在NRF2-p97-NRF2负反循环中
Aryatara Shakya1, Pengfei Liu2, Jack Godek1
1Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA.
Redox biology
|August 13, 2023
概括
蛋白质p97负面调节NRF2,但NRF2也针对p97,创建一个反循环. 癌症的这种双重上调表明抑制NRF2和p97可能是治疗策略.
科学领域:
- 细胞生物学 细胞生物学
- 蛋白质稳定酶的分子机制
- 氧化还原平衡 (redox homeostasis) 是一种
背景情况:
- p97 (VCP) 是一种依赖ATP的分离酶,参与蛋白质稳定.
- p97通过促进其蛋白质体降解来负面调节NRF2.
- NRF2是细胞防御氧化应激的关键转录因子.
研究的目的:
- 调查p97和NRF2.2.之间的监管关系.
- 阐明NRF2-p97-NRF2反循环在氧化还原稳定中的作用.
- 探索向癌症中的NRF2和p97的治疗潜力.
主要方法:
- 通过CRISPR/Cas9基因组编辑来突变p97基因中的ARE.
- 在工程细胞系和人类癌症患者数据中分析p97和NRF2表达.
- 评估NRF2和p97抑制在癌细胞中的协同效应.
主要成果:
- 鉴定出p97是NRF2的基因,建立了一个负反循环.
- p97 ARE-突变细胞显示了改变的p97/NRF2表达和受损的NRF2反应.
- 在人类癌症中观察到NRF2激活和p97表达之间的正相关性.
- 联合抑制NRF2和p97协同杀死具有两者的高表达率的癌细胞.
结论:
- 一个新的NRF2-p97-NRF2负反循环维持了氧化还原平衡.
- NRF2和p97的双重上调与某些癌症有关.
- 同时抑制NRF2和p97为特定癌症患者群体提供了潜在的治疗策略.
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