2009年2月13日,，《生物化學(xué)雜志》(J Biol Chem)發(fā)表了中科院上海生科院生化與細(xì)胞所耿建國研究組關(guān)于NF-κB轉(zhuǎn)錄因子p50亞基調(diào)控組織因子(Tissue Factor)的表達(dá)與功能的研究新進(jìn)展。
NF-κB是一類非常重要的轉(zhuǎn)錄因子,，負(fù)責(zé)調(diào)控多種基因的表達(dá),，在免疫和炎癥反應(yīng)中發(fā)揮重要作用。組織因子作為凝血的主要啟始因子,，其轉(zhuǎn)錄與表達(dá)受NF-κB、AP-1,、Egr-1等轉(zhuǎn)錄因子的調(diào)控,。
在這項(xiàng)工作中，耿建國實(shí)驗(yàn)室的研究人員首次發(fā)現(xiàn),，用p50的特異性抑制劑穿心蓮內(nèi)酯或?qū)50基因敲除,，均可以顯著降低內(nèi)皮細(xì)胞和單核/巨噬細(xì)胞中組織因子的活性。并證實(shí)p65/p50二聚體可以直接與人組織因子啟動(dòng)子上的NF-κB識別位點(diǎn)相結(jié)合,。在穿心蓮內(nèi)酯處理的正常小鼠或p50基因敲除小鼠中,，組織因子的表達(dá)以及由組織因子介導(dǎo)的靜脈血栓的形成都有很大程度的減弱。該項(xiàng)工作首次發(fā)現(xiàn)并確證NF-κB轉(zhuǎn)錄因子的p50亞基調(diào)控了組織因子的轉(zhuǎn)錄表達(dá),，而且此調(diào)控過程對深靜脈血栓的產(chǎn)生非常關(guān)鍵,。這一發(fā)現(xiàn)表明，p50的特異性抑制劑,，例如穿心蓮內(nèi)酯,，對預(yù)防與治療靜脈血栓可能具有非常重要的應(yīng)用價(jià)值。
該項(xiàng)目受到國家科技部,、國家基金委,、中國科學(xué)院及上海市科委的經(jīng)費(fèi)支持。（生物谷Bioon.com）
生物谷推薦原始出處：
J. Biol. Chem., Vol. 284, Issue 7, 4473-4483, February 13, 2009
NF-κB Transcription Factor p50 Critically Regulates Tissue Factor in Deep Vein Thrombosis*
Yi-Dan Li1, Bu-Qing Ye1, Sheng-Xi Zheng, Jin-Tao Wang, Jian-Guo Wang, Ming Chen, Ji-Guo Liu, Xin-Hui Pei?, Li-Jing Wang||, Zhi-Xin Lin?, Kalpna Gupta**, Nigel Mackman, Arne Slungaard**, Nigel S. Key, and Jian-Guo Geng**2
From the Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School of Chinese Academy of Sciences, CAS, Shanghai 200031, China, the Division of Hematology/Oncology, University of North Carolina, Chapel Hill, North Carolina 27599, the ?College of Life Science & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China, the ||Institute of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China, and the **Vascular Biology Center and Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, Minnesota 55455
NF-B transcription factors regulate the expression of tissue factor (TF), a principal initiator of the coagulation cascade. Dominant among them is the p50/p65 heterodimer. Here we report that Andrographolide (Andro; a p50 inhibitor) and genetic deletion of p50 attenuated TF activity in stimulated endothelial cells and monocytes/macrophages. Results of the electrophoretic mobility "supershift" assay and chromatin immunoprecipitation demonstrated the direct interaction of the p50/p65 heterodimer with the NF-κB site of the human TF promoter. Andro-treated and p50 null mice both exhibited blunted TF expression and reduced venous thrombosis, which were recapitulated by an anti-murine TF antibody in vivo. Our findings thus indicate that regulation of TF by NF-κB transcription factor p50 is essential for the pathogenesis of deep vein thrombosis and suggest that specific inhibitors of p50, such as Andro, may be therapeutically valuable for preventing and perhaps treating venous thrombosis.
