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被广泛认为是“基因组的守护者”，因为它能够激活细胞周期停滞或 细胞凋亡对DNA损伤的反应。该项目揭示了p53细胞应激反应在 通过转录上调IRF 9（I型干扰素的中心成分）来加强先天免疫 (IFN)反应我们的研究和其他研究的最新证据表明，p53也直接上调了几种 在先天免疫中起主要作用的途径中的靶基因，包括toll样受体（TLR）、IFN调节性 因子（IRF）、IFN刺激基因（ISG）和肿瘤坏死因子α（TNF-α）。在这 本课题组发现了一个新的p53靶基因CDIP（Cell Death Involved p53 target）， 上调p53依赖的TNF-α表达，并促进TNF-α凋亡超过存活细胞命运 决策我们计划继续研究p53生物学中的这些新方向。目标1 建议是针对调查的贡献，p53依赖的表达，这些新发现的， 靶向先天性抗病毒免疫应答的基因，包括该应答的miRNA组分， 我们也要发挥作用。我们将在项目2和3中探索我们的发现，即I型干扰素增强蛋白质 通过非转录机制以及所涉及的翻译后修饰水平。我们还将 确定MDM 2抑制剂的能力，其在蛋白质水平上增加p53，以增强p53依赖性 体外和体内的先天性抗病毒反应。在目标2中，我们将研究CDIP执行的机制 TNF-α诱导的凋亡超过存活及其在TNF-α抑制人肿瘤细胞生长中的特异性作用。我们 还将利用串联亲和纯化策略来鉴定CDIP相互作用蛋白，并与 项目2解决这个分子的新结构。我们有证据证明产生CDIP的可行性 敲除小鼠，这将有助于阐明CDIP组织表达和任何发育扰动， 以及CDIP功能的丧失如何影响化疗/放疗和TNF-α 灵敏度在目标3中，我们计划将这些研究整合起来，以阐明p53先天免疫是如何在体内发挥作用的。 通过细胞因子信号传导影响化学致癌模型中的肿瘤发生， 已知内源性IFN和TNF-α抑制肿瘤形成。MDM 2小分子拮抗剂将是 应用于剖析p53肿瘤抑制因子在肿瘤发生和发展中的作用。这些调查将是 通过持续的月度会议和内部有经验的调查人员参与的协作互动， 该计划，其中每个人都专注于研究p53调控和效应器的新方面。