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整合素αⅡbβ3缺陷对血小板由内到外信号传导的影响

Effect of the defect of integrin αⅡb β3 on the inside-out signal transduction in platelets
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摘要 目的 :探讨整合素αⅡbβ3缺陷对血小板由内到外信号传导的影响。方法 :采用DNA序列分析、流式细胞术、RT PCR和Westernblotting等检测细胞中转染cDNA的存在、表达及细胞结合PAC 1、纤维蛋白原 (fibrinogen ,Fb)的能力。结果 :血小板无力症 (GT)患者整合素αⅡbβ3明显低下 ,且血小板在ADP激活后不能结合PAC 1,转染β3和αⅡb(突变αⅡbR995A 或正常αⅡb)cDNA的CHO细胞株分别表达αⅡbR995A β3和αⅡbβ3,并且突变株中国仓鼠卵巢细胞(Chinesehamsterovary ,CHO)细胞αⅡb基因 30外显子上第 30 77和 30 78位碱基由CG突变为GC ,导致第 995位精氨酸被替换为丙氨酸 ;在未活化的情况下 ,αⅡbβ3CHO细胞几乎不结合PAC 1,但能结合Fb ,而αⅡbR995Aβ3CHO细胞能结合PAC 1,且Fb明显增加。结论 :αⅡbR995A 突变能诱导血小板内到外信号传导 ,使αⅡbR995Aβ3表现为激活型受体 ;而GT患者却因整合素αⅡbβ3缺陷使αⅡbβ3介导的血小板由内到外信号传导受阻 ,使该GT患者表现出血小板聚集异常。 Objective To investigate the effect of the defect of integrin αⅡb β3 on the inside out signal transduction in platelets. Methods The transfected cDNA, its expression and the ability of cells binding to PAC 1 and fibrinogen were investigated by RT PCR, DNA sequence analysis, flow cytometry and Western blotting. Results The integrin αⅡb β3 level in the patients with Glanzmann's thrombasthenia was significantly lower than that of the normal subjects and the platelets of the patients failed to bind PAC 1 activated by ADP. There were both C3077G and G3078C mutations in exon 30 of mutant αⅡb R995A β3 cDNA, which resulted in an amino acid substitution arginine (R) 995 to alanine (A). CHO cells transfected with wild type αⅡb β3 or mutant αⅡb R995A β3 cDNA respectively expressed normal αⅡb β3 and mutant αⅡb R995A β3. When cells were not activated, wild type αⅡb β3 CHO cells failed to bind PAC 1, but could adhere to fibrinogen, but mutant chimera αⅡb R995A β3 CHO cells were able to bind PAC 1 and exhibited high affinity binding fibrinogen. Conclusion The point mutation in integrin αⅡb R995A can induce the inside out signal transduction in platelets, and have integrin αⅡb R995A β3 locked into an activation state; the defect of αⅡb β3 in patients with GT impairs the inside out signal transduction mediated by αⅡb β3 in platelets and the adhesive functions of platelets.
出处 《湖南医科大学学报》 CSCD 北大核心 2002年第3期207-210,共4页 Bulletin of Hunan Medical University
基金 国家自然科学基金资助 (NO .3 983 0 180 )
关键词 整合素αⅡbβ3 血小板无力症 信号传递 实验研究 抗血小板治疗 integrin αⅡb β3 Glanzmann's thrombasthenia signal transduction,receptor
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  • 1包承鑫,中华血液学杂志,1985年,6期,599页

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