Epigenetic regulation by tumor suppressor p53

抑癌基因 p53 的表观遗传调控

基本信息

  • 批准号:
    9674890
  • 负责人:
  • 金额:
    $ 5.45万
  • 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:
    2018-06-01 至 2019-02-28
  • 项目状态:
    已结题

项目摘要

ABSTRACT p53 is the most commonly mutated gene in human cancer. The p53 protein is a stress- and DNA damage-responsive transcriptional activator that binds to DNA to activate cell protective pathways, including cell cycle arrest, DNA repair, and apoptosis. The majority of p53 mutations in cancer inactivate the tumor suppressor via disruption of p53 DNA binding and hence transcriptional activation activity. The p53 protein is subject to numerous regulatory post-translational modifications, and additionally, the p53 transcription factor binds to target genes to recruit chromatin and histone modifiers as a key mechanism in gene activation. Given p53's normal role in chromatin regulation, p53 mutations and alterations in oncogenesis likely impair epigenetic pathways targeted by p53. Further elucidation of interactions between p53 and chromatin will therefore illuminate cancerous disruptions. Our recent published and preliminary data explore key mechanisms in the function and regulation of p53 as a transcriptional activator and regulating chromatin, and we will clarify these pathways in the proposed studies. First, we find that certain well-known p53 gain-of-function substitution mutations bind to and up- regulate an epigenetic gene signature, which, in turn, modifies histones to activate downstream ras/rho growth pathways. We plan to critically evaluate the mechanism and importance of this epigenetic signature in human tumor-derived cell lines bearing p53 gain-of-function substitutions and with related in vivo mouse models. Second, teratocarcinoma tumors paradoxically express high levels of wild type inactive p53; we show p53 in these cancers is decorated with elevated levels of repressive lysine methylation. In the proposed research, we will determine whether the methylation is crucial to inhibition of wild type p53 in teratocarcinomas. Third, we find that, beyond well-known p53 binding to promoters of target genes, surprisingly, the majority of stress- inducible p53 binding sites are distal to genes, appearing to be at enhancers. In the proposed studies we will address the interplay between p53 and certain histone modifiers in establishing enhancer function and gene activation. Fourth, by way of a high throughput si/shRNA screen for epigenetic regulators of p53-mediated gene activation, we observe an association of p53 with factors that mediate large-scale chromatin architecture. We will investigate direct roles of cohesin and CTCF in regulating the p53 transcriptional response via regulation of specific chromatin looping and architecture. Results from these studies will elucidate epigenetic mechanisms regulating p53 function, will explore involvement of these epigenetic pathways in p53 function in vivo and in cancer, and will launch investigation of tailored epigenetic therapies to ameliorate specific p53-driven cancer phenotypes.
摘要 p53是人类癌症中最常见的突变基因。p53蛋白是一种压力, 损伤响应性转录激活因子,与DNA结合以激活细胞保护途径,包括 细胞周期停滞、DNA修复和凋亡。癌症中的大多数p53突变都与肿瘤无关。 通过破坏p53 DNA结合并因此破坏转录激活活性来抑制p53基因。p53蛋白是 受到许多调节性翻译后修饰,此外,p53转录因子 与靶基因结合以募集染色质和组蛋白修饰剂作为基因激活的关键机制。给定 p53在染色质调节中的正常作用,p53突变和肿瘤发生中的改变可能损害表观遗传 p53靶向通路因此,进一步阐明p53和染色质之间的相互作用, 阐明癌症的破坏。 我们最近发表的和初步的数据探讨了功能和调节的关键机制, p53作为一个转录激活因子和调节染色质,我们将阐明这些途径,在建议 问题研究首先,我们发现某些众所周知的p53功能获得性取代突变与 调节表观遗传基因签名,这反过来又修饰组蛋白以激活下游ras/rho生长 途径。我们计划批判性地评估这种表观遗传标记在人类中的机制和重要性, 携带p53功能获得性取代的肿瘤衍生细胞系和相关的体内小鼠模型。 第二,畸胎癌肿瘤矛盾地表达高水平的野生型失活p53,我们发现, 这些癌症以高水平的抑制性赖氨酸甲基化修饰。在这项研究中,我们 将确定甲基化是否对畸胎瘤中野生型p53的抑制至关重要。三是 发现,除了众所周知的p53与靶基因启动子的结合,令人惊讶的是,大多数压力- 诱导型p53结合位点在基因的远端,似乎在增强子处。在拟议的研究中,我们将 研究p53和某些组蛋白修饰剂在建立增强子功能和基因 activation.第四,通过高通量si/shRNA筛选p53介导的表观遗传调节因子, 基因激活,我们观察到p53与介导大规模染色质结构的因子的关联。 我们将研究cohesin和CTCF在调节p53转录反应中的直接作用, 特定染色质循环和结构的调节。 这些研究的结果将阐明调节p53功能的表观遗传机制, 这些表观遗传途径参与p53在体内和癌症中的功能,并将启动 研究定制的表观遗传疗法以改善特定的p53驱动的癌症表型。

项目成果

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SHELLEY L BERGER其他文献

SHELLEY L BERGER的其他文献

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{{ truncateString('SHELLEY L BERGER', 18)}}的其他基金

The metabolic-epigenetic axis in memory
记忆中的代谢-表观遗传轴
  • 批准号:
    10196896
  • 财政年份:
    2019
  • 资助金额:
    $ 5.45万
  • 项目类别:
The metabolic-epigenetic axis in memory
记忆中的代谢-表观遗传轴
  • 批准号:
    9764788
  • 财政年份:
    2019
  • 资助金额:
    $ 5.45万
  • 项目类别:
The metabolic-epigenetic axis in memory
记忆中的代谢-表观遗传轴
  • 批准号:
    10399581
  • 财政年份:
    2019
  • 资助金额:
    $ 5.45万
  • 项目类别:
The metabolic-epigenetic axis in memory
记忆中的代谢-表观遗传轴
  • 批准号:
    10617251
  • 财政年份:
    2019
  • 资助金额:
    $ 5.45万
  • 项目类别:
Epigenetic regulation of extreme longevity differences in ant castes
蚂蚁种姓极端长寿差异的表观遗传调控
  • 批准号:
    10222537
  • 财政年份:
    2017
  • 资助金额:
    $ 5.45万
  • 项目类别:
Epigenetic regulation of extreme longevity differences in ant castes
蚂蚁种姓极端长寿差异的表观遗传调控
  • 批准号:
    10608683
  • 财政年份:
    2017
  • 资助金额:
    $ 5.45万
  • 项目类别:
Epigenetic regulation of extreme longevity differences in ant castes
蚂蚁种姓极端长寿差异的表观遗传调控
  • 批准号:
    10708181
  • 财政年份:
    2017
  • 资助金额:
    $ 5.45万
  • 项目类别:
Epigenetic Changes associated with Neurodegenerative Diseases
与神经退行性疾病相关的表观遗传变化
  • 批准号:
    8889810
  • 财政年份:
    2012
  • 资助金额:
    $ 5.45万
  • 项目类别:
Epigenetic Changes associated with Neurodegenerative Diseases
与神经退行性疾病相关的表观遗传变化
  • 批准号:
    8273529
  • 财政年份:
    2012
  • 资助金额:
    $ 5.45万
  • 项目类别:
Epigenetic Changes associated with Neurodegenerative Diseases
与神经退行性疾病相关的表观遗传变化
  • 批准号:
    8431739
  • 财政年份:
    2012
  • 资助金额:
    $ 5.45万
  • 项目类别:
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