Roles of C19ORF5 and LRPPRC in Autophagy and Tumor Suppression

C19ORF5 和 LRPPRC 在自噬和肿瘤抑制中的作用

基本信息

批准号：
7984798
负责人：
Leyuan Liu
金额：
$ 24.32万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-02 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7984798
关键词：
Adopted Aneuploid Cells Aneuploidy Autophagocytosis Binding Biochemical Biogenesis Biological Cancer Relapse Cell Death Cell physiology Cells Chromosome Breakage Chromosomes, Human, Pair 19 Collaborations Cytochrome-c Oxidase Deficiency Cytogenetics DNA Double Strand Break Diethylnitrosamine Disease Endoplasmic Reticulum Energy Supply Evolution First Name Functional disorder Garbage Generations Genomic Instability Goals Growth Heat shock proteins Hepatocyte Homeostasis Homologous Gene Human Human Chromosomes Human Development Karyotype Knockout Mice Knowledge Lead Leigh Disease Location Lysosomes Malignant Neoplasms Mediating Metaphase Spread Microtubule-Associated Proteins Mitochondria Mitotic Mus Mutation Names Nerve Degeneration Neurons Open Reading Frames Organelles Oxidative Stress Paclitaxel Pathway interactions Pharmaceutical Preparations Population Primary carcinoma of the liver cells Protein Biosynthesis Proteins Radiation Recurrence Regulation Relapse Research Role Structure-Activity Relationship Testing Tissues Transgenic Organisms Tumor Suppression Tumor Suppressor Proteins Variant age related base biochemical model biological adaptation to stress chemotherapy design docetaxel endoplasmic reticulum stress human disease microtubule-associated protein 1B novel prevent protein aggregate protein aggregation prototype public health relevance stress protein trafficking tumor tumorigenesis wasting

项目摘要

DESCRIPTION (provided by applicant): Mitochondria supply energy for cellular function while their dysfunction causes cell death. Endoplasmic reticulum (ER) mediates protein synthesis and folding and its dysfunction causes ER stress and protein aggregation. Autophagy is activated to clean up defective mitochondria and protein aggregates (aggresomes) through lysosomes to maintain mitochondrial homeostasis and relieve ER stress. Autophagic dysfunction induces oxidative stress that causes DNA double strand breaks and the generation of aneuploidy cells leading to cancers. We discovered that C19ORF5 regulates general autophagy and mitotic mitophagy in collaboration with tumor suppressor RASSF1A-mediated microtubular dynamics and overall autophagic activity via Bcl-2/XL protein-controlled canonical and noncanonical autophagic pathways. We predict that C19ORF5 inhibits the generation of aneuploidy to prevent cancer at its origin and impedes further karyotype evolution that underlies cancer's variability and relapse after therapy. To test the hypothesis, specific aims are designed to characterize (1) the mechanism by which C19ORF5 regulates autophagy, and (2) the mechanism by which C19ORF5 suppresses tumorigenesis through autophagic regulation. The experimental approach will use C19ORF5 knockout mice carrying a transgenic autophagic marker GFP-LC3 and their primary hepatocyte cultures as models for biochemical, cell biological and cancer biological studies. The ultimate goal is to understand the general mechanism of tumor suppression and develop strategies to prevent cancers at their origin and terminate cancer relapse after therapy in general using the hepatoma as a prototype. PUBLIC HEALTH RELEVANCE: It is estimated that about half of ageing-related human diseases are caused by accumulation of cellular garbage due to dysfunction in mechanisms for cleaning up mis-folded/aggregated proteins and worn-out dysfunctional organelles. Autophagy, mitophagy when applied to mitochondria, maintains a healthy population of mitochondria and eliminates the toxic macromolecular waste so that oxidative stress-induced genomic instability is prevented. C19ORF5 regulates autophagy in general and mitophagy in particular and prevents tumorigenesis. The new knowledge will eventually lead to develop strategies to terminate cancer at its earliest origin, sensitize human cancers to radiation treatment and chemotherapy, and prevent tumor re-growth and disease recurrence.

描述（由申请人提供）：线粒体为细胞功能提供能量，而其功能障碍会导致细胞死亡。内质网（ER）介导蛋白质的合成和折叠及其功能障碍会导致ER应力和蛋白质聚集。自噬被激活以清除有缺陷的线粒体和蛋白质聚集体（脂肪组）通过溶酶体维持线粒体稳态并缓解ER应激。自噬功能障碍会诱导氧化应激，从而导致DNA双链断裂并产生导致癌症的非整倍性细胞。我们发现，C19ORF5通过BCL-2/XL蛋白控制的规范和非法规自噬途径与肿瘤抑制剂RASSF1A介导的微管动力学和总体自噬活性调节一般自噬和有丝分裂有线液。我们预测，C19ORF5抑制了非整倍性的产生，以预防癌症的起源，并阻碍核型进化，这是癌症的可变性和治疗后复发的基础。为了检验假设，设计特定的目的旨在表征（1）C19ORF5调节自噬的机制，以及（2）C19ORF5通过自噬调节抑制肿瘤发生的机制。实验方法将使用带有转基因自噬标记GFP-LC3及其原发性肝细胞培养物的C19orf5敲除小鼠作为生化，细胞生物学和癌症生物学研究的模型。最终的目标是了解肿瘤抑制的一般机制，并制定策略以防止癌症起源，并在治疗通常以肝癌为原型的治疗后终止癌症复发。公共卫生相关性：据估计，与老年相关的人类疾病的大约一半是由于细胞垃圾的积累而引起的，这是由于清理错误折叠/聚集的蛋白质和衰竭功能障碍的器官的机制的功能障碍而引起的。自噬，线粒体应用于线粒体时，可以保持健康的线粒体群体并消除有毒的大分子分子废物，从而防止氧化应激诱导的基因组不稳定性。 C19orf5通常调节自噬，尤其是线粒体，并防止肿瘤发生。新知识最终将导致制定以最早起源终止癌症的策略，使人类癌症对放射治疗和化学疗法的敏感，并防止肿瘤的再生和疾病复发。