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Updated: Jun 26, 2025

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发育转录因子TBX3的蛋白静态再激活驱动了BRAF/MAPK介导的瘤发生

Zhenlei Zhang¹, Yufan Wu¹, Jinrong Fu²

¹Department of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.

Nature communications

|May 15, 2024

概括

BRAF^V600E驱动的瘤通过USP15去分化,稳定TBX3,这是一个发育因素. 重新激活这个轴驱动瘤生成,而它的删除导致瘤重新分化,突出了关键的蛋白质静止机制.

科学领域:

细胞生物学细胞生物学
发展生物学发展生物学
癌症生物学癌症生物学

背景情况:

激活MAPK通路,特别是BRAF^V600E,通过诱导上皮质分离来驱动瘤发生.
在瘤发生过程中,血统分化被重新编程的精确机制在很大程度上仍未被探索.

研究的目的:

调查发育因素在BRAF/MAPK介导的脱差和瘤发生中的作用.
阐明由MAPK途径驱动的病态转化背后的蛋白静态机制.

主要方法:

利用淘汰模式 (Usp15,Tbx3) 来评估它们对BRAF^V600E驱动的瘤发育的影响.
研究了胚胎发育和瘤发生期间BRAF/MAPK信号,USP15和TBX3之间的相互作用.
分析了瘤分化标志物和临床数据,将USP15和TBX3表达与BRAF^V600E和预后相关联.

主要成果:

证明了发育因子TBX3的蛋白静态重新激活驱动了BRAF/MAPK介导的脱差和瘤发生.
表明BRAF/MAPK可上调USP15,在胚胎发育过程中稳定TBX3,这一过程在瘤中被重新激活.
发现Usp15淘汰赛以Tbx3依赖的方式抑制BRAF^V600E驱动的瘤发育,删除导致瘤重新分化和破坏甲状腺毛囊生成.

结论:

USP15-TBX3轴是BRAF/MAPK信号传输的关键下游效应因子,对于发育恒常和病理转化都至关重要.
瘤发生依赖于通过重新启动胚胎调节程序而实现的上皮脱差.
USP15 TBX3 的稳定代表了一个关键的蛋白质静止机制,将发育途径与癌症进展联系起来,提供了潜在的治疗点.

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