Restore the Tumor-Suppressive Activities of p53 Mutants

恢复 p53 突变体的肿瘤抑制活性

基本信息

  • 批准号:
    10716397
  • 负责人:
  • 金额:
    $ 37.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-01 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract This project is focused on reactivation of p53 mutants by peptidase D (PEPD). p53 tumor suppressor is the most frequently mutated protein in cancer. Most p53 mutations are missense mutations, causing a single amino acid change in each mutant, and are clustered within its DNA binding domain. p53 mutations nullify its tumor suppressor functions and/or endow oncogenic functions. PEPD, also known as prolidase, is a dipeptidase important for collagen metabolism. However, we recently found that PEPD binds to both wild- type p53 (p53WT) and various mutants via their proline-rich domain (PRD) and that disrupting the binding by PEPD knockdown (KD) not only activates p53WT but also reactivates its mutants. This is a novel function of PEPD, which does not require its enzymatic activity. Our long-term goal is to advance the understanding of regulation and function of p53WT and its mutants. The objective of the present proposal is to delineate the reactivation of oncogenic hotspot p53 mutants by PEPD KD and to assess the tumor-suppressing activities of the reactivated p53 mutants. The central hypothesis of the proposal is that PEPD binds to nearly half of each p53 mutant in cells and that, while PEPD is not required for their oncogenic activities, disrupting PEPD binding to p53 mutants induces post-translational modifications (PTMs) of the mutants that cause their refolding and reactivation. We will test the hypothesis in three specific aims: 1) to determine binding of p53 mutants to PEPD and their reactivation by PEPD KD; 2) to determine the molecular mechanism by which PEPD KD reactivates p53 mutants, focusing on the roles of PTMs, K373 acetylation in particular, in driving refolding and reactivation of the mutants; 3) to determine the tumor-inhibitory activities of the reactivated p53 mutants. We will pursue these aims by focusing on some of the most common oncogenic p53 mutants in cancer, including conformation mutants (R175H, G245C, and R249S) and contact mutants (R248Q, R273H, and R280K). Cell lines and mouse tumor models, including patient-derived xenografts, will be used. PEPD KD will be achieved using siRNA and a doxycycline-regulated system. The proposed research is significant, because it may bring about a paradigm shift in understanding of the biology and regulation of p53 mutants, which in turn may offer innovative cancer treatment strategies. The expected outcome of this project includes: 1) showing that PEPD binds to nearly half of each p53 mutant in the nucleus and cytosol; 2) showing that disrupting the PEPD-p53 mutant complex by PEPD KD frees the mutant for PTMs which drive refolding and reactivation of the mutant, whether it is a conformation mutant or a contact mutant, and K373 acetylation by p300/CBP is key to this process; and 3) showing that the tumor-suppressive activities of the reactivated p53 mutants are similar to that of activated p53WT. As such, our research will bring to light a critical intrinsic reactivation mechanism of p53 mutants, which may have far-reaching implications in p53 research and may break new ground for developing novel cancer therapeutic strategies.
项目摘要/摘要 该项目的重点是通过肽酶D(PEPD)重新激活p53突变体。 p53肿瘤抑制剂是 癌症中最常见的突变蛋白。大多数p53突变是错义突变,导致一个 每个突变体的氨基酸变化,并聚集在其DNA结合结构域中。 p53突变无效 它的肿瘤抑制功能和/或endow肿瘤功能。 PEPD,也称为衍生酶,是 二肽酶对胶原蛋白代谢很重要。但是,我们最近发现PEPD与两个野生结合 p53型(p53wt)和各种突变体通过其富含脯氨酸的结构域(PRD),并破坏结合的结合 PEPD敲低(KD)不仅激活p53wt,而且重新激活其突变体。这是一个新颖的功能 PEPD,不需要其酶活性。我们的长期目标是提高对 p53wt及其突变体的调节和功能。本提案的目的是描述 通过PEPD KD重新激活致癌热点P53突变体,并评估肿瘤抑制活性 重新激活的p53突变体。该提案的中心假设是PEPD结合了近一半 细胞中的每个p53突变体,尽管其致癌活动并不需要PEPD,但仍破坏了PEPD 与p53突变体的结合诱导突变体的翻译后修饰(PTM)引起其 重折叠和重新激活。我们将以三个特定目的测试假设:1)确定p53的结合 PEPD的突变体及其通过PEPD KD重新激活; 2)确定分子机制 PEPD KD重新激活p53突变体,尤其是PTM的作用,特别是K373乙酰化的作用,在驱动 突变体的重折叠和重新激活; 3)确定重新激活的肿瘤抑制活性 p53突变体。我们将通过关注一些最常见的致癌p53突变体来追求这些目标 在癌症中,包括构象突变体(R175H,G245C和R249)和接触突变体(R248Q,,, R273H和R280K)。将使用细胞系和小鼠肿瘤模型,包括患者衍生的异种移植物。 PEPD KD将使用siRNA和强力霉素调节的系统实现。拟议的研究是 重要的是,因为它可能会导致对生物学和调节的理解的范式转移 p53突变体,反过来可能提供创新的癌症治疗策略。预期的结果 项目包括:1)表明PEPD与细胞核和细胞质中每个p53突变体的近一半结合; 2)表明PEPD KD破坏PEPD-P53突变体配合物,使PTM的突变体释放 突变体的驱动和重新激活,无论是构象突变体还是接触突变体,并且 p300/cbp的K373乙酰化是此过程的关键。 3)表明肿瘤抑制活动 重新激活的p53突变体与活化的p53wt相似。因此,我们的研究将揭露 p53突变体的关键内在重新激活机制,在p53中可能具有深远的影响 研究并可能会为制定新的癌症治疗策略而打破新的基础。

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)

暂无数据

数据更新时间:2024-06-01

YUESHENG ZHANG的其他基金

Combating Cetuximab Resistance in Colorectal Cancer
对抗结直肠癌中的西妥昔单抗耐药性
  • 批准号:
    10600411
    10600411
  • 财政年份:
    2022
  • 资助金额:
    $ 37.52万
    $ 37.52万
  • 项目类别:
Overcoming Drug Resistance in HER2-positive Breast Cancer
克服 HER2 阳性乳腺癌的耐药性
  • 批准号:
    10639498
    10639498
  • 财政年份:
    2020
  • 资助金额:
    $ 37.52万
    $ 37.52万
  • 项目类别:
Overcoming Drug Resistance in HER2-positive Breast Cancer
克服 HER2 阳性乳腺癌的耐药性
  • 批准号:
    10663396
    10663396
  • 财政年份:
    2020
  • 资助金额:
    $ 37.52万
    $ 37.52万
  • 项目类别:
Overcoming Drug Resistance in HER2-positive Breast Cancer
克服 HER2 阳性乳腺癌的耐药性
  • 批准号:
    10207554
    10207554
  • 财政年份:
    2020
  • 资助金额:
    $ 37.52万
    $ 37.52万
  • 项目类别:
Combating Cetuximab Resistance in Colorectal Cancer
对抗结直肠癌中的西妥昔单抗耐药性
  • 批准号:
    9287314
    9287314
  • 财政年份:
    2017
  • 资助金额:
    $ 37.52万
    $ 37.52万
  • 项目类别:
Combating Cetuximab Resistance in Colorectal Cancer
对抗结直肠癌中的西妥昔单抗耐药性
  • 批准号:
    9891024
    9891024
  • 财政年份:
    2017
  • 资助金额:
    $ 37.52万
    $ 37.52万
  • 项目类别:
Combating Cetuximab Resistance in Colorectal Cancer
对抗结直肠癌中的西妥昔单抗耐药性
  • 批准号:
    10115631
    10115631
  • 财政年份:
    2017
  • 资助金额:
    $ 37.52万
    $ 37.52万
  • 项目类别:
Combating Cetuximab Resistance in Colorectal Cancer
对抗结直肠癌中的西妥昔单抗耐药性
  • 批准号:
    9453661
    9453661
  • 财政年份:
    2017
  • 资助金额:
    $ 37.52万
    $ 37.52万
  • 项目类别:
Gender Disparity in Bladder Cancer and Chemopreventive Intervention
膀胱癌的性别差异和化学预防干预
  • 批准号:
    8605175
    8605175
  • 财政年份:
    2013
  • 资助金额:
    $ 37.52万
    $ 37.52万
  • 项目类别:
Gender Disparity in Bladder Cancer and Chemopreventive Intervention
膀胱癌的性别差异和化学预防干预
  • 批准号:
    9198759
    9198759
  • 财政年份:
    2013
  • 资助金额:
    $ 37.52万
    $ 37.52万
  • 项目类别:

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