p53-mediated dead cell clearance in response to DNA damage and tumorigenesis

p53 介导的死细胞清除响应 DNA 损伤和肿瘤发生

• 批准号: 9194665
• 负责人: SAM W LEE
• 金额: $ 36.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9194665
• 关键词: Antitumor Response; Apoptosis; Apoptotic; Autoantigens; Autoimmunity; Cell Death; Cell membrane; Cell model; Cell physiology; Cells; Cessation of life; Chronic; Coculture Techniques; DNA Damage; Data; Databases; Death Domain; Development; Disease; Eating; Environment; Event; Excision; Failure; Fostering; Gene Targeting; Generations; Genotoxic Stress; Health; Human; Immune; Immune Tolerance; Immune response; Immunity; Immunoglobulins; Immunologic Surveillance; In Vitro; Inflammation; Investigation; Knockout Mice; Lead; Life; Ligands; Link; Maintenance; Malignant Neoplasms; Mediating; Modeling; PDCD1LG1 gene; Pathway interactions; Phagocytes; Phagocytosis; Phase; Physiological; Process; Protein Family; Protein p53; Role; Signal Transduction; Stress; System; T cell response; T-Lymphocyte; TP53 gene; Testing; Tissues; Work; base; cancer cell; cancer therapy; cytotoxicity; immune activation; in vivo; inhibitor/antagonist; member; mouse model; neoplastic cell; receptor; response; tumor; tumor progression; tumorigenesis

Project Summary Programmed cell death/apoptosis occurs throughout life in all tissues of the body and more than a billion of cells die everyday as part of normal processes. Thus rapid and efficient clearance of cell corpses is a vital prerequisite for homeostatic maintenance of tissue health. Failure to clear dying cells can lead to the accumulation of autoantigens in tissues that foster diseases such as cancer, chronic inflammation, autoimmunity and developmental abnormalities. High level of cell death can occur within tumor environment in cancer therapy, and the mechanisms through which dying tumor cells are cleared influence tumor-specific immunity. Thus, manipulation of the immunological context of dead cell removal has great potential for the control of tumor progression and generation of an antitumor response, which is still an outstanding issue and understanding this specific mechanism warrants investigation. Enormous efforts have been made toward understanding various mechanisms of tumor suppressor p53-mediated cell death/apoptosis. However, the involvement of p53 in post- apoptosis has not been implicated until now. In this application, we identified a first post- apoptotic target gene of p53, death domain1α, DD1α, which is highly responsive to genotoxic stresses/DNA damage. We found that p53 controls apoptotic cell clearance of through its target DD1α, suggesting that p53 promotes both the pro-apoptotic pathway and the post-apoptotic events. Moreover, DD1α appears to function as a negative immune-checkpoint regulator that modulates immune responses/T cell function, suggesting the role of DD1α in immune tolerance. DD1α has similarity with several members of the immunoglobulin superfamily with the IgV domain, including TIM family proteins and immune checkpoint co-inhibitors PD-1 and PD-L1. The public database indicates that expression of DD1α is increased in multiple human cancers, implicating its immune modulating function in cancer. Based on these data, we propose two major aims focused on mechanisms of understanding the roles of a newly found post-apoptotic target of p53 and investigating the potential to enhance the anti-tumor immune responses.

项目概要 程序性细胞死亡/凋亡发生在身体的所有组织中，并且超过 作为正常过程的一部分，每天有十亿个细胞死亡。从而快速有效地清除 细胞尸体是维持组织健康稳态的重要先决条件。无法清除 垂死的细胞会导致组织中自身抗原的积累，从而引发以下疾病： 癌症、慢性炎症、自身免疫和发育异常。 在癌症治疗中，肿瘤环境中可能会发生高水平的细胞死亡，并且 死亡肿瘤细胞被清除的机制会影响肿瘤特异性免疫。 因此，操纵死细胞去除的免疫学背景对于以下方面具有巨大潜力： 控制肿瘤进展和产生抗肿瘤反应，这仍然是一个 悬而未决的问题和理解这一特定机制值得调查。 人们为了解肿瘤的各种机制付出了巨大的努力 抑制 p53 介导的细胞死亡/凋亡。然而，p53 参与后 直到现在还没有涉及细胞凋亡。在此应用中，我们确定了第一个后 p53、死亡域1α、DD1α等凋亡靶基因，对基因毒性高度敏感 压力/DNA 损伤。我们发现p53通过其靶点控制凋亡细胞的清除 DD1α，表明 p53 促进促凋亡途径和凋亡后途径 事件。此外，DD1α 似乎充当负免疫检查点调节剂， 调节免疫反应/T 细胞功能，表明 DD1α 在免疫耐受中的作用。 DD1α 与免疫球蛋白超家族的几个成员具有 IgV 相似性 结构域，包括 TIM 家族蛋白和免疫检查点联合抑制剂 PD-1 和 PD-L1。这 公共数据库表明 DD1α 的表达在多种人类癌症中增加， 暗示其在癌症中的免疫调节功能。根据这些数据，我们提出两个建议 主要目标集中于理解新发现的凋亡后作用的机制 p53 的靶标并研究增强抗肿瘤免疫反应的潜力。