Effectors of p53 Pro-survival and Pro-apoptotic Signaling Pathways

p53 促生存和促凋亡信号通路的效应器

• 批准号: 8288893
• 负责人: Stuart A Aaronson
• 金额: $ 46.64万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288893
• 关键词: Address; Affect; Affinity Chromatography; Agreement; Antiviral Agents; Antiviral Response; Apoptosis; Apoptotic; Biochemical; Biology; Cell Cycle Arrest; Cell Death; Cell Death Inhibition; Cell Survival; Cells; Cellular Stress; Cessation of life; Cytokine Signaling; DNA Damage; Development; Gene Targeting; Genes; Genome; Genotoxic Stress; Growth; HIV; Human; Immune response; Immunity; In Vitro; Interferon Type I; Interferons; Investigation; Knock-out; Knockout Mice; Lead; MDM2 gene; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Molecular; Mus; Natural Immunity; Noxae; Pathway interactions; Play; Post-Translational Protein Processing; Production; Protein p53; Proteins; Regulation; Reporting; Research Personnel; Role; Signal Pathway; Signal Transduction; Structure; TNF gene; Tissues; Toll-like receptors; Translating; Tumor Necrosis Factor-alpha; Tumor Suppression; Tumor Suppressor Proteins; Up-Regulation; Virus Diseases; base; biological adaptation to stress; cancer therapy; chemical carcinogenesis; cytokine; design; experience; human TLR3 protein; human TNF protein; in vivo; influenzavirus; inhibitor/antagonist; innate immune function; irradiation; loss of function; meetings; mouse model; neoplastic cell; novel; p53 Signaling Pathway; programs; reconstitution; response; small molecule; tumor; tumor initiation; tumor progression; tumorigenesis

p53 is widely known as 'the guardian of the genome' due to its ability to activate either cell cycle arrest or apoptosis in response to DNA damage. This project has uncovered a novel role of p53 cell stress responses in enforcing innate immunity by transcriptional upregulation of IRF9, a central component of the type I interferon (IFN) response. Recent evidence from our studies and others indicates that p53 also directly upregulates several target genes in pathways that play a major role in innate immunity including toll-like receptors (TLRs), IFNregulatory factors (IRFs), IFN-stimulated genes (ISGs) and tumor necrosis factor alpha (TNF-a). Within this project, we discovered a novel p53 target gene, CDIP (Cell Death Involved p53 target), which markedly upregulates p53 dependent expression of TNF-a, and promotes TNF-a apoptosis over survival cell fate decisions. We plan to continue our investigations addressing these novel directions in p53 biology. Aim 1 of this proposal is directed toward investigating the contribution of p53 dependent expression of these newly identified target genes to the innate antiviral immune response including a miRNA component of this response identified by us to play a role as well. We will explore with Projects 2 and 3, our findings that type I IFNs enhance protein levels by a non-transcriptional mechanism as well as the posttranslational modifications involved. We will also determine the ability of MDM2 inhibitors, which increase p53 at the protein level to enhance p53-dependent innate antiviral responses in vitro and in vivo. In Aim 2 we will investigate mechanisms by which CDIP enforces TNF-a induced apoptosis over survival and its specific role in TNF-a growth inhibition of human tumor cells. We will also utilize a tandem affinity purification strategy to identify CDIP Interacting proteins and collaborate with Project 2 to solve the novel structure of this molecule. We have evidence for feasibility of generating a CDIP knockout mouse that should help to elucidate CDIP tissue expression and any developmental perturbations due to loss of function on development, as well as how loss of CDIP function affects chemo/irradiation and TNF-a sensitivity. In Aim 3, we plan to integrate these investigations toward elucidating how p53 innate immune functions through cytokine signaling impact tumorigenesis in chemical carcinogenesis models in which endogenous IFNs and TNF-a are known to inhibit tumor formation. MDM2 small molecule antagonists will be applied to dissect p53 tumor suppressor functions in tumor initiation and progression. These investigations will be aided by continuing monthly meetings and collaborative interactions involving experienced investigators within the Program, each of whom is focused on studying novel aspects of p53 regulation and effectors.

p53由于能够激活细胞周期停滞或 响应DNA损伤的凋亡。该项目发现了p53细胞应力反应的新作用 通过转录IRF9的转录上调（I型干扰素的核心组成部分）来实施先天免疫力 （IFN）响应。我们研究的最新证据和其他证据表明，p53也直接上调了几个 途径中的靶基因在先天免疫中起主要作用，包括收费受体（TLR） 因子（IRF），IFN刺激的基因（ISG）和肿瘤坏死因子α（TNF-A）。在此 项目，我们发现了一个新颖的p53靶基因CDIP（细胞死亡涉及p53靶标），显着 上调TNF-A的p53依赖性表达，并促进TNF-A凋亡对生存细胞命运的凋亡 决定。我们计划继续我们的调查，以解决P53生物学中的这些新方向。目标1 提案针对研究这些新鉴定的p53依赖性表达的贡献 靶基因对先天抗病毒免疫反应，包括该反应的miRNA成分 我们也发挥作用。我们将通过项目2和3进行探索，我们的发现I型IFN可以增强蛋白质 通过非转录机制以及涉及的翻译后修饰的水平。我们也会 确定MDM2抑制剂的能力，该抑制剂在蛋白质水平上增加p53以增强p53依赖性 天生的抗病毒反应在体外和体内。在AIM 2中，我们将研究CDIP执行的机制 TNF-A诱导生存性凋亡及其在人类肿瘤细胞的TNF-A生长抑制中的特定作用。我们 还将利用串联亲和力纯化策略来识别CDIP相互作用的蛋白质并与 项目2解决该分子的新结构。我们有证据表明生成CDIP的可行性 淘汰小鼠应有助于阐明CDIP组织表达和任何发育扰动 发育功能的丧失以及CDIP功能的丧失如何影响化学/辐射和TNF-A 灵敏度。在AIM 3中，我们计划将这些调查整合为阐明p53先天免疫 通过细胞因子信号传导的功能会影响化学癌变模型中的肿瘤发生，其中 已知内源性IFN和TNF-A抑制肿瘤的形成。 MDM2小分子拮抗剂将是 应用于在肿瘤起始和进展中剖析p53肿瘤抑制器的功能。这些调查将是 通过继续每月会议和协作互动的帮助，涉及经验丰富的调查人员 该程序，每个程序都专注于研究p53调节和效应子的新方面。