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THUNDER樣機最新應(yīng)用展示 | 天津醫(yī)科大學趙麗課題組

更新時間:2024-06-07      點擊次數(shù):528
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刊登雜志:

naturecommunications 

影響因子:

16.6

文章題目:

Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis

用戶機構(gòu):

天津醫(yī)科大學趙麗課題組

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摘要:

MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation. However, how lineage differentiation events are reprogrammed remains unexplored. Here, we demonstrate that proteostatic reactivation of developmental factor, TBX3, accounts for BRAF/MAPK-mediated dedifferentiation and tumorigenesis. During embryonic development, BRAF/MAPK upregulates USP15 to stabilize TBX3, which orchestrates organogenesis by restraining differentiation. The USP15-TBX3 axis is reactivated during tumorigenesis, and Usp15 knockout prohibits BRAFV600E-driven tumor development in a Tbx3-dependent manner. Deleting Tbx3 or Usp15 leads to tumor redifferentiation, which parallels their overdifferentiation tendency during development, exemplified by disrupted thyroid folliculogenesis and elevated differentiation factors such as Tpo, Nis, Tg. The clinical relevance is highlighted in that both USP15 and TBX3 highly correlates with BRAFV600E signature and poor tumor prognosis. Thus, USP15 stabilized TBX3 represents a critical proteostatic mechanism downstream of BRAF/MAPK-directed developmental homeostasis and pathological transformation, supporting that tumorigenesis largely relies on epithelial dedifferentiation achieved via embryonic regulatory program reinitiation.




本研究表明,發(fā)育因子TBX3的蛋白抑制再激活,解釋了BRAF/ mapk介導(dǎo)的去分化和腫瘤發(fā)生。在胚胎發(fā)育過程中,BRAF/MAPK上調(diào)USP15以穩(wěn)定TBX3, TBX3通過抑制分化來協(xié)調(diào)器官發(fā)生。Usp15 - tbx3軸在腫瘤發(fā)生過程中被重新激活,Usp15敲除以tbx3依賴的方式阻止BRAFV600E驅(qū)動的腫瘤發(fā)展。刪除Tbx3或Usp15會導(dǎo)致腫瘤再分化,這與它們在發(fā)育過程中的過度分化傾向相似,例如甲狀腺濾泡發(fā)生中斷和分化因子如Tpo、Nis、Tg升高。研究結(jié)果表明,USP15和TBX3均與BRAFV600E特征和腫瘤預(yù)后不良高度相關(guān)。因此,USP15穩(wěn)定的TBX3代表了BRAF/ mapk導(dǎo)向的發(fā)育穩(wěn)態(tài)和病理轉(zhuǎn)化下游的關(guān)鍵蛋白抑制機制,支持腫瘤發(fā)生主要依賴于通過胚胎調(diào)控程序重新啟動實現(xiàn)的上皮去分化。




THUNDER 應(yīng)用

采用PLA法驗證USP15和TBX3在K1細胞中的共定位。

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