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JBC:NF-κB p50亚基调控组织因子表达和功能的新机制

来源:中科院 2009-02-18 14:33

2009年2月13日,《生物化学杂志》(J  Biol  Chem)发表了中科院上海生科院生化与细胞所耿建国研究组关于NF-κB转录因子p50亚基调控组织因子(Tissue  Factor)的表达与功能的研究新进展。

NF-κB是一类非常重要的转录因子,负责调控多种基因的表达,在免疫和炎症反应中发挥重要作用。组织因子作为凝血的主要启始因子,其转录与表达受NF-κB、AP-1、Egr-1等转录因子的调控。

在这项工作中,耿建国实验室的研究人员首次发现,用p50的特异性抑制剂穿心莲内酯或将p50基因敲除,均可以显著降低内皮细胞和单核/巨噬细胞中组织因子的活性。并证实p65/p50二聚体可以直接与人组织因子启动子上的NF-κB识别位点相结合。在穿心莲内酯处理的正常小鼠或p50基因敲除小鼠中,组织因子的表达以及由组织因子介导的静脉血栓的形成都有很大程度的减弱。该项工作首次发现并确证NF-κB转录因子的p50亚基调控了组织因子的转录表达,而且此调控过程对深静脉血栓的产生非常关键。这一发现表明,p50的特异性抑制剂,例如穿心莲内酯,对预防与治疗静脉血栓可能具有非常重要的应用价值。

该项目受到国家科技部、国家基金委、中国科学院及上海市科委的经费支持。(生物谷Bioon.com)

生物谷推荐原始出处:

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.

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