p62 in Cancer: Mechanism and Regulation

p62 在癌症中的作用：机制和调控

基本信息

批准号：
9806742
负责人：
Yi Zhang
金额：
$ 10.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2019-07-02 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9806742
关键词：
Adopted Advisory Committees Affinity Autophagocytosis Binding Biology Biophysics CRISPR/Cas technology Cell Death Cell Line Cell Proliferation Cell Survival Cells Cellular biology Cessation of life Chromatin Co-Immunoprecipitations Complex Cytosol DNA Damage DNA Repair Data Development Dipeptides Embryo Epigenetic Process Excision Faculty Failure Fibroblasts Foundations Goals Grant Growth H2AFX gene Hematopoietic Neoplasms Histone H3 Immunofluorescence Immunologic Lasers Lead Learning Ligand Binding Ligands Light Link Malignant Neoplasms Measurement Mediating Mentors Mentorship Methods Molecular Molecular Conformation Monitor Multiple Myeloma Mus Nuclear Nutrient Osteogenesis Pathway interactions Phase Phenotype Positioning Attribute Regulation Regulatory Pathway Research Research Personnel Resistance Resolution Rest Role Scientist Secure Signal Pathway Signal Transduction Site Stains Stress Structural Biologist Structural Models Structure Structure-Activity Relationship Tail Testing Therapeutic Training Ubiquitin arginylglutamate bone cancer cell cancer therapy career career development cell growth combination cancer therapy design endoplasmic reticulum stress experimental study fighting human disease interdisciplinary approach irradiation misfolded protein mutant new therapeutic target novel novel strategies recruit research and development response skills small molecule structural biology therapy resistant tumor

项目摘要

Project Summary/Abstract A context dependent role of autophagy has been implicated in cancer, and modulation of autophagy has becoming a new experimental strategy in cancer treatment. Sequestosome1 (SQSTM1/p62) is a known autophagy adaptor and mediates cell proliferation, survival and death through multiple signaling pathways, including mTORC1 activation and autophagy. Accumulation and misregulation of p62 has been linked to tumor formation, progression and resistance to therapy, thus p62 is emerging as a new therapeutic target in cancer treatment. Recent studies from our lab and others revealed a critical role of p62 in the autophagic cascade responsible for sequestration of misfolded proteins generated during endoplasmic reticulum (ER) stress, and importantly, small molecules targeting the ZZ domain of p62 (p62ZZ) have been shown to inhibit multiple myeloma (MM) cell growth. Yet how p62ZZ ligands inhibits MM cell growth and more broadly, how p62 senses stress and regulates cellular pathways are still not fully understood. We also found that p62ZZ binds histone H3 tail, linking the chromatin targeting of p62 to a recently discovered role of p62 in DNA damage response, which is frequently targeted in cancer therapeutics. MM is still an uncurbable blood cancer today and is characterized by constitutive high ER-stress. We hypothesize that the conformational state and intracellular level of p62, controlled by its interaction with cellular signals, is the determinant to activate a specific pathway such as mTORC1 activation, autophagy and DNA repair. Treating cells with p62 ligands hijacks p62 and inhibits its normal function, leading to accumulation of stress and cell growth suppression. This application aims to determine the mechanism of action that directly targeting p62ZZ inhibits MM cell growth (Aim1);; elucidate the molecular mechanisms underlying p62-dependent selective activation of mTORC1 or autophagy pathways (Aim2);; and define the role of p62 chromatin targeting in DNA damage response (Aim3). The K99 phase of the proposed studies will be conducted under the mentorship of Dr. Tatiana Kutateladze, who is a well-regarded structural biologist in the epigenetics field and has a strong record in mentoring young scientists. For the cellular experiments related to autophagy and DNA damage response, I will learn from and collaborate with Dr. Andrew Thorburn, a leading expert in the field of autophagy, and Dr. Joshua Black who is an expert in chromatin biology. My progress in research and career development will be closely monitored by the dedicative and supportive advisory committee. The goal for the K99 phase is to complete Aim1 and initiate the rest aims of the proposal and build a strong foundation for my transition to becoming an independent investigator. My long-term goal is to elucidate the mechanisms of p62-dependent signaling and regulatory pathways, using multidisciplinary approaches, particularly those have been implicated in human diseases. A K99 grant would greatly aid me by providing critical training, helping me secure a faculty position and allowing me to start my career as an independent researcher.

项目摘要/摘要自噬的背景依赖性作用在癌症中隐含，自噬的调节具有成为癌症治疗中的新实验策略。 secestosome1（SQSTM1/p62）是已知的自噬适配器并通过多种信号通路介导细胞增殖，存活和死亡，包括MTORC1激活和自噬。 p62的积累和不调节与肿瘤有关形成，进展和对治疗的抵抗力，因此p62正在成为癌症的新治疗靶点治疗。我们实验室和其他人的最新研究揭示了p62在自噬级联中的关键作用负责隔离内质网（ER）应力期间产生的错误折叠的蛋白质和重要的是，针对p62（p62zz）Zz结构域的小分子已显示可抑制多发性骨髓瘤（MM）细胞生长。然而，p62zz配体如何抑制MM细胞生长，更广泛地抑制p62感觉应激和调节细胞途径仍未完全了解。我们还发现p62zz结合了组蛋白H3尾巴，链接 p62靶向p62在DNA损伤反应中的作用，这是经常是针对癌症治疗剂。 MM当今仍然是一种不可扰的血液癌，其特征是本构型高ER应力。我们假设p62的构象状态和细胞内水平由其控制与细胞信号的相互作用是确定激活特定途径，例如MTORC1激活，自噬和DNA修复。用p62配体劫持p62的细胞并抑制其正常功能，领先压力和细胞生长抑制的积累。该应用程序旨在确定直接靶向P62ZZ的作用抑制MM细胞生长（AIM1）;阐明分子机制 MTORC1或自噬途径的基本p62依赖性选择性激活（AIM2）;;并定义角色 DNA损伤反应中的p62染色质靶向（AIM3）。拟议研究的K99阶段将是在塔蒂亚娜·库特塔德兹（Tatiana Kutateladze）博士的心态下进行，他是一位备受赞誉的结构生物学家表观遗传学领域，在心理年轻科学家方面具有良好的记录。对于与自噬和DNA损伤响应，我将与领先的Andrew Thorburn博士一起学习并合作自噬领域的专家和染色质生物学专家的Joshua Black博士。我的进度研究和职业发展将受到敬业和支持咨询委员会的密切监控。 K99阶段的目标是完成AIM1并启动该提案的其余目标并建立强大我的过渡成为独立调查员的基础。我的长期目标是阐明使用多学科方法，依赖p62的信号传导和调节途径的机制，特别是在人类疾病中暗示的。 K99的赠款通过提供关键来极大地帮助我培训，帮助我确保教师职位，并允许我开始作为独立研究人员的职业。