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

• 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
• 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

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.

摘要 蛋白毒性应激或蛋白酶体对细胞蛋白酶体活性的抑制 抑制剂药物启动了一条进化上保守的途径， 作为补偿反应的蛋白酶体的重新合成。我们以前的研究 建立了转录因子Nrf 1作为一个关键球员在这一压力反应途径。 Nrf 1通过其与抗氧化反应元件结合的能力，该元件通常存在于 蛋白酶体基因的调节区，诱导它们的表达， 蛋白酶体抑制作为一种内质网（ER）结合的转录因子， 在管腔中的大量多肽中，Nrf 1的激活涉及其逆转位到 细胞质中的一种方式，依赖于ATP酶p97/VCP。这之后是 蛋白水解加工和随后的转录活性形式的动员 Nrf 1到细胞核。对Nrf 1通路的进一步了解可能有助于阐明 细胞科普蛋白毒性应激的复杂机制。为了符合 父母补助金，这个补充的目的是剖析激活的NRF机制1 途径，并测试抑制Nrf 1途径是否会导致 蛋白酶体抑制剂治疗癌细胞。因此，拟议的工作路线是 不仅从促进Nrf 1生物学基础研究的角度来看是重要的， 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