P53 Signaling and Cellular Response after Stress
压力后 P53 信号传导和细胞反应
基本信息
- 批准号:7809840
- 负责人:
- 金额:$ 26.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-30 至 2010-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): In response to NOT-OD-09-058, NIH Announces the availability of Recovery Act Funds for Competitive Revision Applications, we propose a competing revision for the R01 grant CA070856 entitled, "p53 Signaling and Cellular Response After Stress." The p53 signaling pathway is the most commonly subverted pathway yet identified in human tumors. Completed and ongoing experiments funded by this grant have and will continue to test the hypothesis that p53 regulates cellular outcome after stress through transcriptional regulation of target genes that coordinate pathways of growth arrest, repair, and survival versus apoptosis. Three original aims are under pursuit: (1) To determine the role of novel p53 target gene products involved in regulating cell survival after stress (with focus on EDN2); (2) To determine the role of novel p53 target gene products involved in regulating cell sensitivity to genotoxic stress (with initial focus on RPS27L and ISG20L1); and (3) To determine the mechanisms involved in dictating constitutive versus stress-inducible regulation of target genes by p53 and it family members. We have made progress on all three aims as evidenced by publications; and, we will continue our characterization of select p53 target genes as proposed. However, a gene-at-a-time approach is limiting given that no single target gene can explain more than a fraction of the tumor suppressive activity of p53. Instead, p53 regulates the transcription of an extensive network of genes involved in diverse functions such as cell cycle arrest, apoptosis, senescence, and autophagy. The complexity of the p53 response extends beyond just its genomic binding profile, and is reflected by the existence of two p53 homologs (p63 and p73) that can physically and functionally interact with p53 and one another. We overlaid comprehensive p53 genomic binding site data with microarray expression data to generate a panel of novel, p53-regulated target genes. Further, we compared this panel of p53 target genes with similarly derived panels from our p63 and p73 analyses and determined which of the target genes have unique or shared regulation by other members of the p53 family. A critical next step is to filter this panel of genes and prioritize the order of subsequent analyses given the significant investment of time and resources required for the in depth characterization of each target gene product (i.e., antibody production, model systems, and translation to human disease). We propose a new aim that involves functional characterization of a panel of novel, p53 family target genes in physiologically relevant models systems using an efficient, high-throughput approach. This aim is an expanded area of investigation that will require recruitment of additional personnel as well as purchase of equipment and supplies, all actions that will stimulate the economy and expand our understanding of the most commonly subverted pathway yet identified in human tumors.
PUBLIC HEALTH RELEVACNE: In response to AARA NOT-OD-09-058, Recovery Act Funds for Competitive Revision Applications, we propose a competing revision for the R01 grant CA070856 entitled, "p53 Signaling and Cellular Response After Stress." Completed and ongoing experiments funded by this grant have and will continue to test the hypothesis, through three specific aims, that p53 regulates cellular outcome after stress through transcriptional regulation of target genes that coordinate pathways of growth arrest, repair, and survival versus apoptosis. We propose a new aim that involves functional characterization of a panel of novel, p53 family target genes in physiologically relevant models systems using an efficient, high-throughput approach; this aim represents an expanded area of investigation that will require recruitment of additional personnel as well as purchase of equipment and supplies, all actions that will stimulate the economy and expand our understanding of the most commonly subverted pathway yet identified in human tumors.
描述(由申请人提供):为了响应NOT-OD-09-058,NIH宣布了竞争性修订申请的恢复法案资金的可用性,我们建议对R01赠款CA070856进行竞争性修订,其标题为“ p53压力后p53信号和蜂窝响应。” p53信号通路是在人类肿瘤中尚未确定的最常见的途径。由这笔赠款资助的完成和正在进行的实验已经并且将继续检验以下假设:p53通过转录调节靶基因的转录调节,这些假设可以调节靶基因,这些靶基因是协调生长停滞,修复和生存与细胞凋亡的途径。正在追求三个最初的目标:(1)确定新型p53靶基因产物在压力后涉及调节细胞存活的作用(侧重于EDN2); (2)确定新型p53靶基因产物在调节细胞对遗传毒性应激的敏感性中的作用(最初关注RPS27L和ISG20L1); (3)确定p53和IT家族成员对目标基因的本构和应力诱导型调节所涉及的机制。出版物证明,我们在所有三个目标上都取得了进步。而且,我们将按照提出的选择继续表征某些p53靶基因。然而,鉴于没有单个靶基因可以解释p53的肿瘤抑制活性的一小部分,因此限制了一次时间的方法。取而代之的是,p53调节了参与各种功能的广泛基因网络的转录,例如细胞周期停滞,凋亡,衰老和自噬。 p53响应的复杂性超出了其基因组结合曲线的范围,并且由两个p53同源物(p63和p73)的存在反映,它们可以在物理上和功能上与p53彼此相互作用。我们用微阵列表达数据覆盖了全面的p53基因组结合位点数据,以生成一组新型p53调节的靶基因。此外,我们将此p53靶基因的小组与来自我们p63和p73分析的类似得出的面板进行了比较,并确定了哪些靶基因具有p53家族其他成员的独特或共同调节。下一步的一个关键是要过滤这组基因,并确定随后分析的顺序,鉴于每个靶基因产物(即抗体产生,模型系统和对人类疾病的翻译)所需的时间和资源的大量投资。我们提出了一个新的目标,该目标涉及使用高效,高通量方法在生理相关模型系统中进行新型p53家族靶基因的功能表征。这个目标是扩大的调查领域,需要招募其他人员以及购买设备和供应,所有这些行动都将刺激经济并扩展我们对人类肿瘤中尚未确定的最常见颠覆途径的理解。
公共卫生相关:为了回应AARA NOT-OD-09-058,用于竞争性修订应用程序的恢复法案,我们建议对R01赠款CA070856进行竞争性修订,标题为“ P53压力后的信号和蜂窝响应”。由这笔赠款资助的完成和正在进行的实验将通过三个特定目的来检验该假设,即p53通过转录调节靶基因来调节压力后的细胞结局,这些靶基因是求解生长停滞,修复和生存与凋亡的生长途径的靶基因。我们提出了一个新的目标,该目标涉及使用高效,高通量方法在生理相关模型系统中进行新型p53家族靶基因的功能表征。这个目标代表了一个扩大的调查领域,需要招募其他人员以及购买设备和供应,所有这些行动都将刺激经济并扩展我们对人类肿瘤中最常见的途径的理解。
项目成果
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数据更新时间:2024-06-01
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