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：
10673815
负责人：
Yi Zhang
金额：
$ 24.9万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10673815
关键词：
Adopted Advisory Committees Affinity Autophagocytosis Binding Biology Biophysics Black race CRISPR/Cas technology Cell Death Cell Death Induction Cell Line Cell Proliferation Cell Survival Cells Cellular Structures Cellular biology Cessation of life Chromatin Collaborations 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 Immunoprecipitation Lasers Learning Ligand Binding Ligands Link Malignant Neoplasms Measurement Mediating Mentors Mentorship Methods Modeling 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 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.

项目概要/摘要自噬的背景依赖性作用与癌症有关，并且自噬的调节已被证实 Sequestosome1 (SQSTM1/p62) 成为癌症治疗的新实验策略是众所周知的。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 的积累和失调与肿瘤有关。形成、进展和对治疗的抵抗，因此 p62 正在成为癌症的新治疗靶点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) 应激期间产生的错误折叠蛋白质，以及重要的是，靶向 p62 ZZ 结构域 (p62ZZ) 的小分子已被证明可以抑制多发性骨髓瘤 (MM) 细胞生长。然而，p62ZZ 配体如何抑制 MM 细胞生长，更广泛地说，p62 如何感知压力和调节细胞途径仍未完全了解。我们还发现 p62ZZ 结合组蛋白 H3 尾部，连接 p62 的染色质靶向最近发现的 p62 在 DNA 损伤反应中的作用，这种作用经常被 MM 至今仍是一种无法遏制的血液癌症，其特点是持续性的。我们追求 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，是激活特定途径（例如 mTORC1 激活）的决定因素，自噬和 DNA 修复。用 p62 配体处理细胞会劫持 p62 并抑制其正常功能，从而导致。该应用旨在确定压力积累和细胞生长抑制的机制。直接靶向 p62ZZ 抑制 MM 细胞生长的作用（Aim1）；阐明分子机制 mTORC1 或自噬途径的潜在 p62 依赖性选择性激活（Aim2）；并定义其作用 DNA 损伤反应中 p62 染色质靶向的研究（Aim3）。在 Tatiana Kutateladze 博士的指导下进行，Tatiana Kutateladze 博士是一位著名的结构生物学家表观遗传学领域，并在指导年轻科学家相关的细胞实验方面拥有良好的记录。自噬和 DNA 损伤反应，我将向 Andrew Thorburn 博士学习并与他合作，他是一位领先的自噬领域的专家，以及染色质生物学专家 Joshua Black 博士的进展。研究和职业发展将受到奉献和支持的咨询委员会的密切监督。 K99阶段的目标是完成Aim1并启动提案的其余目标并建立一个强大的我的长期目标是阐明成为一名独立调查员的基础。使用多学科方法研究 p62 依赖性信号传导和调节途径的机制，特别是那些与人类疾病有关的疾病，K99 资助将通过提供关键的帮助来极大地帮助我。培训，帮助我获得教职，并让我开始作为一名独立研究员的职业生涯。