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JNK相互作用蛋白通过JNK途径影响鼻咽癌的增殖和凋亡
引用本文:胡智,陶永光,唐发清,杨力芳,赵燕,曾亮,罗非君,曹亚.JNK相互作用蛋白通过JNK途径影响鼻咽癌的增殖和凋亡[J].生物化学与生物物理进展,2003,30(4):579-585.
作者姓名:胡智  陶永光  唐发清  杨力芳  赵燕  曾亮  罗非君  曹亚
作者单位:中南大学湘雅医学院肿瘤研究所,长沙,410078
基金项目:国家重点基础研究发展规划项目 (973 ) (G19980 5 12 0 1),国家自然科学基金资助项目 (3 0 0 0 0 0 87)~~
摘    要:EB病毒编码的瘤蛋白潜伏膜蛋白(LMP1)所介导的活化蛋白(AP-1)信号转导途径在细胞增殖、分化、转化与凋亡方面发挥着重要作用.越来越多的证据表明,AP-1信号转导通路中上游激酶JNK在鼻咽癌的发生发展过程中起着重要作用.最近克隆出来的JNK相互作用蛋白(JIP-1)是一种能抑制JNK核移位的胞浆锚蛋白.为探讨JIP在LMP1调控AP-1信号通路中的作用机制,采用间接免疫荧光法和报告基因法,发现JIP通过有效地抑制磷酸化的JNK从胞浆移位入核,从而抑制LMP1上调的AP-1活性.同时,JIP导入鼻咽癌细胞中,MTT法发现JIP能够明显抑制鼻咽癌细胞的生长.进一步发现转染JIP后细胞的集落形成率与对照组相比大约降低了53.6%,也抑制了细胞. 提示JIP可明显抑制细胞的增殖作用.进一步采用流式细胞术分析,结果发现JIP引起细胞G1/S期细胞阻滞,说明JIP是抑制细胞增殖的重要调节子.进一步采用流式细胞术定量发现,转染JIP后细胞的24 h凋亡百分率由1.25%上升到8.25%,上升约6.6倍,48 h由1.04%上升到31.45%,上升约30倍. 采用激光共聚焦显微镜发现,转染JIP后细胞核发生显著变化,核质由均匀状态固缩成高凝集状态,形成了典型的胞膜体.提示JIP可有效地促进细胞凋亡.结果表明,JIP可通过抑制活化的JNK核移位,降低LMP1所介导的AP-1信号通路.并进一步发现JIP可有效地抑制细胞增殖和细胞凋亡,从而提示JIP可作为新的治疗肿瘤潜在靶分子.

关 键 词:鼻咽癌  活化蛋白1  JNK  JNK相互作用蛋白  增殖  细胞周期  凋亡
收稿时间:2002/12/27 0:00:00
修稿时间:2003/1/28 0:00:00

Effect of JIP on The Proliferation and Apoptosis of Nasopharyngeal Carcinoma Cells Through Interaction With JNK Mediated Pathway
HU Zhi,TAO Yong-Guang,TANG Fa-Qing,YANG Li-Fang,ZHAO Yan,ZENG Liang,LUO Fei-Jun and CAO Ya.Effect of JIP on The Proliferation and Apoptosis of Nasopharyngeal Carcinoma Cells Through Interaction With JNK Mediated Pathway[J].Progress In Biochemistry and Biophysics,2003,30(4):579-585.
Authors:HU Zhi  TAO Yong-Guang  TANG Fa-Qing  YANG Li-Fang  ZHAO Yan  ZENG Liang  LUO Fei-Jun and CAO Ya
Affiliation:Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China;Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China;Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China;Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China;Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China;Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China;Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China;Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China
Abstract:Activator protein 1 (AP-1) is known to be constitutively activated by the Epstein-Barr latent membrane protein 1 in nasopharyngeal carcinoma cells. Increasing evidence indicated that C-jun N-terminal kinase (JNK), the key upstream kinase of AP-1 mediated signal transduction pathway, plays a key role in the carcinogenesis and progression of nasopharyngeal carcinoma. JNK interacting protein 1 (JIP-1) was newly identified as a potent inhibitor of JNK. The effect of JIP on the proliferation of nasopharyngeal carcinoma cells through interaction with the AP-1 signaling pathway was detected using immunofluroscence, reporter gene, MTT, colony formation and flow cytometric analysis. In nasopharyngeal carcinoma cells, data suggested that JIP down-regulated AP-1 activity through the inhibition of the translocation of phospho-JNK from the cytoplasm to the nucleus. Furthermore, JIP inhibited the rates of cell survival and colony formation. The number of cells in S phase decreased and the number of cells in G1/G0 phase increased after the flow cytometric analysis, suggesting that JIP induced growth arrest of Tet-on-LMP1-HNE2 cells in G1/S phase of the cell cycle. The results, therefore, demonstrated that JIP, by inhibiting AP-1-mediated signal transduction pathway, interfered the cell cycle and may act as an important negative regulator of the proliferation of nasopharyngeal carcinoma cells. Also, it was detected by flow cytometry analysis and laser scanning confocal microscope that JIP triggered the apoptosis of NPC cells. In conclusion, JIP represents a promising new therapeutic molecule for nasopharyngeal carcinoma.
Keywords:nasopharyngeal carcinoma    activator protein 1 (AP-1)  c-jun N-terminal kinase  JNK interacting protein  proliferation  cell cycle  apoptosis
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