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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结