Distinct endoplasmic reticulum signaling pathways regulate apoptotic and necrotic cell death following iodoacetamide treatment.
Distinct endoplasmic reticulum signaling pathways regulate apoptotic and necrotic cell death following iodoacetamide treatment.
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不同的内质网信号通路在碘乙酰胺治疗后调节细胞凋亡和坏死性细胞死亡。
DOI：
10.1021/tx990054q
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发表时间：
1999
影响因子：
4.1
通讯作者：
Stevens,JL
中科院分区：
文献类型：
--
作者：
vanDeWater,B;Wang,Y;Asmellash,S;Liu,H;Zhan,Y;Miller,E;Stevens,JL
环境胁迫诱导内质网(ER)中葡萄糖调节蛋白(GRP)和细胞质中热休克蛋白(HSPs)的合成。碘乙酰胺(IDAM)是一种典型的烷化剂，可诱导肾上皮细胞GRP和HSP的合成，并导致坏死，这是通过预先激活ER应激反应(ER前应激)来防止的[Liu，H.，et al.(1997)J.Biol.化学272,21751−21759]。在这项研究中，我们研究了导致IDAM诱导细胞凋亡的生化途径，并研究了内质网应激反应在凋亡细胞死亡中的作用。抗氧化剂N，N‘-二苯基-对苯二胺(DPPD)阻止了IDAM处理后的细胞坏死，但细胞继续死亡，细胞脱落，caspase-3激活，多(ADP-核糖)聚合酶(PARP)裂解和DNA梯形形成，所有这些都被一般的caspase抑制剂zVAD阻断。与IDAM诱导的坏死一样，二硫苏糖醇可以防止细胞凋亡，但细胞通透性钙螯合剂不能，这表明不同的生化途径介导了这两种形式的细胞死亡。内质网前应激，而不是热休克，可阻止IDAM诱导的细胞凋亡。PkASgrp78细胞由于表达agrp78反义RNA而缺乏GRP78诱导，对坏死更敏感。然而，这些细胞对IDAM诱导的凋亡具有抵抗力，并增加了Grp94的基础水平和约50 kDa的含有KDEL的蛋白。因此，grp78反义基因的表达扰乱了内质网的功能，并激活了与抗凋亡有关的其他内质网应激基因的表达。综上所述，这些数据描述了不同的信号通路，ER通过这些通路调节化学毒物引起的细胞凋亡和坏死。
Environmental stress induces the synthesis of glucose-regulated proteins (Grps) in the endoplasmic reticulum (ER) and heat shock proteins (Hsps) in the cytoplasm. Iodoacetamide (IDAM), a prototypical alkyating agent, induces both Grp and Hsp synthesis in renal epithelial cells and causes necrosis which is prevented by prior activation of the ER stress response (pre-ER stress) [Liu, H., et al. (1997)J. Biol. Chem.272, 21751−21759]. In this study, we examined the biochemical pathways leading to IDAM-induced apoptosis and investigated the role of the ER stress response in apoptotic cell death. The antioxidantN,N‘-diphenyl-p-phenylenediamine (DPPD) prevented necrosis after IDAM treatment, but the cells went on to die with hallmarks of apoptosis, i.e., cell detachment, caspase-3 activation, cleavage of poly(ADP-ribose)polymerase (PARP), and DNA-ladder formation, all of which were blocked by the general caspase inhibitor zVAD. As with IDAM-induced necrosis, dithiothreitol protected against apoptosis, but cell permeable calcium chelators did not, suggesting that distinct biochemical pathways mediate these two forms of cell death. Pre-ER stress, but not heat shock, prevented IDAM-induced apoptosis. pkASgrp78 cells are deficient in Grp78 induction due to expression of agrp78antisense RNA and are more sensitive to necrosis. However, these cells were resistant to IDAM-induced apoptosis and had increased basal levels of Grp94 and a KDEL-containing protein of about 50 kDa. Thus, the expression ofgrp78antisense perturbs ER functions and activates expression of other ER stress genes accounting for the resistance to apoptosis. Taken together, the data describe functionally distinct signaling pathways through which the ER regulates apoptosis and necrosis caused by chemical toxicants.