C端融合伙伴活动有助于YAP1::TFE3的致癌功能
bioRxiv : the preprint server for biology
|April 28, 2025
概括
通过激活TEAD,YAP1基因融合驱动癌症. TFE3的融合合作伙伴是TFE3.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症遗传学 癌症遗传学
背景情况:
- YAP1基因融合是各种人类瘤中强大的致癌驱动因素.
- YAP1融合蛋白表现出TEAD-依赖的致癌活性,抵抗Hippo通路信号.
- 在YAP1融合瘤发生过程中,C端融合伙伴的作用还未得到充分研究.
研究的目的:
- 调查TFE3域对YAP1::TFE3融合的致癌功能的贡献.
- 分析TFE3域突变/删除对YAP1::TFE3活性和瘤形成的体外和体内影响.
主要方法:
- 利用RCAS/tv-a系统在体内表达八种不同的YAP1基因融合.
- 通过改变TFE3的DNA结合 (LZ,bHLH) 和激活域 (AD),生成了YAP1::TFE3的突变变体.
- 进行了体外和体内功能测试,以评估瘤活性和瘤发育.
主要成果:
- 与其他YAP1融合相比,TFE3诱导了明显的瘤组织形态学.
- 在体外,TFE3 DNA结合域突变降低了TFE3活性,但增加了YAP1活性.
- 在体内,TFE3 DNA 结合域的缺失产生了 YAP1 类瘤; TFE3 激活域的损失取消了瘤的形成.
结论:
- TFE3 域对 YAP1::TFE3.3 的致癌活性有显著的贡献.
- TFE3激活域对于YAP1::TFE3驱动的瘤形成至关重要.
- 了解这些领域的贡献可以为向癌症治疗提供信息.
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