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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：
Hua Lu
金额：
$ 35.4万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
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：
https://reporter.nih.gov/project-details/10543734
关键词：
Address Aflatoxin B1 Area Asia Automobile Driving Binding Biochemical Biogenesis Biological CDK4 gene Cell Cycle Cell Cycle Progression Cell Nucleus Cell Proliferation Cell Survival Cells Central Africa China Clinical Trials Combined Modality Therapy Cyclin D1 Development Diagnosis Disseminated Malignant Neoplasm Dominant-Negative Mutation Drug resistance Exposure to FBXW7 gene Future Gene Expression Genes Genetic Genetic Transcription Genomics Goals Growth HBV and Aflatoxin Hepatitis B Infection Hepatitis B Virus Hot Spot Human Invaded Knock-in Knock-in Mouse Knowledge Light Link Liver Malignant Epithelial Cell Malignant Neoplasms Manuscripts Mediating Molecular Molecular Target Mus Mutate Mutation NIMA Nuclear Nuclear Import Oncogenic Oncoproteins Pathway interactions Patients Peptidylprolyl Isomerase Phosphorylation Phosphotransferases Play Primary carcinoma of the liver cells Proliferating Protein Biosynthesis Publishing Research Ribosomes Role Sequence Analysis Signal Pathway TP53 gene Testing Transcript Tumor Suppressor Genes c-myc Genes cancer cell cancer stem cell cancer therapy cell growth cis-trans-Isomerases cohort combinatorial design dietary exposed human population gain of function insight loss of function mutant programs rational design stem cell division transcription factor tumorigenesis

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：
Biochemical and biophysical research communications
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.