TMEM127通过促进RET无化,定位和降解来抑制瘤的发展
Qianjin Guo1, Zi-Ming Cheng1, Hector Gonzalez-Cantú1
1Division of Hematology/Medical Oncology, Department of Medicine, University of Texas Health San Science Center at Antonio (UTHSCSA), San Antonio, TX, USA.
Cell reports
|September 2, 2023
概括
TMEM127基因的丢失,在染细胞瘤中发生突变,导致RET蛋白的积累和信号的增加. 用抑制剂准RET可以逆转瘤生长,揭示TMEM1277.
科学领域:
- 内分泌学 在内分泌学.
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- TMEM127基因编码了一种具有未知功能的跨膜蛋白.
- 在TMEM127中发生的突变被发现在神经脊顶细胞衍生出的瘤 - - 发黑细胞瘤中.
- 乳色细胞瘤是上腺髓的瘤.
研究的目的:
- 为了研究TMEM127在染细胞瘤发育中的功能.
- 阐明将TMEM127突变与瘤形成联系起来的分子机制.
- 探索针对TMEM127突变染细胞瘤中RET通路的治疗策略.
主要方法:
- 瘤细胞的单核分辨率分析.
- 对TMEM127和RET蛋白相互作用和信号的研究.
- 使用人类细胞和小鼠淘汰模式.
- 在体外和体内评估RET抑制剂的疗效.
主要成果:
- TMEM127突变瘤与RET突变瘤共享前体细胞.
- 丧失TMEM127会导致RET蛋白的积累和信号增加.
- TMEM127通过无素-蛋白酶体系统促进RET降解.
- 选择性RET抑制剂在TMEM127缺乏模型中逆转了增加的细胞增殖和瘤负担.
结论:
- TMEM127是调节RET蛋白稳定性的泛素系统的一个组成部分.
- 由于TMEM127功能丧失突变,异常的RET稳定驱动着染细胞瘤的发展.
- 针对RET途径提供了一个潜在的治疗策略,用于TMEM127突变染细胞瘤.
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