Nrf1-dependent Proteotoxic Stress Response - Diversity Supplement

Nrf1 依赖性蛋白毒性应激反应 - 多样性补充剂

基本信息

批准号：
10378935
负责人：
Senthil Kumar Radhakrishnan
金额：
$ 5.07万
依托单位：
VIRGINIA COMMONWEALTH 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：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378935
关键词：
Antioxidants Aspartic Endopeptidases Autophagocytosis Basic Science Binding Biology Cancer cell line Cell Nucleus Cells Clip Co-Immunoprecipitations Critical Thinking Cytosol DNA Binding Endoplasmic Reticulum Ensure Erythroid Feedback Foundations Genes Genetic Genetic Transcription Goals Grant Holly Human Human Pathology Knowledge Laboratories Lead Light Malignant Neoplasms Mammals Mediator of activation protein Membrane Mentors Methods Molecular Molecular Chaperones Motion Mutagenesis N-terminal Neurodegenerative Disorders Nuclear Nucleic Acid Regulatory Sequences Oral Organism Output Paper Parents Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Positioning Attribute Process Proteasome Inhibition Proteasome Inhibitor Proteins Proteolytic Processing Proteomics Publishing Recovery Regulation Research Response Elements Role Stress Testing Training Transcript Transcriptional Activation Transmembrane Domain Work Writing Yeasts attenuation biological adaptation to stress cancer cell career development career networking experience experimental study human disease loss of function multicatalytic endopeptidase complex novel strategies p97 ATPase parent grant polypeptide promoter protein degradation proteotoxicity response skills symposium therapeutic target transcription factor valosin-containing protein

项目摘要

ABSTRACT Proteotoxic stress or inhibition of cellular proteasome activity by proteasome inhibitor drugs sets in motion an evolutionarily conserved pathway that directs the de novo synthesis of proteasomes as a compensatory response. Our previous studies established the transcription factor Nrf1 as a key player in this stress-response pathway. Nrf1, by its ability to bind to the anti-oxidant response elements typically found in the regulatory regions of proteasome genes, induces their expression in response to proteasome inhibition. As an endoplasmic reticulum (ER)-bound transcription factor with a bulk of its polypeptide in the lumen, Nrf1 activation involves its retrotranslocation into the cytosol in a manner that depends on the ATPase p97/VCP. This is followed by proteolytic processing and subsequent mobilization of the transcriptionally active form of Nrf1 to the nucleus. Further understanding of the Nrf1 pathway could shed light on the intricate mechanisms by which cells cope with proteotoxic stress. In line with the aims of the parent grant, this supplement aims to dissect the mechanism of activation of the Nrf1 pathway and to test if inhibition of Nrf1 pathway leads to increased efficacy of proteasome inhibitor treatment in cancer cells. Thus, the proposed line of work is important not only from a basic research stand-point of furthering Nrf1 biology; it is also significant from a translational perspective as well, since it has the potential to illuminate novel strategies to modulate the cellular protein clearance pathways in various human diseases.

抽象的蛋白酶体对细胞蛋白酶体活性的蛋白毒性应激或抑制抑制剂药物启动了一条进化上保守的途径，指导 de 蛋白酶体的新合成作为补偿反应。我们之前的研究确立了转录因子 Nrf1 作为该应激反应途径的关键角色。 Nrf1 能够与通常存在于体内的抗氧化反应元件结合蛋白酶体基因的调节区域，诱导其表达以响应蛋白酶体抑制。作为内质网 (ER) 结合转录因子 Nrf1 的大部分多肽位于管腔中，Nrf1 的激活涉及其逆转录转位到以依赖于 ATP 酶 p97/VCP 的方式进入细胞质。接下来是转录活性形式的蛋白水解加工和随后的动员 Nrf1 至细胞核。对 Nrf1 通路的进一步了解可以揭示细胞应对蛋白毒性应激的复杂机制。符合以下目标家长资助，本补充旨在剖析 Nrf1 的激活机制途径并测试 Nrf1 途径的抑制是否会导致功效增加蛋白酶体抑制剂治疗癌细胞。因此，拟议的工作范围是不仅从促进 Nrf1 生物学的基础研究角度来看很重要；这也是从翻译的角度来看也很重要，因为它有可能阐明调节各种人类细胞蛋白质清除途径的新策略疾病。