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名校學(xué)者解讀Wnt/β連環(huán)蛋白
點(diǎn)擊次數(shù)：1435 發(fā)布時(shí)間：2012-12-17
Wnt/β連環(huán)蛋白信號(hào)肽在癌癥中扮演了關(guān)鍵的角色，研究表明β-catenin 在癌癥的引發(fā)和發(fā)展進(jìn)程中起到關(guān)鍵作用。一個(gè)由哈佛大學(xué)、斯坦福大學(xué)等機(jī)構(gòu)的科研人員在這一方面的研究上取得新突破，相關(guān)論文發(fā)表在2012年12月13日的Cell雜志上。
Wnt/β-連環(huán)蛋白信號(hào)途徑在動(dòng)物生長發(fā)育過程中發(fā)揮了重要作用。一旦該通路中相關(guān)信號(hào)傳遞發(fā)生異常改變, 就可能導(dǎo)致該通路異?；罨? 從而影響生物的胚胎發(fā)育、能量代謝等一系列生理過程, 甚至?xí)?dǎo)致腫瘤的發(fā)生及惡化。
YAP（Yes—assoeiatedprotein）即Yes相關(guān)蛋白，是一種連接蛋白和轉(zhuǎn)錄共激活因子，在正常機(jī)體細(xì)胞內(nèi)發(fā)揮著信號(hào)轉(zhuǎn)導(dǎo)和基因轉(zhuǎn)錄調(diào)節(jié)的作用。近年研究發(fā)現(xiàn)，YAP是Hippo通路中的靶因子，該通路通過抑制YAP的活性調(diào)控細(xì)胞增生和凋亡間平衡，抑制組織細(xì)胞過度生長。
為破解β-catenin的具體作用機(jī)制，研究人員對(duì)85種癌細(xì)胞中β-catenin的活化進(jìn)行分類，結(jié)果發(fā)現(xiàn)了YAP1的調(diào)整作用在β-catenin活化癌細(xì)胞信號(hào)網(wǎng)絡(luò)中起到關(guān)鍵作用，YAP1和TBX5轉(zhuǎn)錄因子和β-catenin形成復(fù)合體。Yap 1通過酪氨酸激酶YES1磷酸化，結(jié)果推動(dòng)BCL2L1和BIRC5等細(xì)胞抗凋亡基因定位。這樣一個(gè)小分子抑制劑阻礙擴(kuò)散癌癥細(xì)胞系和動(dòng)物模型中β- catenin依賴的癌細(xì)胞增殖。這些結(jié)果表明β- catenin-yap1-tbx5復(fù)合體是β- catenin活化癌細(xì)胞中起到至關(guān)重要的作用。
原文摘要：
β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis
Wnt/β-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic β-catenin regulates several biological processes essential for cancer initiation and progression. To decipher the role of β-catenin in transformation, we classified β-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that β-catenin active cancers are dependent on a signaling pathway involving the transcriptional regulator YAP1. Specifically, we found that YAP1 and the transcription factor TBX5 form a complex with β-catenin. Phosphorylation of YAP1 by the tyrosine kinase YES1 leads to localization of this complex to the promoters of antiapoptotic genes, including BCL2L1 and BIRC5. A small-molecule inhibitor of YES1 impeded the proliferation of β-catenin-dependent cancers in both cell lines and animal models. These observations define a β-catenin-YAP1-TBX5 complex essential to the transformation and survival of β-catenin-driven cancers.