Control of mutant p53 stability via the mevalonate pathway-DNAJA1 axis

通过甲羟戊酸途径-DNAJA1 轴控制突变体 p53 的稳定性

基本信息

  • 批准号:
    9523990
  • 负责人:
  • 金额:
    $ 35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-03-09 至 2023-02-28
  • 项目状态:
    已结题

项目摘要

The overall 5-year survival rate of patients with head and neck squamous cell carcinoma (HNSCC) is less than 50%, and ~75% of human HNSCC cases have mutations in the tumor suppressor p53. The vast majority of p53 mutations are missense mutations that show oncogenic activities, with strong correlation with poor prognosis in patients with HNSCC. Recent evidence indicates that stabilization of mutant p53 (mutp53) in tumors is crucial for its oncogenic activities, while its knockdown attenuates tumor progression. Although there are numerous publications on the function and regulation of wild-type p53 (wtp53), little is known about mechanisms controlling mutp53 levels in tumors and the workable strategies that induce mutp53 degradation. The goal of this proposal is to discover efficient strategies to specifically degrade mutp53 in HNSCC and elucidate the underlying mechanisms. To identify compounds that reduce mutp53 levels, we performed high throughput screening of chemical libraries and identified “statins”, a class of drugs that inhibit cholesterol production, as degradation inducers of structurally misfolded mutp53 proteins. Statins showed minimal effects on wtp53 and DNA contact mutp53 with native structure. Reduction in mevalonte-5-phosphate (MVP), but not other metabolites in the mevalonate (MV) pathway, triggered mutp53 degradation by CHIP ubiquitin ligase in a protein prenylation-independent manner. Statins also inhibited binding of mutp53 to DNAJA1, a molecular chaperone of the Hsp40 family which plays a role in refolding of misfolded proteins. Indeed, mutp53 degradation by statins was nullified by MVP supplementation, as well as by DNAJA1 overexpression. These data suggest that MVP positively regulates the DNAJA1-mutp53 binding and that DNAJA1 stabilizes misfolded mutp53. However, it is still unclear how reduced MVP leads to inhibition of DNAJA1-mutp53 binding. Based on our compelling preliminary data showing that reduction in MVP by knockdown of mevalonate kinase (MVK) increased acetylation of mutp53, we hypothesize that acetylation of mutp53 upon MVP reduction inhibits the mutp53-DNAJA1 binding, which promotes mutp53 degradation, leading to tumor suppression. We will test this hypothesis and establish the role of DNAJA1 in the malignant progression of HNSCC cells. In Aim 1, we will determine the mechanism by which reduced MVP leads to inhibited binding of mutp53 with DNAJA1 to induce mutp53 degradation and tumor suppression. In Aim 2, we will test the hypothesis that DNAJA1 promotes HNSCC progression in a misfolded mutp53-dependent manner. In Aim 3, we will characterize potential DNAJA1 inhibitors identified through molecular docking studies for their abilities to bind to DNAJA1, induce mutp53 degradation, and reduce the malignant properties of HNSCC cells. Completion of this study will reveal a novel mechanism of mutp53 stabilization via unexpected functional link between MVP and DNAJA1 and will establish the MV pathway and DNAJA1 as novel therapeutic targets for mutp53-carrying cancers. This study may also identify a DNAJA1 inhibitor as a potential compound that can be used for HNSCC therapy.
头颈鳞状细胞癌(HNSCC)患者的总体 5 年生存率低于 50% 和~75% 的人类 HNSCC 病例的肿瘤抑制因子 p53 存在突变。绝大多数 p53 突变是显示致癌活性的错义突变,与较差的致癌活性有很强的相关性。 HNSCC 患者的预后。最近的证据表明突变体 p53 (mutp53) 的稳定性 肿瘤对其致癌活性至关重要,而其敲低则可减弱肿瘤进展。虽然有 关于野生型 p53 (wtp53) 的功能和调控的出版物有很多,但人们对此知之甚少 控制肿瘤中 mutp53 水平的机制以及诱导 mutp53 降解的可行策略。 该提案的目标是发现特异性降解 HNSCC 中 mutp53 的有效策略, 阐明根本机制。为了识别降低 mutp53 水平的化合物,我们进行了高 对化学库进行通量筛选并鉴定出“他汀类药物”,这是一类抑制胆固醇的药物 作为结构错误折叠的 mutp53 蛋白的降解诱导剂。他汀类药物效果甚微 wtp53 和 DNA 使 mutp53 与天然结构接触。 5-磷酸甲羟戊酸 (MVP) 减少,但不减少 甲羟戊酸 (MV) 途径中的其他代谢物,通过 CHIP 泛素连接酶触发 mutp53 降解 蛋白质异戊二烯化独立方式。他汀类药物还抑制 mutp53 与 DNAJA1 的结合,DNAJA1 是一种分子 Hsp40 家族的分子伴侣,在错误折叠蛋白质的重折叠中发挥作用。确实,mutp53 通过补充 MVP 以及 DNAJA1 过表达,他汀类药物的降解作用被抵消。这些 数据表明 MVP 正向调节 DNAJA1-mutp53 结合,并且 DNAJA1 稳定错误折叠 mutp53。然而,目前尚不清楚 MVP 的减少如何导致 DNAJA1-mutp53 结合的抑制。基于 我们令人信服的初步数据表明,通过敲除甲羟戊酸激酶 (MVK) 可减少 MVP mutp53 的乙酰化增加,我们假设 MVP 还原后 mutp53 的乙酰化会抑制 mutp53-DNAJA1 结合,促进 mutp53 降解,从而抑制肿瘤。我们将测试这个 假设并建立 DNAJA1 在 HNSCC 细胞恶性进展中的作用。在目标 1 中,我们将 确定减少 MVP 导致 mutp53 与 DNAJA1 结合受到抑制的机制,以诱导 mutp53 降解和肿瘤抑制。在目标 2 中,我们将检验 DNAJA1 促进的假设 HNSCC 以错误折叠的 mutp53 依赖性方式进展。在目标 3 中,我们将描述潜力 通过分子对接研究鉴定出 DNAJA1 抑制剂能够与 DNAJA1 结合,诱导 mutp53降解,降低HNSCC细胞的恶性特性。完成这项研究将揭示 通过 MVP 和 DNAJA1 之间意想不到的功能联系实现 mutp53 稳定的新机制,并将 建立 MV 通路和 DNAJA1 作为携带 mutp53 的癌症的新治疗靶点。这项研究 还可能将 DNAJA1 抑制剂鉴定为可用于 HNSCC 治疗的潜在化合物。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ 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 }}

Tomoo Iwakuma其他文献

Tomoo Iwakuma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('Tomoo Iwakuma', 18)}}的其他基金

The 10th International MDM2 Workshop
第十届国际MDM2研讨会
  • 批准号:
    10814471
  • 财政年份:
    2023
  • 资助金额:
    $ 35万
  • 项目类别:
Control of mutant p53 stability via the mevalonate pathway-DNAJA1 axis
通过甲羟戊酸途径-DNAJA1 轴控制突变体 p53 的稳定性
  • 批准号:
    10320158
  • 财政年份:
    2021
  • 资助金额:
    $ 35万
  • 项目类别:
Control of mutant p53 stability via the mevalonate pathway-DNAJA1 axis
通过甲羟戊酸途径-DNAJA1 轴控制突变体 p53 的稳定性
  • 批准号:
    10339474
  • 财政年份:
    2021
  • 资助金额:
    $ 35万
  • 项目类别:
The role of MDM2-MTBP axis in cancer metastasis
MDM2-MTBP轴在癌症转移中的作用
  • 批准号:
    8694358
  • 财政年份:
    2014
  • 资助金额:
    $ 35万
  • 项目类别:
The role of MDM2-MTBP axis in cancer metastasis
MDM2-MTBP轴在癌症转移中的作用
  • 批准号:
    8842602
  • 财政年份:
    2014
  • 资助金额:
    $ 35万
  • 项目类别:
DISSECTING ROLES OF MTBP IN OSTEOSARCOMA METASTASIS
剖析 MTBP 在骨肉瘤转移中的作用
  • 批准号:
    7720778
  • 财政年份:
    2008
  • 资助金额:
    $ 35万
  • 项目类别:
DISSECTING ROLES OF MTBP IN OSTEOSARCOMA METASTASIS
剖析 MTBP 在骨肉瘤转移中的作用
  • 批准号:
    7610681
  • 财政年份:
    2007
  • 资助金额:
    $ 35万
  • 项目类别:
UNCOVERING THE MECHANISMS OF OSTEOSARCOMA METASTASIS SUPPRESSION BY MTBP
揭示 MTBP 抑制骨肉瘤转移的机制
  • 批准号:
    8168370
  • 财政年份:
    2004
  • 资助金额:
    $ 35万
  • 项目类别:
UNCOVERING THE MECHANISMS OF OSTEOSARCOMA METASTASIS SUPPRESSION BY MTBP
揭示 MTBP 抑制骨肉瘤转移的机制
  • 批准号:
    8360720
  • 财政年份:
    2004
  • 资助金额:
    $ 35万
  • 项目类别:
DISSECTING ROLES OF MTBP IN OSTEOSARCOMA METASTASIS
剖析 MTBP 在骨肉瘤转移中的作用
  • 批准号:
    7960535
  • 财政年份:
    2004
  • 资助金额:
    $ 35万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 35万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 35万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 35万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 35万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 35万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 35万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 35万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了