Molecular basis of tumor suppression by Cdk4/6 inhibition

Cdk4/6 抑制抑制肿瘤的分子基础

基本信息

  • 批准号:
    10553261
  • 负责人:
  • 金额:
    $ 34.73万
  • 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 2023-12-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY The retinoblastoma protein (Rb) pathway is a critical regulator of cell proliferation and a promising target for cancer therapeutics. Rb normally inhibits the transcription program for cell division driven by E2F transcription factors and thus promotes cell cycle arrest in G0/G1. Rb is commonly inactivated by Cyclin-dependent kinase (Cdk) phosphorylation in cancer cells, including by Cdk4/6-CycD complexes. Key unanswered questions in this central cellular pathway include how Cdk4/6 activity is regulated, how specific Rb phosphorylation events mediate E2F activation, why is Rb a more potent tumor suppressive than its close paralogs p107 and p130, and what are the mechanisms of resistance to chemical Cdk4/6 inhibitors. These inhibitors have shown promise in the clinic, but we need to better exploit how they act and what factors influence their response. We will apply our unique combined expertise in biochemical and genetic approaches to answer previously intractable questions about the Cdk4/6-Rb pathway and tumor suppression. Our first goal is to uncover the mechanisms of Cdk4/6-CycD activation in cancer cells. We will use structural, biochemical, and cellular assays to investigate the critical role of the p27 protein in modulating Cdk4/6 activity and the cellular response to Cdk4/6 small molecule inhibitors. Our second goal is to reveal the key molecular changes that occur upon inactivating phosphorylation and the key molecular features that confer tumor suppressor potency to Rb. We will examine how specific Cdk phosphorylation events in Rb lead to its inactivation in cells. We will also explore a small domain in Rb that we hypothesize confers unique tumor suppressive ability compared to p107 and p130. Finally, our third goal is to identify new regulators of the Cdk4/6-Rb pathway using unbiased screening approaches. These new regulators may dictate how we use Cdk inhibitors as therapeutics and innovate new strategies for targeting cancer cell division. These experiments will address fundamental issues in the field of cell-cycle regulation and will transform our understanding of Rb tumor suppressor function, how it is regulated, and how it may be rescued to arrest cancer growth.
项目摘要 视网膜母细胞瘤蛋白(Rb)通路是细胞增殖的关键调节因子,也是治疗视网膜母细胞瘤的有希望的靶点。 癌症治疗学Rb通常抑制由E2 F转录驱动的细胞分裂的转录程序 细胞周期阻滞在G 0/G1期。Rb通常被细胞周期蛋白依赖性激酶失活 (Cdk)在癌症细胞中,包括通过Cdk 4/6-CycD复合物的磷酸化。 在这个中央细胞通路中关键的未回答的问题包括Cdk 4/6活性是如何调节的, 特异性Rb磷酸化事件介导E2 F激活,为什么Rb比E2 F更有效地抑制肿瘤, 它的近亲p107和p130,以及对化学Cdk 4/6抑制剂的抗性机制是什么。 这些抑制剂在临床上显示出了希望,但我们需要更好地利用它们的作用方式和影响因素, 影响他们的反应。我们将运用我们独特的生物化学和遗传学方法的综合专业知识 回答以前关于Cdk 4/6-Rb通路和肿瘤抑制的棘手问题。 我们的第一个目标是揭示癌细胞中Cdk 4/6-CycD激活的机制。我们将使用结构, 生物化学和细胞分析来研究p27蛋白在调节Cdk 4/6活性中的关键作用 以及对Cdk 4/6小分子抑制剂的细胞应答。我们的第二个目标是揭示 失活磷酸化后发生的变化和赋予肿瘤的关键分子特征 抑制Rb的能力。我们将研究Rb中特异性Cdk磷酸化事件是如何导致其 在细胞中失活。我们还将探索Rb中的一个小区域,我们假设它赋予了独特的肿瘤 与p107和p130相比抑制能力。最后,我们的第三个目标是确定新的监管机构 使用无偏筛选方法的Cdk 4/6-Rb途径。这些新的监管机构可能会决定我们如何使用Cdk 抑制剂作为治疗剂,并创新靶向癌细胞分裂的新策略。 这些实验将解决细胞周期调控领域的基本问题,并将改变我们的研究。 了解Rb肿瘤抑制功能,它是如何调节的,以及如何拯救它以阻止 癌症生长

项目成果

期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Structure and function of MuvB complexes.
MUVB复合物的结构和功能。
  • DOI:
    10.1038/s41388-022-02321-x
  • 发表时间:
    2022-05
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Mueller, Gerd A.;Asthana, Anushweta;Rubin, Seth M.
  • 通讯作者:
    Rubin, Seth M.
RB depletion is required for the continuous growth of tumors initiated by loss of RB.
  • DOI:
    10.1371/journal.pgen.1009941
  • 发表时间:
    2021-12
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
    Doan A;Arand J;Gong D;Drainas AP;Shue YT;Lee MC;Zhang S;Walter DM;Chaikovsky AC;Feldser DM;Vogel H;Dow LE;Skotheim JM;Sage J
  • 通讯作者:
    Sage J
Molecular mimicry: HUWE1 binds an atypical site in MIZ1 by adopting a typical BTB fold.
分子模拟:HUWE1 通过采用典型的 BTB 折叠结合 MIZ1 中的非典型位点。
  • DOI:
    10.1016/j.str.2021.10.005
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Asthana,Anushweta;Rubin,SethM
  • 通讯作者:
    Rubin,SethM
Tet enzymes are essential for early embryogenesis and completion of embryonic genome activation.
  • DOI:
    10.15252/embr.202153968
  • 发表时间:
    2022-02-03
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Arand J;Chiang HR;Martin D;Snyder MP;Sage J;Reijo Pera RA;Wossidlo M
  • 通讯作者:
    Wossidlo M
Integrating Old and New Paradigms of G1/S Control.
  • DOI:
    10.1016/j.molcel.2020.08.020
  • 发表时间:
    2020-10-15
  • 期刊:
  • 影响因子:
    16
  • 作者:
    Rubin SM;Sage J;Skotheim JM
  • 通讯作者:
    Skotheim JM
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Seth Michael Rubin其他文献

Seth Michael Rubin的其他文献

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{{ truncateString('Seth Michael Rubin', 18)}}的其他基金

Determining and targeting mechanisms controlling cancer cell division
确定和靶向控制癌细胞分裂的机制
  • 批准号:
    10818060
  • 财政年份:
    2023
  • 资助金额:
    $ 34.73万
  • 项目类别:
Computer hardware for EM data processing and storage
用于电磁数据处理和存储的计算机硬件
  • 批准号:
    10768461
  • 财政年份:
    2022
  • 资助金额:
    $ 34.73万
  • 项目类别:
Molecular Mechanisms of Cell Cycle Dependent Gene Expression
细胞周期依赖性基因表达的分子机制
  • 批准号:
    10668378
  • 财政年份:
    2022
  • 资助金额:
    $ 34.73万
  • 项目类别:
Carina Villegas Diversity Supplement
Carina Villegas 多样性补充品
  • 批准号:
    10814701
  • 财政年份:
    2022
  • 资助金额:
    $ 34.73万
  • 项目类别:
Molecular Mechanisms of Cell Cycle Dependent Gene Expression
细胞周期依赖性基因表达的分子机制
  • 批准号:
    10405868
  • 财政年份:
    2022
  • 资助金额:
    $ 34.73万
  • 项目类别:
Project 3: Defining and targeting mechanisms of E2F transcription factor regulation
项目3:E2F转录因子调控的定义和靶向机制
  • 批准号:
    10332382
  • 财政年份:
    2022
  • 资助金额:
    $ 34.73万
  • 项目类别:
Determining and targeting mechanisms controlling cancer cell division
确定和靶向控制癌细胞分裂的机制
  • 批准号:
    10332379
  • 财政年份:
    2022
  • 资助金额:
    $ 34.73万
  • 项目类别:
Determining and targeting mechanisms controlling cancer cell division
确定和靶向控制癌细胞分裂的机制
  • 批准号:
    10597160
  • 财政年份:
    2022
  • 资助金额:
    $ 34.73万
  • 项目类别:
Project 3: Defining and targeting mechanisms of E2F transcription factor regulation
项目3:E2F转录因子调控的定义和靶向机制
  • 批准号:
    10597169
  • 财政年份:
    2022
  • 资助金额:
    $ 34.73万
  • 项目类别:
The MARC Program at UCSC
UCSC 的 MARC 项目
  • 批准号:
    10401889
  • 财政年份:
    2021
  • 资助金额:
    $ 34.73万
  • 项目类别:

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