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.

项目摘要 程序性细胞死亡/凋亡在整个生命过程中发生在身体的所有组织中，超过 作为正常过程的一部分，每天有10亿个细胞死亡。从而快速有效地清关 细胞身体是维持组织健康的重要前提条件。未清关 死亡的细胞会导致自身抗原在组织中积累，从而导致疾病，如 癌症、慢性炎症、自身免疫和发育异常。 在癌症治疗中，高水平的细胞死亡可以发生在肿瘤环境中，并且 死亡的肿瘤细胞被清除的机制影响肿瘤特异性免疫。 因此，对去除死亡细胞的免疫学背景的操纵具有很大的潜力 控制肿瘤进展和产生抗肿瘤反应，这仍然是一种 突出的问题和对这一具体机制的理解值得调查。 人们为了解肿瘤的各种机制做出了巨大的努力。 抑制子P53介导的细胞死亡/凋亡。然而，P53蛋白参与了细胞凋亡的后反应。 到目前为止，细胞凋亡还没有被牵扯进来。在此应用程序中，我们确定了第一个帖子- 对遗传毒性高度敏感的P53、死亡结构域1α、Dd1α的凋亡靶基因 压力/DNA损伤。我们发现P53通过其靶点控制细胞的凋亡清除 Dd1α，提示P53既促进了促凋亡途径，又促进了凋亡后途径 事件。此外，Dd1α似乎是一种负免疫检查点调节因子， 调节免疫反应/T细胞功能，提示DD1α在免疫耐受中的作用。 DD1α与免疫球蛋白超家族中的几个成员具有相似性 结构域，包括TIM家族蛋白和免疫检查点共抑制物PD-1和PD-L1。这个 公共数据库显示，DD1α在多种人类癌症中表达增加， 这意味着它在癌症中具有免疫调节功能。基于这些数据，我们提出了两个 主要目的集中在了解新发现的细胞凋亡后的作用机制。 靶向P53，并研究其增强抗肿瘤免疫反应的可能性。