VHL通过PHD1-依赖的Beclin1氧化抑制了自和瘤生长
Zheng Wang1,2, Meisi Yan3, Leiguang Ye4
1Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, 310029, Hangzhou, China.
The EMBO journal
|February 15, 2024
概括
·希佩尔-林道 (VHL) 蛋白抑制营养应激诱导的自,这是清细胞细胞癌 (ccRCC) 中的一个关键过程. 缺少VHL增加了自,使患者的预后恶化,并建议联合自和HIF2α抑制作为潜在的ccRCC治疗.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- ·希佩尔-林道 (VHL) 蛋白质是低氧诱导因子 (HIF) 的关键调节者,在清细胞细胞癌 (ccRCC) 中经常发生突变.
- 不完全理解VHL在瘤抑制中的确切作用,独立于其HIF调节功能.
- 自是一种细胞降解过程,与癌症的发展和进展有关.
研究的目的:
- 研究VHL蛋白的潜在的HIF独立瘤抑制功能.
- 阐明VHL调节自的机制,特别是在对营养压力的反应中.
- 探索针对VHL缺乏ccRCC中的自的治疗潜力.
主要方法:
- 在零星的ccRCC标本中分析VHL和自水平.
- 生物化学测试以确定VHL与自调节器Beclin1.1之间的相互作用.
- 使用野生类型和突变Beclin1 (P54A) 的功能研究来评估VHL对自启动的影响.
- 在体内研究涉及与自和HIF2α抑制剂联合治疗VHL缺乏的小鼠瘤.
主要成果:
- 在ccRCC标本中VHL缺乏与显著升高的自水平和较差的患者预后有关.
- VHL直接与Beclin1结合 (在Pro54上氧化),以抑制Beclin1-VPS34复合物的形成,从而抑制自开始.
- 非氧化Beclin1突变体的表达取消了VHL介导的自抑制,并降低了VHL的瘤抑制活性.
- 自和HIF2α的联合抑制有效地抑制了VHL缺乏的小鼠模型中的瘤生长.
结论:
- 通过抑制营养物质压力诱导的自,VHL具有以前未知的HIF独立瘤抑制作用.
- 由Beclin1基化调解的VHL-Beclin1相互作用对于VHL的自抑制功能至关重要.
- 针对自和HIF2α同时呈现出对VHL缺乏ccRCC的有前途的治疗策略.
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