Micro-RNA-dependent regulation of the UPR

UPR 的 Micro-RNA 依赖性调节

• 批准号: 8596329
• 负责人: John Alan Diehl
• 金额: $ 30.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596329
• 关键词: Apoptosis; Apoptotic; Attenuated; Base Pairing; Biological; Biological Process; Cell Cycle; Cell Cycle Progression; Cell Death; Cell Survival; Cells; Chemosensitization; Chromatin; Collaborations; Cyclin D1; Defect; Development; Endoplasmic Reticulum; Enzymes; Equilibrium; Foundations; Functional RNA; Gene Expression; Genes; Genetic Translation; Glucose; Goals; Growth; Growth Factor; Homeostasis; IFNAR1 gene; Instruction; Integral Membrane Protein; Interferons; Introns; Malignant Neoplasms; Mammalian Cell; Mediating; Mediator of activation protein; Metabolic; MicroRNAs; Molecular; Molecular Chaperones; Normal Cell; Nucleotides; Nutrient; Oncogenic; Organelles; Organism; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathway interactions; Phosphotransferases; Play; Proliferating; Protein Kinase; Proteins; RNA; Regulation; Role; Signal Pathway; Signal Transduction; Stress; Structure; Testing; Tissues; Transducers; Translations; Tumor Volume; Tumor-Derived; Virus Diseases; Work; biological adaptation to stress; cancer cell; cancer therapy; cell growth; deprivation; design; endoplasmic reticulum stress; glucose metabolism; inhibitor/antagonist; insight; interest; mRNA Transcript Degradation; mammalian genome; neoplastic cell; novel; prevent; protein misfolding; protein transport; response; small molecule; stem; transcription factor; transcription factor CHOP; tumor growth; tumor progression; tumorigenesis; ubiquitin-protein ligase

Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. In normal cells, limits in nutrient availability trigger growth arrest and/or apoptosis, thereby preventing cellular expansion under such conditions. The goal of this proposal is to determine the role of the endoplasmic reticulum stress response/Unfolded Protein Response (UPR) in sensing limitations in glucose availability, and thereby facilitating cellular adaptation. PERK, one of three proximal signal transducers of the UPR, plays a central role in mediating cell fate decisions; this kinase has recently been demonstrated to function in the potentiation of tumor growth and survival. Central to our understanding of PERK-dependent survival is dissecting the significance of PERK pro-survival signaling through ATF4 versus PERK-dependent apoptotic signals through the induction of CHOP. Critically, how pro-survival signals are balanced with the induction of the pro-apoptotic transcription factor, CHOP, has remained poorly understood for over a decade. Our preliminary work suggests an overarching hypothesis that temporal regulation of miR- 211 coordinates cellular adaptation with apoptosis in cells exposed to endoplasmic reticulum stress. To test this hypothesis we will 1) determine the mechanisms of ER stress-dependent induction of miR-211 accumulation; 2) elucidate the mechanism(s) that regulate miR-211 stability; and 3) determine the role of miR-211 in tumorigenesis. These studies will provide critical new insight into the mechanisms whereby the PERK protein kinase regulates cell homeostasis in response to stress. There are obvious points of cross- talk between this proposal and Project 2 which focuses on how the UPR antagonizes myc induced apoptosis and potentiates tumor cell adaptation. Through collaboration with Project 2, we will assess the role of m|R- 211 as a mediator of cell growth and survival in myc-dependent tumorigenesis. Project 1 intersects with Project 3 through common interests on how PERK regulates IFNAR1, the IFNAR1 E3 ligase and IFNAR1 signaling during tumorigenesis. Through collaboration with Project 3, we will detrmine how miR-211 regulates IFNAR1 regulation during ER stress and tumorigenesis as well as assess miR-211 regulation of downstream interferon signaling. The.findings steming from the work proposed herein will provide a foundation for the design of novel anti-cancer therpeutics. RELEVANCE (See instructions): Recent work has revealed that inactivation of PERK promotes tumor progression, providing support for the development of small molecule inhibitors of PERK for cancer treatment. While these studies provide clear biological support for such approaches, our understanding of how PERK regulates cell survival versus ' apoptosis following oncogenic insult is limited. The work described in this project will delineate molecular mechanisms whereby PERK regulates the temporal onset of apoptosis.

快速增殖的癌细胞必须在微环境中茁壮成长，其中代谢营养物， 当肿瘤体积扩大超过既定的体积时，葡萄糖、氧气和生长因子变得有限。 组织的血管分布。在正常细胞中，营养可用性的限制触发生长停滞和/或凋亡， 从而防止细胞在这种条件下扩张。本提案的目的是确定 内质网应激反应/未折叠蛋白反应（UPR）在感受限制中的作用 葡萄糖可用性，从而促进细胞适应。PERK，三个近端信号之一 UPR的转换器，在介导细胞命运决定中起着核心作用;这种激酶最近被 证实在增强肿瘤生长和存活中起作用。我们理解的核心是 PERK依赖性生存是剖析PERK促生存信号转导的意义，通过ATF 4与 通过CHOP诱导的PERK依赖性凋亡信号。重要的是，支持生存的信号 与促凋亡转录因子CHOP的诱导相平衡， 十多年了我们的初步工作提出了一个总体假设，即miR的时间调控- 211在暴露于内质网应激的细胞中协调细胞适应与凋亡。测试 我们将1）确定miR-211的ER应激依赖性诱导机制 积累; 2）阐明调节miR-211稳定性的机制;和3）确定miR-211的作用。 miR-211与肿瘤发生这些研究将提供关键的新的洞察机制， PERK蛋白激酶调节细胞对应激的稳态反应。有明显的交叉点-- 这个建议和项目2之间的谈话，项目2的重点是UPR如何拮抗myc诱导的凋亡 并增强肿瘤细胞的适应性。通过与项目2的合作，我们将评估m的作用|R-- 211作为myc依赖性肿瘤发生中细胞生长和存活的介导物。项目1与 项目3通过对PERK如何调节IFNAR 1，IFNAR 1 E3连接酶和IFNAR 1的共同兴趣 在肿瘤发生过程中的信号传导。通过与项目3的合作，我们将确定miR-211 在ER应激和肿瘤发生过程中调节IFNAR 1调节，以及评估miR-211对 下游干扰素信号传导。本文所提出的工作的结果将提供一个 为设计新型抗癌疗法奠定了基础。 相关性（参见说明）： 最近的研究表明，PERK的失活促进了肿瘤的进展，为肿瘤的发生提供了支持。 开发用于癌症治疗的PERK小分子抑制剂。虽然这些研究提供了明确的 生物学支持这样的方法，我们的理解如何PERK调节细胞存活与' 致癌损伤后的细胞凋亡是有限的。在这个项目中描述的工作将描绘分子 PERK调节细胞凋亡时间起始的机制。