P53 Signaling and Cellular Response after Stress

压力后 P53 信号传导和细胞反应

• 批准号: 7809840
• 负责人: JENNIFER A PIETENPOL
• 金额: $ 26.97万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/7809840
• 关键词: Address; Antibody Formation; Apoptosis; Area; Autophagocytosis; Binding; Binding Sites; Biochemical; Biological; Biological Models; Cell Cycle Arrest; Cell Death; Cell Survival; Cell physiology; Cells; Cellular Stress; Cessation of life; Chemosensitization; Data; EDN2 gene; Endothelin-2; Equipment and Supplies; Event; Family; Family member; Frequencies; Funding; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genomics; Genotoxic Stress; Grant; Growth; Health; Histones; Homologous Gene; Human; Human Resources; Investigation; Investments; Lead; Mediating; Mutation; Normal Cell; Nucleic Acid Regulatory Sequences; Outcome; Pathway interactions; Play; Post-Translational Protein Processing; Property; Proteins; Public Health; Publications; Recovery; Regulation; Research; Resources; Ribosomal Proteins; Role; Set protein; Signal Transduction; Stress; TP53 gene; Testing; Therapeutic; Time; Transactivation; Transcriptional Regulation; Translating; Translations; Tumor Suppression; Tumor Suppressor Proteins; United States National Institutes of Health; Work; cancer cell; candidate validation; human disease; member; novel; p53 Signaling Pathway; programs; repaired; research study; response; senescence; theories; tumor; tumorigenesis

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）：作为对NOT-OD-09-058的回应，NIH宣布恢复法案基金可用于竞争性修订申请，我们提出了一个竞争性修订R 01赠款CA 070856，题为“压力后p53信号传导和细胞反应”。“p53信号通路是人类肿瘤中最常见的颠覆通路。由该基金资助的已完成和正在进行的实验已经并将继续测试这一假设，即p53通过调节靶基因的转录调节来调节应激后的细胞结果，这些靶基因协调生长停滞、修复和存活与凋亡的途径。本研究的主要目的有三：（1）确定p53靶基因产物在应激后细胞存活调控中的作用（重点是EDN 2）;（2）确定新的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RPS 27 L和ISG 20 L1）;和（3）确定p53及其家族成员对靶基因的组成型与胁迫诱导型调控中所涉及的机制。我们已经取得了所有三个目标的出版物所证明的进展，我们将继续我们的特性选择p53靶基因的建议。然而，一次一个基因的方法是有限的，因为没有一个单一的靶基因可以解释超过一部分的p53的肿瘤抑制活性。相反，p53调节广泛的基因网络的转录，这些基因参与不同的功能，如细胞周期停滞、凋亡、衰老和自噬。p53反应的复杂性不仅仅是其基因组结合谱，而是通过两种p53同源物（p63和p73）的存在来反映，这两种同源物可以在物理和功能上与p53相互作用。我们覆盖了全面的p53基因组结合位点数据与微阵列表达数据，以产生一组新的，p53调控的靶基因。此外，我们将这组p53靶基因与我们的p63和p73分析的类似衍生组进行了比较，并确定哪些靶基因具有p53家族其他成员的独特或共享调控。关键的下一步骤是过滤这组基因，并优先考虑后续分析的顺序，因为深入表征每个靶基因产物需要大量的时间和资源（即，抗体生产、模型系统和转化为人类疾病）。我们提出了一个新的目标，涉及一组新的，p53家族靶基因在生理相关的模型系统中使用一种有效的，高通量的方法的功能表征。这一目标是一个扩大的调查领域，需要招募更多的人员以及购买设备和用品，所有这些行动都将刺激经济，并扩大我们对人类肿瘤中最常见的颠覆途径的理解。 公共卫生相关：为了响应AARA NOT-OD-09-058，恢复法案基金竞争性修订申请，我们提出了一个竞争性修订的R 01赠款CA 070856题为“p53信号和细胞反应后的压力。“由该基金资助的已完成和正在进行的实验已经并将继续通过三个具体目标来测试这一假设，即p53通过靶基因的转录调节来调节应激后的细胞结果，这些靶基因协调生长停滞，修复和存活与凋亡的途径。我们提出了一个新的目标，涉及一组新的，p53家族靶基因在生理相关的模型系统中使用一种有效的，高通量的方法的功能表征;这一目标意味着调查领域的扩大，需要征聘更多的人员以及购买设备和用品，所有这些行动都将刺激经济，并扩大我们对人类肿瘤中最常见的颠覆途径的理解。