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）：为了回应 NOT-OD-09-058，NIH 宣布可用于竞争性修订申请的恢复法案基金，我们建议对 R01 拨款 CA070856 进行竞争性修订，题为“p53 信号传导和细胞响应后压力。” p53 信号通路是人类肿瘤中迄今为止发现的最常被破坏的通路。由这笔资金资助的已完成和正在进行的实验已经并将继续检验这样的假设：p53 通过目标基因的转录调节来调节应激后的细胞结果，这些目标基因协调生长停滞、修复、存活与凋亡的途径。我们正在追求三个最初的目标：（1）确定新的p53靶基因产物在应激后调节细胞存活中的作用（重点是EDN2）； (2) 确定新型p53靶基因产物在调节细胞对基因毒性应激敏感性中的作用（首先关注RPS27L和ISG20L1）； (3)确定p53及其家族成员对靶基因进行组成型调控和应激诱导型调控所涉及的机制。出版物证明，我们在所有三个目标上都取得了进展；并且，我们将继续按照建议对选定的 p53 靶基因进行表征。然而，考虑到没有任何单一靶基因可以解释 p53 肿瘤抑制活性的一小部分以上，一次基因方法是有局限性的。相反，p53 调节涉及多种功能（例如细胞周期停滞、细胞凋亡、衰老和自噬）的广泛基因网络的转录。 p53 反应的复杂性超出了其基因组结合谱的范围，并通过两个 p53 同源物（p63 和 p73）的存在反映出来，它们可以在物理上和功能上与 p53 和彼此相互作用。我们将全面的 p53 基因组结合位点数据与微阵列表达数据叠加，生成一组新颖的 p53 调控靶基因。此外，我们将这组 p53 靶基因与来自我们的 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同调控。考虑到深入表征每个目标基因产物（即抗体生产、模型系统和翻译为人类）所需的大量时间和资源，下一步关键是过滤这组基因并优先考虑后续分析的顺序。疾病）。我们提出了一个新目标，涉及使用高效、高通量方法在生理相关模型系统中对一组新颖的 p53 家族靶基因进行功能表征。这一目标是扩大研究领域，需要招募更多人员以及购买设备和用品，所有行动都将刺激经济并扩大我们对人类肿瘤中迄今为止发现的最常见破坏途径的了解。 公共健康相关：为了响应 AARA NOT-OD-09-058（竞争性修订申请恢复法案基金），我们提议对 R01 拨款 CA070856 进行一项竞争性修订，题为“压力后的 p53 信号传导和细胞响应”。由这笔资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检验这一假设，即 p53 通过目标基因的转录调节来调节应激后的细胞结果，这些目标基因协调生长停滞、修复和存活与凋亡的途径。我们提出了一个新目标，涉及使用高效、高通量的方法在生理相关模型系统中对一组新颖的 p53 家族靶基因进行功能表征；这一目标代表了一个扩大的调查领域，需要招募更多人员以及购买设备和用品，所有行动都将刺激经济并扩大我们对人类肿瘤中迄今为止发现的最常见破坏途径的了解。