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Non-apoptotic functions of caspase-2 in cell division and genomic stability

Caspase-2 在细胞分裂和基因组稳定性中的非凋亡功能

基本信息

批准号：
10153813
负责人：
Lisa Bouchier-Hayes
金额：
$ 32.53万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153813
关键词：
Aging Aneuploidy Apoptosis Apoptotic CASP2 gene Caspase Cell Cycle Cell Cycle Checkpoint Cell Cycle Progression Cell Cycle Regulation Cell Death Cell Line Cell Nucleolus Cell Proliferation Cell Survival Cell division Cell physiology Cells Chromosome abnormality Co-Immunoprecipitations Complement Complex Cytoplasm Cytosol DNA DNA Damage DNA Repair DNA replication fork Data Defect Disease Engineering Ensure Exposure to Fluorescence Foundations Fractionation Frequencies GOLGA3 gene Genes Genome Genome Stability Genomic Instability Human Image Impairment Kinetics Knowledge Laboratories Lesion Life Lymphoma MDM2 gene Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Measurable Measures Mission Molecular Mutate NPM1 gene National Institute of General Medical Sciences Nucleolar Proteins Pathway interactions Peptide Hydrolases Phenotype Phosphoproteins Physiological Play Prevention Process Prognosis Proliferating Proteins Public Health Publishing Regulation Research Role Site Stimulus TP53 gene Techniques Testing Tumor Suppression Tumor Suppressor Proteins Visualization base cell type design disease diagnosis experimental study functional outcomes homologous recombination imaging modality innovation insight irradiation malignant breast neoplasm mouse model novel nucleophosmin prevent recruit repaired replication stress response tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Several groups have shown a strong association between caspase-2 deficiency and accelerated tumorigenesis in murine models of lymphoma, breast, and lung cancer. Such phenotypes are often accompanied by enhanced cell proliferation and increased genomic instability with minimal measurable apoptotic defects. Therefore caspase-2 appears to play a crucial role in maintaining genomic stability and may do so independent of its role in apoptosis. To test this, this proposal will study the mechanisms of caspase-2 is activation during the DNA damage response with a focus on the upstream caspase-2 regulator PIDD. The central hypothesis is that DNA damage induces two distinct caspase-2 activation platforms – a cytoplasmic platform that is PIDD independent and a nucleolar platform that requires PIDD – each providing access to distinct substrates that regulate genomic instability by both pro-apoptotic and non-apoptotic mechanisms. This hypothesis has been formulated based on published and preliminary data produced in the applicant’s laboratory showing that caspase-2 is activated in the cytoplasm and in the nucleolus and that the nucleolar activation is dependent on the nucleolar phosphoprotein nucleophosmin (NPM1) for both assembly and function. This hypothesis will be tested by pursuing two specific aims: 1) Determine the mechanisms of caspase-2 activation in the nucleolus versus the cytosol; and 2) Identify the relative contributions of the nucleolar and cytoplasmic complexes to downstream caspase-2 functions and how these protect from genomic instability. Under the first aim, an already proven imaging-based method for measuring caspase-2 activation, will be used to investigate the distinct mechanisms of differential caspase-2 activation in the nucleolus and in the cytosol. These experiments will specifically probe the roles of PIDD and NPM1. Under the second aim, based on preliminary data that shows that caspase-2-deficient cells, proliferate faster and accumulate more DNA damage following replication stress, the requirement of the nucleolar and cytoplasmic complexes for apoptotic and non-apoptotic caspase-2 functions will be explored in the context of apoptosis, cell cycle regulation, substrate cleavage and DNA repair mechanisms. The approach is innovative because it utilizes novel imaging-based techniques that are designed to assess caspase-2 activation in single cells so that the relationship between the localization of caspase-2 activation with apoptosis, DNA damage, and cell division will be directly explored on a per cell basis. It also provides a new paradigm of caspase activation in the nucleolus. The proposed research is significant because it is proposed that site-specific activation of caspase-2 in the cytosol and nucleolus governs distinct functions of this protease that cooperate to protect from genomic instability. These mechanisms may underlie the known physiological roles of caspase-2 in tumor suppression and in protecting against accelerated aging. Ultimately, such knowledge has the potential to inform how diseases where caspase pathways are disrupted can be treated or prevented.

项目总结/文摘