Chinese Journal of Tissue Engineering Research ›› 2017, Vol. 21 ›› Issue (36): 5886-5891.doi: 10.3969/j.issn.2095-4344.2017.36.025
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Xiong Fei1, Wei Yi-shan2
Received:
2017-07-30
Online:
2017-12-28
Published:
2018-01-04
Contact:
Wei Yi-shan, M.D., Chief physician, Department of Pediatric Orthopedics, the Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
About author:
Xiong Fei, Studying for master’s degree, Inner Mongolia Medical University, Hohhot 010059, Inner Mongolia Autonomous Region, China
CLC Number:
Xiong Fei1, Wei Yi-shan2. Endoplasmic reticulum stress and apoptosis of chondrocytes[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(36): 5886-5891.
2.1 内质网应激与细胞凋亡 遗传或环境损伤会引起细胞内钙稳态失衡、氧化应激、营养缺乏、糖基化抑制和蛋白质错误折叠,从而破环内质网功能,内质网应激随之形成[2-5],细胞中会出现未折叠蛋白反应,然后内质网超载反应会随之出现,最后会减少蛋白质的合成,同时蛋白质会出现正确的折叠,应激过度也会启动对应的凋亡分子[6-7]。 2.1.1 未折叠蛋白反应和细胞凋亡 蛋白激酶样内质网激酶(PERK)及转录激活因子6(ATF6)和1型内质网转膜蛋白激酶(IRE-1),它们是内质网应激的感受蛋白质,能够联结GRP78/BIP构成平稳的复合物,介导未折叠蛋白反应[8]。当内质网应激没有发生时,它们处于结合的状态,该状态没有活性,当内质网应激发生时,积聚的未折叠蛋白能够让GRP78/BIP从3种跨膜的蛋白上分离开来,转而去连接未折叠蛋白。感受蛋白分离后会被活化并导致未折叠蛋白反应的产生[3,9-10],未折叠蛋白反应可以庇护由内质网应激所激发的细胞损害,修复细胞功能,有停歇初期的蛋白质组成,内质网的分子伴侣和折叠有关的酶的转录激活和内质网有关降解,为了提高不正确蛋白质折叠的处理,增进内质网对积蓄的蛋白质处置,有利于维护细胞的一般功能和细胞的生存。 PERK、ATF6和IRE-l信号不光是可以发动ERS的生存路线,惨重或长期的内质网应激毁损了内质网的功能时,内质网应激所带领的凋亡的信号线路照样能够被这3个信号通路启动(图2)[11],致使细胞产生凋亡,然后去掉受伤的细胞.目前认为,激活CHOP/GADD153基因的转录路线;C-Jun氨基酸末端激酶(C-Jun N-terminal kinase,JNK) 的激活通路;内质网中Caspase-12被激活。"
CHOP/GADD153基因的激活转录:CHOP/ GADD153内质网应激特异的转录因子,CHOP从属于转录因子 CCAAT/增强子结合蛋白(C/EBP)家族,经常结合转录因子CCAAT/增强子结合蛋白(C/EBP)家族的其他成员,然后会导致二聚体的出现,在一般的情况下,基本不会有CHOP的表达。当出现一个内质网的应激时,通过激活IRE1、PERK和 ATF-6能够产生大量的CHOP。在内质网应激反应的跨膜蛋白IRE1 和ATF-6激活后进入细胞核,连接ERS反应元件,驱动CHOP转录与表达,最后致使凋亡。ATF4在PERK/elF2α的下游,AARE域在CHOP启动子上,ATF4能够与AARE 域联合,随后出现CHOP的表达,在CHOP的表达中PERK与elF2α及其ATF4三者形成的复合物是必不可少的。有研究说明,升高CHOP,将能够对抗细胞凋亡的蛋白物Bcl-2的表达起下降作 用[12],对细胞内的谷胱甘肽的产生有抑制的作用,也对促成反馈性氧中介物(的产生有着抑制的作用,进而发生细胞凋亡。 c-Jun氨基端激酶激活途径:应激条件下,IRE1活化后能够召集C-JUN氨基末端激酶(C-Jun N-terminal kinase,JNK)和肿瘤坏死因子受体有关因子(TRAF2),肿瘤坏死因子受体有关因子刺激细胞凋亡信号激酶1 (ASK1),继而发生IRE-1、TRAF2和ASK1构成的三聚体,然后引起C-JUN氨基末端激酶,并诱导细胞凋亡[13-14]。 Caspase -12的激活:细胞凋亡中内质网的应激的关键分子是caspase-12,只有在内质网应激发生的时候才能被激活,而在线粒体或死亡受体凋亡路线中不被激活[15]。当内质网产生应激时, caspase-12能够经过以下的路线被激活(表1)。"
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