核无处不在允许Hippo-YAP信号用于肝脏发育和瘤发生
Jinsong Wei1,2, Zhifa Cao1,3, Qing Li3
1Department of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Nature chemical biology
|May 16, 2025
概括
E3结合酶UBR5针对VGLL4进行降解,激活Hippo-YAP信号,这对肝脏发育和癌症至关重要. 这一发现揭示了核无所不在作为YAP依赖癌症的潜在治疗策略.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 发展生物学 发展生物学
背景情况:
- 海马-YAP信号调节器官发育,并与瘤发生有关.
- VGLL4通过抑制YAP与TEAD转录因子的结合,充当一个关键的转录抑制剂.
研究的目的:
- 为了确定负责VGLL4降解的E3酶.
- 阐明UBR5-VGLL4-YAP轴在肝脏发育和人类癌症中的作用.
主要方法:
- 通过ubiquitination测试,识别UBR5作为VGLL4的E3酶.
- 在小鼠肝脏发育中的Ubr5和Vgll4表达模式的分析.
- 在患者衍生瘤器官中研究UBR5-VGLL4-YAP轴.
主要成果:
- UBR5被确定为核E3结合酶,该结合酶在Lys61处聚-ubiquitinatesVGLL4,导致其降解.
- 在小鼠肝脏发育过程中观察到Ubr5和Vgll4的相互表达.
- 向核E3连接酶抑制了患者衍生的瘤器官的扩张.
结论:
- 通过UBR5介导的VGLL4降解是调节核Hippo-YAP信号的关键机制.
- UBR5-VGLL4-YAP通路对于肝胆道系统的发育至关重要,在人类胰腺癌中是失调的.
- 核无处不在为依赖YAP的恶性瘤提供了一个有前途的治疗标.
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