Deciphering the Molecular Pathways Driving p53 Dependent Cell Death

破译驱动 p53 依赖性细胞死亡的分子途径

基本信息

  • 批准号:
    9112781
  • 负责人:
  • 金额:
    $ 5.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-01 至 2018-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The p53 gene is the most commonly mutated tumor suppressor with inactivating mutations in over 50% of all human cancers. The remaining half of cancers contain wild-type p53, but harbor additional means of p53 inactivation. Recent cancer therapies focused on restoring p53's tumor suppressive program include the small molecule inhibitor Nutlin-3, which activates dormant p53 through inhibiting the interaction between p53 and its endogenous repressor MDM2. Importantly, this non-genotoxic approach would replace toxic chemotherapy treatments, which carry harmful side-effects by activating p53 through means of DNA damage. Despite the considerable momentum with Nutlin-3, its efficacy is currently limited by the heterogeneity of the p53 response, where most cancer cells undergo reversible cell cycle arrest, as opposed to a therapeutically favorable apoptotic response. In order to improve p53-based therapies, a better understanding of the mechanisms governing p53-induced apoptosis is needed. Additionally, previous studies demonstrate that p53s tumor suppressive function is dependent on its role as a transcription factor, yet no direct p53 target t date has been identified as crucial to p53-mediated tumor suppression. The objectives herein are to identify the cellular factors necessary to tip the balance of the p53 response toward apoptosis, and to determine what direct p53 transcriptional targets are necessary for p53 mediated cell death. To answer these questions the following specific aims will be developed: 1) Identify novel mediators of p53-dependent apoptosis in response to non- genotoxic activation of p53 by Nutlin-3, 2) Identify direct transcriptional targets necessary for p53-mediated cell death, and 3) Determine the impact of novel mediators of p53-dependent apoptosis on tumor suppression in vivo. In answering these questions, a powerful functional genomics approach will be applied in two pediatric cancer cell lines, which have been identified as having strong apoptotic responses to Nutlin-3. For an unbiased approach to identify novel mediators of p53-dependent apoptosis, a positive selection screen with a genome wide shRNA library will be utilized, and validation of top candidates will clearly identify genes that, when knocked down, confer resistance to Nutlin treatment. For direct p53 transcriptional targets essential for cell death, a similar positive selection screen will be conducted, only now with a uniquely comprised focused P53TARGET shRNA library, targeting ~300 direct p53 targets. After validation of top candidates, investigations into the mechanism by which these genes mediate p53-dependent apoptosis will be conducted. To translate these findings into clinical relevance, the identified apoptotic regulators will also be tested for their ability to mediate p53-dependent cell death in a tumor xenograft (in vivo) model. Results herein will illuminate the cellular factors essential for p53-mediated cell death, which is vital for the improvement of p53-reactivation strategies. Once effective, this treatment option will be available to all cancers that retain wild-type p53, nearly11 million people worldwide.
 描述(申请人提供):P53基因是最常见的突变的肿瘤抑制基因,在所有人类癌症中有超过50%的突变是失活突变。其余一半的癌症含有野生型P53,但有其他方法使P53失活。最近的癌症治疗集中在恢复P53的S肿瘤抑制计划上,包括小分子抑制剂Nutlin-3,它通过抑制P53与其内源性抑制子MDM2之间的相互作用来激活休眠的P53。重要的是,这种非遗传毒性的方法将取代毒性化疗,后者通过DNA损伤激活p53,从而带来有害的副作用。尽管Nutlin-3有相当大的势头,但其疗效目前受到P53反应异质性的限制,在P53反应中,大多数癌细胞经历可逆的细胞周期停滞,而不是治疗上有利的凋亡反应。为了改进基于P53的治疗,需要更好地了解P53诱导细胞凋亡的机制。此外,以前的研究表明,p53S的肿瘤抑制功能依赖于其作为转录因子的作用,但尚未发现直接的p53靶点t日期对p53介导的肿瘤抑制至关重要。本研究的目的是确定使P53反应的平衡向凋亡倾斜所必需的细胞因子,并确定P53介导的细胞死亡所必需的直接P53转录靶点。为了回答这些问题,将开发以下特定的目标:1)寻找新的P53依赖的细胞凋亡介质,以响应Nutlin-3对P53的非遗传毒性激活,2)确定P53介导的细胞死亡所必需的直接转录靶点,以及3)确定新的P53依赖的凋亡介质在体内对肿瘤抑制的影响。为了回答这些问题,一种强大的功能基因组学方法将被应用于两种儿科癌症细胞系,这两种细胞系已被确认对Nutlin-3具有强烈的凋亡反应。对于一种公正的方法来确定p53依赖的细胞凋亡的新的介体,将利用具有全基因组shRNA文库的阳性选择筛选,并且对首选候选的验证将清楚地识别当被击倒时,对Nutlin治疗产生耐药性的基因。对于细胞死亡所必需的直接P53转录靶点,将进行类似的阳性选择筛选,只是现在使用唯一组成的聚焦P53TARGET shRNA文库,靶向约300个直接P53靶点。在确认了最佳候选基因后,将对这些基因介导P53依赖的细胞凋亡的机制进行调查。为了将这些发现转化为临床意义,还将测试已识别的凋亡调节因子在介导p53依赖的细胞死亡中的能力。 肿瘤异种移植(体内)模型。本文的结果将阐明P53介导的细胞死亡所必需的细胞因素,这对于改进P53再激活策略是至关重要的。一旦有效,这种治疗方案将适用于所有保留野生型p53的癌症,全世界近1100万人。

项目成果

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Anna Guarnieri其他文献

Anna Guarnieri的其他文献

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{{ truncateString('Anna Guarnieri', 18)}}的其他基金

Deciphering the Molecular Pathways Driving p53 Dependent Cell Death
破译驱动 p53 依赖性细胞死亡的分子途径
  • 批准号:
    9313849
  • 财政年份:
    2015
  • 资助金额:
    $ 5.8万
  • 项目类别:

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