近日,，國際著名學術(shù)期刊Molecular and Cellular Biology在線刊登了了中科院上海生命科學研究院和上海交通大學醫(yī)學院健康所核酸與分子醫(yī)學研究組研究人員的最新研究成果“AU-Rich Element-Dependent Translation Repression Requires the Cooperation of Tristetraprolin and RCK/P54,。”,，文章中，研究人員在RNA結(jié)合蛋白調(diào)節(jié)信使RNA翻譯研究中取得了新進展,。
ARE-mRNA是3′-UTR區(qū)富含AU序列(AU-rich element, ARE)為特征的一類mRNA,，它們在轉(zhuǎn)錄后水平受到多蛋白網(wǎng)絡(luò)多層次的嚴密調(diào)控。Tristetraprolin(TTP)是至今研究最為廣泛的ARE結(jié)合蛋白,，其基因敲除小鼠會導致嚴重的自身免疫性疾病,。已有研究表明，TTP調(diào)節(jié)ARE-mRNA的降解,，但TTP是否通過其它機制調(diào)控ARE-mRNA的表達,，尚不清楚,。
祁美雁博士、研究生王志章等在荊清研究員的指導下,，利用多個不同的報告子系統(tǒng),，發(fā)現(xiàn)TTP顯著抑制靶基因與多聚核糖體的結(jié)合,，從而抑制ARE-mRNA的翻譯效率,。研究發(fā)現(xiàn)，TTP抑制免疫細胞內(nèi)源TNF-α蛋白的合成速率,。進一步研究表明,，解旋酶RCK/P54是TTP所介導的翻譯抑制所必需的互作蛋白，二者協(xié)同作用,，共同抑制ARE-mRNA與多聚核糖體的結(jié)合及其翻譯效率,。
該研究拓寬了人們對TTP生物學功能的認識，有助于闡明ARE-mRNA轉(zhuǎn)錄后調(diào)節(jié)的分子機制和深入探索自身免疫性疾病的發(fā)病機理,。
該項研究主要由健康所,、長海醫(yī)院、美國佐治亞醫(yī)學院,、美國UMDNJ合作完成,。該課題獲得國家科技部、國家自然科學基金委和中國科學院的經(jīng)費資助,。（生物谷Bioon.com）
doi:10.1128/MCB.05340-11
PMC:
PMID:
AU-Rich Element-Dependent Translation Repression Requires the Cooperation of Tristetraprolin and RCK/P54.
Mei-Yan Qi1, Zhi-Zhang Wang1, Zhuo Zhang2, Qin Shao1, An Zeng1, Xiang-Qi Li1, Wen-Qing Li1, Chen Wang1, Fu-Ju Tian1, Qing Li1, Jun Zou1, Yong-Wen Qin2, Gary Brewer1,4, Shuang Huang2,3 and Qing Jing1,2,*
AU-rich elements (AREs), residing in the 3′ UTR of many labile mRNAs, are important cis-acting elements to modulate the stability of these mRNAs by collaborating with trans-acting factors such as Tristetraprolin (TTP). AREs also regulate translation, but the underlying mechanism is not fully understood. Here we examined the function and mechanism of TTP in ARE-mRNA translation. Through a luciferase-based reporter system, we demonstrate that TTP represses ARE reporter mRNA translation by employing knockdown, overexpression, and tethering assays in 293T cells. Polyribosome fractionation experiments showed that TTP shifts target mRNAs to lighter fractions. In murine RAW264.7 macrophages, knocking down TTP produces significantly more TNF-α than the control, while the corresponding mRNA level has a marginal change. Furthermore, knockdown of TTP increases the biosynthesis rate of TNF-α cytokine, suggesting that TTP can exert effects at translational levels. Finally, we demonstrate that general translational repressor RCK may cooperate with TTP to regulate ARE-mRNA translation. Collectively, our studies reveal a novel function of TTP in repressing ARE-mRNA translation and that RCK is a functional partner of TTP in promoting TTP-mediated translational repression.
