Nucleolar signaling in cancer

癌症中的核仁信号传导

基本信息

批准号：
10064617
负责人：
DIMITRI G PESTOV
金额：
$ 8.05万
依托单位：
ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064617
关键词：
ATM Signaling Pathway ATM function Anabolism Antineoplastic Agents Biogenesis Biological Cancer Biology Cancer Patient Cell Death Cell Line Cell Nucleolus Cell Survival Cell model Cells Cellular biology Chromatin Complement Confocal Microscopy Cyclic AMP-Dependent Protein Kinases DNA DNA Damage Data Defense Mechanisms Dissection Doxycycline Gap Junctions Genetic Goals Heterochromatin Hybrids Immunofluorescence Immunologic Impairment Instruction Invaded Isopropyl Thiogalactoside Knowledge Laboratories Lead Learning Link Malignant Neoplasms Mediating Mediator of activation protein Metabolism Modality Modeling Molecular Mutate Normal Cell Organelles Oxidation-Reduction Oxidative Stress Pathway interactions Patients Pharmaceutical Preparations Physiological Play Process Protein Deficiency Protein Kinase RNA Reagent Recombinant DNA Regulation Research Resistance Resources Ribosomes Role Sensory Signal Pathway Signal Transduction Site Stains Stress Structure System TP53 gene Testing Therapeutic Intervention Time Treatment Efficacy Work anti-cancer therapeutic ataxia telangiectasia mutated protein biological adaptation to stress cancer therapy chemotherapeutic agent chemotherapy combinatorial comparative drug sensitivity genome integrity genotoxicity improved insight interest mutant neoplastic cell novel novel therapeutic intervention oxidation protein activation protein complex response stressor therapy outcome transcriptome transcriptome sequencing tumor

项目摘要

Project Summary/Abstract The nucleolus is a cellular organelle that carries out the synthesis of ribosomes and has a multitude of sensory and regulatory functions in the cell. Interference with biosynthetic processes in the nucleolus triggers a p53- dependent nucleolar stress response that promotes cell death in some contexts but can be cytoprotective in others, leading to increased cell resistance to genotoxic drugs. The regulatory functions of the nucleolus are thus important for understanding tumor responses to chemotherapy agents, but how exactly nucleolar stress influences therapeutic outcomes is not known. Our recent studies suggest that nucleolar stress may cross- activate components of the DNA damage response (DDR) pathway that helps to maintain genome integrity. We hypothesize that the capacity of the nucleolus to engage the DDR machinery is important for the timely activation of cellular defense mechanisms essential for cell survival. This proposal focuses on the signaling link between the nucleolus and the ATM protein kinase, a key mediator of the DDR. Using our previously developed cell models for the conditional inhibition of specific ribosome biosynthesis steps, we will determine whether ATM activation during nucleolar stress occurs in a similar or different way compared with its activation by DNA damage and oxidative stress. We will also examine chromatin markers associated with the stressed nucleolus and their possible colocalization with ATM complexes. Finally, profiling transcriptome changes in ATM-proficient and deficient cells will be used to assess the biological role of ATM in the nucleolar stress response. This study will advance our understanding of the signaling mechanisms induced by nucleolar stress. The generated knowledge will be important as it can be applied to increase the differential margins of drug sensitivity in normal and tumor cells and thus improve the efficacy of therapeutic interventions in cancer patients.

项目概要/摘要核仁是一种细胞器，负责合成核糖体，并具有多种感觉功能和细胞内的调节功能。干扰核仁中的生物合成过程会触发 p53- 依赖性核仁应激反应，在某些情况下促进细胞死亡，但在某些情况下可以起到细胞保护作用其他，导致细胞对基因毒性药物的抵抗力增加。核仁的调节功能是因此对于了解肿瘤对化疗药物的反应很重要，但核仁应激究竟如何影响治疗结果尚不清楚。我们最近的研究表明，核仁应激可能会交叉激活 DNA 损伤反应 (DDR) 途径的组成部分，有助于维持基因组完整性。我们假设核仁参与 DDR 机制的能力对于及时激活细胞生存所必需的细胞防御机制。本提案重点关注信令链路核仁和 ATM 蛋白激酶（DDR 的关键介质）之间。使用我们之前的开发了用于条件抑制特定核糖体生物合成步骤的细胞模型，我们将确定与其激活相比，核仁应激期间ATM的激活是否以相似或不同的方式发生 DNA 损伤和氧化应激。我们还将检查与压力相关的染色质标记核仁及其可能与 ATM 复合物的共定位。最后，分析转录组变化 ATM 充足和缺乏的细胞将用于评估 ATM 在核仁应激中的生物学作用回复。这项研究将增进我们对核仁应激诱导的信号传导机制的理解。生成的知识非常重要，因为它可以应用于增加药物的差异利润正常细胞和肿瘤细胞的敏感性，从而提高癌症治疗干预的功效患者。