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

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.
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Hua Lu其他文献

Hua Lu的其他文献

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{{ 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:
The Eighth International Mdm2 Workshop
第八届国际Mdm2研讨会
  • 批准号:
    9022188
  • 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:

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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
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