YAP/TAZ与RBM39相互作用,使其对印苏拉姆产生抗药性
Toshinori Ando1, Kento Okamoto2, Yume Ueda2
1Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, 734-8551, Japan. toando19@hiroshima-u.ac.jp.
Oncogenesis
|July 14, 2024
概括
河马的路径 河马的路径
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:
- 河马通路及其效应体与具有PDZ结合动机 (YAP/TAZ) 的YES相关蛋白/转录协活性剂调节细胞生长和器官发育.
- 河马通路和YAP/TAZ的失调在固体癌症中很常见,包括头部和部状细胞癌 (HNSCC).
- 对于YAP/TAZ核相互作用和对印迪苏拉姆等拼接抑制剂的抵抗机制尚不清楚.
研究的目的:
- 为了识别新的YAP/TAZ相互作用分子.
- 阐明抗印苏拉姆的耐药机制,一种针对RNA结合基因蛋白39 (RBM39) 的剪接抑制剂.
- 探索针对癌症中YAP/TAZ/RBM39相互作用的治疗潜力.
主要方法:
- 蛋白质组分析以确定YAP/TAZ相互作用的蛋白质.
- 调查印苏拉姆对RBM39,YAP/TAZ活动和下游目标的影响.
- 评估YAP/TAZ过活化对印地苏拉姆抗性的作用.
- 在体外和体内实验实验以验证发现.
主要成果:
- 确定RNA结合动机蛋白39 (RBM39) 是一种新的YAP/TAZ相互作用分子.
- RBM39促进了YAP/TAZ转录活性,indisulam通过影响整合素/原表达和焦粘附激酶 (FAK) 活性来降低这种活性.
- 通过延迟RBM39降解,恢复FAK活性,并促进替代拼接,YAP/TAZ过度激活赋予了对印迪苏拉姆的耐药性.
结论:
- 通过保持RBM39稳定性和下游信号传输,YAP/TAZ过度激活驱动了对indisulam的抗性.
- 针对YAP/TAZ/RBM39相互作用可能为患有Hippo信号失调的癌症提供一种新的治疗策略.
- 了解抵抗机制对于开发有效的癌症疗法至关重要.
相关概念视频
01:14Rab Proteins
Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
02:15Experimental RNAi
RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
01:31Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...