中国科技核心期刊
CN:31-1600/Q
ISSN:1004-0374
“健康与疾病的免疫”国际学术研讨会通知      关于有网站冒充本刊网站的声明
《生命科学》 2013, 25(8): 829-837
细胞存亡调控蛋白c-FLIP:癌细胞TRAIL耐受的关键蛋白
彭 琼,沈悦海,王冠林,张宽仁*
    
(昆明理工大学生命科学与技术学院,昆明 650500)
摘 要: c-FLIP 是TNF 家族成员诱导凋亡的主要耐受因子和关键抗凋亡调控因子。人类细胞的c-FLIP 有3种亚型:c-FLIPL、c-FLIPS 和c-FLIPR。研究发现,c-FLIP 具有多种生物学功能,尤其是c-FLIPL,不仅参与调节TNF 家族受体诱导的凋亡、坏死和自噬,还参与调节存活信号及Wnt 通路,并与胚胎心血管发育及多种疾病,特别是癌症的发生发展密切相关。肿瘤凋亡因子TRAIL 可诱导癌细胞凋亡而不伤害正常细胞。但在临床应用中,癌细胞对TRAIL 的耐受现象是亟需突破的难关。c-FLIP-FADD 相互作用是癌细胞TRAIL 耐受的主要原因,发展相应的蛋白- 蛋白相互作用小分子拮抗剂,并与IAP 拮抗剂和TRAIL 联用将是特异性治疗癌症的理想策略。
 
The cell death and survival regulator c-FLIP is a key protein of cancer
    with resistance to TRAIL-induced apoptosis
PENG Qiong, SHEN Yue-Hai, WANG Guan-Lin, CHANG Kwen-Jen*
(Faculty of Life Science and Technology, Kunming University of Life Science and Technology, Kunming 650500, China)
Abstract: The c-FLIP protein is a major resistance factor and critical anti-apoptotic regulator that inhibits tumor necrosis factor family-induced apoptosis. The c-FLIP is expressed as long (c-FLIPL),short (c-FLIPS),and c-FLIPR splice variants in human cells. Recent studies revealed that c-FLIP has a variety of biological functions. Especially,c-FLIPL variant is involved not only in programmed cell death including TNF receptor(TNFR)-mediated apoptosis, necrosis and autophagy,but also in the regulation of survival signals mediated by TNFRs and Wnt pathway, as well as related to embryonic development of cardiovascular system and the development of several diseases,particularly,cancers. TNF-related apoptosis-inducing ligand (TRAIL) can induce apoptotic cell death in a variety of cancer cells while sparing in normal cells. However,cancer resistance to TRAIL composes a significant challenge for its clinical application. The c-FLIP-FADD interaction is the main mechanism for TRAIL resistance. Therefore,to develop a small molecule drug inhibiting c-FLIP-FADD interaction,which can activate the extrinsic apoptosis pathway while combining with IAP antagonist and TRAIL, shall be an ideal strategy of developing selective cancer therapy without inducing toxicity to normal cells.
 
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