最新一期《細胞生物學雜志》（Journal of Cell biology）報道了中國科學院上海生命科學研究院生物化學與細胞生物學研究所李林,、李逸平研究組合作完成的最新科研進展：Wnt信號途徑中的關鍵分子Dishevelled蛋白，通過c-Jun蛋白的介導作用，結(jié)合到下游靶基因的啟動子上并調(diào)控了啟動子上的轉(zhuǎn)錄復合物的形成,。這一成果揭示了Dishevelled蛋白在細胞核中調(diào)控Wnt信號的作用機制,，并闡明了c-Jun蛋白在Wnt信號途徑中的新功能。
Wnt信號轉(zhuǎn)導途徑是一類在生物體進化過程中高度保守的信號轉(zhuǎn)導途徑,，調(diào)控早期胚胎發(fā)育,；同時在成體中Wnt信號途徑異常活化會導致人類一系列高發(fā)性腫瘤的發(fā)生,。在Wnt信號途徑激活的過程中,，Dishevelled蛋白在細胞質(zhì)中接受上游信號通過抑制APC、Axin以及GSK3β等蛋白形成的復合物的功能,，從而穩(wěn)定了細胞質(zhì)中游離的β-catenin蛋白,；細胞質(zhì)中積累的β-catenin蛋白進入細胞核與TCF/LEF家族的轉(zhuǎn)錄因子結(jié)合從而開啟了下游靶基因的轉(zhuǎn)錄。
科研人員發(fā)現(xiàn),，Wnt信號可以誘導Dishevelled和c-Jun兩個蛋白在細胞核中的相互作用并結(jié)合到Wnt下游靶基因的啟動子上,，與TCF和β-catenin等蛋白形成穩(wěn)定的轉(zhuǎn)錄復合物。Dishevelled蛋白的主要作用是在啟動子上調(diào)控β-catenin蛋白與TCF轉(zhuǎn)錄因子之間的相互作用,，從而使得β-catenin蛋白可以穩(wěn)定地結(jié)合到靶基因的啟動子上,。另外，c-Jun蛋白在Wnt信號途徑中的主要功能是作為Dishevelled蛋白與TCF轉(zhuǎn)錄因子之間的接頭蛋白而發(fā)揮作用,。c-Jun蛋白作為原癌基因與一系列腫瘤的發(fā)生都有關聯(lián),，而Wnt信號途徑的異常活化也與眾多的腫瘤的發(fā)生有關,；近年來研究也發(fā)現(xiàn)Dishevelled蛋白在許多腫瘤組織中異常高表達,。“自然中國”在對該文的評述中認為，該工作揭示的Dishevelled與c-Jun兩個蛋白調(diào)節(jié)Wnt信號的新機制為癌癥及其他退行性疾病的治療提供了又一個可能的藥物靶點,。該研究還得到了上海生科院斑馬魚研究平臺的支持,。（來源：中科院上海藥物研究所）
生物谷推薦原始出處：
（Journal of Cell biology），,，Xiao-qing Gan, Yi-ping Li, and Lin Li
Nuclear Dvl, c-Jun, β-catenin, and TCF form a complex leading to stabiLization of β-catenin–TCF interaction
Xiao-qing Gan1, Ji-yong Wang1, Ying Xi1, Zhi-li Wu2, Yi-ping Li2, and Lin Li1
1 State Key Laboratory of Molecular Biology and 2 Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Correspondence to L. Li: [email protected]
In canonical Wnt signaling, Dishevelled (Dvl) is a critical cytoplasmic regulator that releases β-catenin from degradation. Here, we find that Dvl and c-Jun form a complex with β-catenin–T-cell factor 4 (TCF-4) on the promoter of Wnt target genes and regulate gene transcription. The complex forms via two interactions of nuclear Dvl with c-Jun and β-catenin, respectively, both of which bind to TCF. Disrupting the interaction of Dvl with either c-Jun or β-catenin suppresses canonical Wnt signaling–stimulated transcription, and the reduction of Dvl diminished β-catenin–TCF-4 association on Wnt target gene promoters in vivo. Expression of a TCF-Dvl fusion protein largely rescued the c-Jun knockdown Wnt signaling deficiency in mammalian cells and zebrafish. Thus, we confirm that c-Jun functions in canonical Wnt signaling and show that c-Jun functions as a scaffold in the β-catenin–TCFs transcription complex bridging Dvl to TCF. Our results reveal a mechanism by which nuclear Dvl cooperates with c-Jun to regulate gene transcription stimulated by the canonical Wnt signaling pathway.
