu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('Hua Lu', 18)}}的其他基金
Validating p53 Ser46 crotonylation as a potential target for possible anti-cancer therapy
验证 p53 Ser46 巴豆酰化作为可能的抗癌治疗的潜在靶点
- 批准号:
10492834 - 财政年份:2022
- 资助金额:
$ 35.4万 - 项目类别:
Validating p53 Ser46 crotonylation as a potential target for possible anti-cancer therapy
验证 p53 Ser46 巴豆酰化作为可能的抗癌治疗的潜在靶点
- 批准号:
10671541 - 财政年份:2022
- 资助金额:
$ 35.4万 - 项目类别:
Digital Nanoplasmonic Quantification of Tumor-derived Extracellular Vesicles in Plasma Microsamples
血浆微样品中肿瘤源性细胞外囊泡的数字纳米等离子体定量
- 批准号:
10037327 - 财政年份:2020
- 资助金额:
$ 35.4万 - 项目类别:
The Role of p53-R249S’s GOF in HCC development
p53-R249S GOF 在 HCC 发展中的作用
- 批准号:
10317044 - 财政年份:2019
- 资助金额:
$ 35.4万 - 项目类别:
Role of the AMPK-MDMX-p53 pathway in cancer
AMPK-MDMX-p53 通路在癌症中的作用
- 批准号:
9753938 - 财政年份:2019
- 资助金额:
$ 35.4万 - 项目类别:
Targeting GRP78 for p53 activation as anti-cancer therapy
靶向 GRP78 激活 p53 作为抗癌疗法
- 批准号:
9008031 - 财政年份:2015
- 资助金额:
$ 35.4万 - 项目类别:
Dual Targeting of the p53 pathway for development of anti-cancer therapy
双重靶向 p53 通路以开发抗癌疗法
- 批准号:
9102015 - 财政年份:2012
- 资助金额:
$ 35.4万 - 项目类别:
Dual Targeting of the p53 pathway for development of anti-cancer therapy
双重靶向 p53 通路以开发抗癌疗法
- 批准号:
8551655 - 财政年份:2012
- 资助金额:
$ 35.4万 - 项目类别:
Dual Targeting of the p53 pathway for development of anti-cancer therapy
双重靶向 p53 通路以开发抗癌疗法
- 批准号:
8421099 - 财政年份:2012
- 资助金额:
$ 35.4万 - 项目类别:
相似海外基金
Early life aflatoxin B1 exposure and epigenetic programming in Nigerian Newborns
尼日利亚新生儿生命早期黄曲霉毒素 B1 暴露和表观遗传编程
- 批准号:
10518414 - 财政年份:2022
- 资助金额:
$ 35.4万 - 项目类别:
Early life aflatoxin B1 exposure and epigenetic programming in Nigerian Newborns
尼日利亚新生儿生命早期黄曲霉毒素 B1 暴露和表观遗传编程
- 批准号:
10706327 - 财政年份:2022
- 资助金额:
$ 35.4万 - 项目类别:
Aflatoxin B1 hepatocarcinogenesis in the mGSTA3-/- mouse
黄曲霉毒素 B1 在 mGSTA3-/- 小鼠中的肝癌发生
- 批准号:
8827703 - 财政年份:2012
- 资助金额:
$ 35.4万 - 项目类别:
Aflatoxin B1 hepatocarcinogenesis in the mGSTA3-/- mouse
黄曲霉毒素 B1 在 mGSTA3-/- 小鼠中的肝癌发生
- 批准号:
9031727 - 财政年份:2012
- 资助金额:
$ 35.4万 - 项目类别:
Aflatoxin B1 hepatocarcinogenesis in the mGSTA3-/- mouse
黄曲霉毒素 B1 在 mGSTA3-/- 小鼠中的肝癌发生
- 批准号:
8629710 - 财政年份:2012
- 资助金额:
$ 35.4万 - 项目类别:
Aflatoxin B1 hepatocarcinogenesis in the mGSTA3-/- mouse
黄曲霉毒素 B1 在 mGSTA3-/- 小鼠中的肝癌发生
- 批准号:
8293559 - 财政年份:2012
- 资助金额:
$ 35.4万 - 项目类别:
Aflatoxin B1 hepatocarcinogenesis in the mGSTA3-/- mouse
黄曲霉毒素 B1 在 mGSTA3-/- 小鼠中的肝癌发生
- 批准号:
8464677 - 财政年份:2012
- 资助金额:
$ 35.4万 - 项目类别:
Monoclonal antibody-based electronic immunosensor for the determination of aflatoxin B1
基于单克隆抗体的电子免疫传感器测定黄曲霉毒素B1
- 批准号:
412237-2010 - 财政年份:2011
- 资助金额:
$ 35.4万 - 项目类别:
Engage Grants Program
Increased Nucleotide Excision Repair Activity of Aflatoxin-B1-N7-Guanine Adducts but not Aflatoxin-B1-Formamidopyrimidine Adducts in Livers of Mice Exposed Chronically to Aflatoxin-B1
长期暴露于黄曲霉毒素-B1 的小鼠肝脏中黄曲霉毒素-B1-N7-鸟嘌呤加合物的核苷酸切除修复活性增加,但黄曲霉毒素-B1-甲酰胺嘧啶加合物的核苷酸切除修复活性不增加
- 批准号:
240887 - 财政年份:2011
- 资助金额:
$ 35.4万 - 项目类别:
Modulation of Aflatoxin B1-induced hepatocarcinogenesis by RB loss
通过 RB 损失调节黄曲霉毒素 B1 诱导的肝癌发生
- 批准号:
7225591 - 财政年份:2006
- 资助金额:
$ 35.4万 - 项目类别: