内质网应激介导COPD肺泡上皮细胞凋亡及GRP78抗凋亡作用
|
摘要
研究背景肺泡上皮细胞凋亡是COPD发病的重要机制之一。内质网应激(ERS)介导的细胞凋亡途径是一条新的细胞凋亡途径。有关ERS标志性分子GRP78的生物学功能的研究已经引起生物学家们的广泛重视,GRP78在ERS时表达增加,被认为可以减轻ERS,从而减少细胞凋亡。GRP78表达上调的信号传导通路目前不完全清楚,有研究提示p38MAPK途径可以上调GRP78的表达。吸烟是COPD最重要的发病因素。香烟烟雾中富含氧自由基和多种毒性成分,氧化应激和毒性物质都是ERS的诱发因素,因此吸烟很可能触发ERS。国内外研究均证实,在COPD中,香烟烟雾可以引起p38MAPK的活化。结合上述研究,我们推测在COPD发生过程中,吸烟可能通过诱导ERS导致肺泡上皮细胞凋亡从而参与COPD肺气肿的形成,在此过程中GRP78表达上调,发挥抗凋亡作用,p38MAPK途径在香烟烟雾诱导肺泡上皮细胞GRP78表达过程中起重要的调控作用。本研究拟以COPD大鼠及香烟烟雾提取物(CSE)干预的A549细胞为主要模型,探讨香烟烟雾诱导ERS的发生、GRP78的抗凋亡作用以及p38MAPK途径在GRP78表达过程中的调控作用。
第一章COPD大鼠肺组织内质网应激与细胞凋亡
目的观察COPD大鼠肺组织内质网应激的发生及肺泡上皮细胞的凋亡情况。
方法24只Wistar大鼠随机均分为2组：正常对照组和COPD模型组。采用被动吸烟加气管内注射脂多糖法建立COPD大鼠模型。造模完成后,测定各组大鼠的肺功能、观察肺组织病理学变化、免疫组化检测GRP78在肺组织中的表达和分布,RT-PCR检测GRP78、CHOP mRNA水平,Western blot检测GRP78、CHOP、active caspase-12蛋白水平。TUNEL法检测肺泡上皮细胞凋亡
结果COPD模型组大鼠FEV0.3/FVC (%)、动态肺顺应性(Cdyn)均较对照组明显降低,而气道阻力(RI)明显增高；免疫组化结果显示GRP78表达于肺泡上皮细胞、支气管上皮细胞、血管内皮细胞等细胞的细胞浆中,以肺泡上皮细胞明显。对照组GRP78呈弱阳性表达,阳性产物为棕黄色颗粒；模型组GRP78呈强阳性表达,阳性产物为棕褐色颗粒。与对照组相比,模型组肺组织GRP78表达显著增高；RT-PCR结果显示COPD模型组大鼠支气管肺组织中GRP78 mRNA和CHOP mRNA表达量较对照组显著增高；Western blot结果显示COPD模型组大鼠肺组织中GRP78、CHOP、active caspase-12蛋白表达较正常对照组显著增高；TUNEL法结果显示COPD模型组肺泡上皮细胞凋亡指数较正常对照组显著增高。
结论采用被动吸烟加气管内注射脂多糖的方法,成功复制出了COPD大鼠模型;COPD大鼠肺组织发生了内质网应激,尤以肺泡上皮细胞明显；COPD大鼠肺泡上皮细胞凋亡增加,内质网应激可能是介导肺泡上皮细胞发生凋亡的重要途径。
第二章香烟烟雾提取物诱导肺泡上皮细胞GRP78的表达及其抗凋亡作用
目的观察CSE对A549细胞GRP78表达的影响,并探讨GRP78抗细胞凋亡作用。
方法第一部分,体外培养A549细胞,给予不同浓度(0%-10%)和不同时间(0h-24h)的CSE干预后,以RT-PCR、Western blot分别检测GRP78 mRNA和蛋白表达；第二部分,将A549细胞分为四个处理组：对照组,5%CSE组,GRP78siRNA+5%CSE组,control siRNA+5%CSE组。以RT-PCR、Western blot分别检测GRP78 mRNA和蛋白的表达水平,Western blot检测active caspase-3蛋白表达水平,TUNEL检测A549细胞凋亡指数(AI)的变化。
结果随着CSE浓度的增加或干预时间的延长,A549细胞GRP78 mRNA及GRP78蛋白表达量逐渐增加,以5%CSE、干预12h组增加最明显,但继续增加CSE浓度或延长干预时间,GRP78表达并不增加,反而下降；小干扰GRP78后,RT-PCR、Western blot检测小干扰组GRP78表达显著下降,GRP78siRNA成功下调了GRP78基因表达；GRP78水平下调后,A549细胞active caspase-3的蛋白表达水平和细胞凋亡指数与单纯的CSE刺激组比较显著升高。
结论低浓度、短时间CSE刺激后,A549细胞启动了保护性的非折叠蛋白反应,GRP78表达上调。但高浓度、长时间CSE刺激,内质网出现功能障碍,其保护机制失代偿,GRP78表达反而下降；GRP78抵抗香烟烟雾提取物诱导的A549细胞凋亡。
第三章p38MAPK在香烟烟雾提取物诱导肺泡上皮细胞GRP78表达过程中的调控
目的明确p38MAPK在CSE诱导肺泡上皮细胞GRP78表达过程中的调控作用。
方法第一部分,24只Wistar大鼠随机均分为2组：正常对照组和COPD模型组。采用被动吸烟加气管内注射脂多糖法建立大鼠COPD模型。造模完成后,Western blot检测各组大鼠肺组织内P-p38、GRP78蛋白表达水平,并将二者进行相关性分析；第二部分,将A549细胞分为三个处理组：对照组,5%CSE组,SB203580+5%CSE组,以RT-PCR、Western blot分别检测GRP78 mRNA和蛋白的表达水平变化。
结果COPD模型组大鼠支气管肺组织中P-p38蛋白表达水平较对照组显著升高,且P-p38蛋白水平与GRP78蛋白表达呈正相关(r=0.848, P<0.01); p38MAPK抑制剂SB203580干预后,P-p38蛋白表达水平显著降低。抑制了p38MAPK通路活化后再给予CSE干预,GRP78 mRNA及GRP78蛋白表达水平较单纯的CSE刺激组显著降低。
结论COPD中p38MAPK途径发生了磷酸化激活；p38MAPK途径能上调香烟烟雾提取物诱导的GRP78表达水平。
Background The apoptosis of alveolar epithelial cell plays an important role in the pathogenesis of chronic obstructive pulmonary disease(COPD). In recent years, it has been reported that endoplasmic reticulum(ER) may be a new location which participates in intracellular pathway of cell apoptosis. That is called ER stress-mediated apoptosis pathway. GRP78, a 78kDa glucose regulated protein, is a major ER chaperone and plays a critical role in regulating ER homeostasis. Previous studies revealed that p38 mitogen-activated protein kinase (MAPK) may be involved in the induction of GRP78. Cigarette smoke, has been regarded as the main risk factor that triggers development of COPD. Some components in cigarette smoke including ROS, nicotine, heavy metals, and aldehyde may have the potential to induce ER stress. It has been reported that oxidative stress can activate p38MAPK pathway, which play an important role in the inflammation of airway in COPD. Based on these results, we speculate that cigarette smoke can cause ER stress and thereby contributes to apoptosis of lung epithelial cells. Induction of GRP78 protects cells from apoptosis, and p38 MAPK may involved in the up-regulating of GRP78. In present study, we use smoke-induced COPD rat and cigarette smoke extract (CSE) treated human alveolar epithelial cells (A549) as models, to explore the mechanisms of ER stress in COPD, the anti-apoptosis role of GRP78 and the regulative effect of MAPK pathway in this process.
Chapter One The ER stress and ER stress-mediated apoptosis in the lung tissues of COPD rat
Objective To study the ER stress and the apoptosis of alveolar epithelial cell in COPD rat model.
Methods 24 Wister rats were divided into two groups at random: control group and COPD group. COPD rat model was established by intratracheal instillation of lipopolysaccharide (LPS) twice and exposure to cigarette smoke daily. The spirometry was conducted and the pathological changes were observed after the model was established. The mRNA of GRP78 and CHOP were detected by reverse transcription-polymerase chain reaction (RT-PCR).The expression of GRP78 in the lung tissues was examined by immunohistochemistry and the protein expression of GRP78, CHOP and caspase-12 was detected by Western blot.TUNEL was used to analyze alveolar epithelial cell apoptosis.
Results Significant decrease of FEV0.3/FVC, Cdyn and increase of RI were found in the COPD group compared with the control group. Immunoperoxidase staining showed GRP78 was localized in the cytoplasm of bronchial epithelial cells, endothelial cells, especially in alveolar epithelial cells, and the GRP78 expression significantly increased in the COPD group. The levels of GRP78 and CHOP mRNA were higher in the COPD group than in the control group. The expression of GRP78, CHOP and active caspase-12 protein were increased in the COPD group. Apoptosis was observed with an in situ TUNEL assay, more apoptotic alveolar epithelial cells were found in the COPD group.
Conclusion The COPD rat models was successfully established by intratracheal instillation of LPS and exposure to cigarette smoke; ER stress was triggered in the lung tissues of COPD rat. Alveolar epithelial cell apoptosis was increased in the COPD group. The ER stress-mediated apoptosis pathway may participate in the alveolar epithelial cell apoptosis in COPD.
Chapter Two GRP78 induction by cigarette smoke extract and its anti-apoptosis effect
Objective To investigate the induction of GRP78 mediated by cigarette smoke extract(CSE), and the anti-apoptosis effect of GRP78.
Methods In part one, cultured A549 cells were exposed to CSE at various concentrations and for defferent durations. GRP78 expression was detected by RT-PCR and Western blot. In part two, A549 cells were divided into 4 groups:control group,5%CSE group, GRP78siRNA+5% CSE group, control siRNA+5% CSE group, measured the GRP78 expression by RT-PCR and Western blot, detected the active caspase-3 expression by Western blot,and TUNEL assay was used to detect apoptosis.
Results Part one, the expression of GRP78 was gradually increased as raising the CSE concentration or prolonging the treated time. When A549 cells were treated with 5% CSE for 12 hours, the GRP78 expression level reach the peak value. When continue to raise the CSE concentration or prolong the durations, the GRP78 expression was decreased. Part two, pretreated with GRP78 siRNA and then stimulated with CSE significantly reducing the GRP78 expression, indicated that GRP78 gene expression was successfully inhibited by GRP78 siRNA, accompany with the increase of active caspase-3 expression and A549 cells apoptosis.
Conclusion In A549 cells, low CSE concentration or short stimulation time up-regulate GRP78 expression via unfolded protein response. But high CSE concentration or long duration could down-regulate GRP78 expression because of the broken compensation of protection mechanism; GRP78 counteract A549 cells apoptosis induced by cigarette smoke.
Chapter Three CSE up-regulates GRP78 expression in A549 cells via p38MAPK pathway
Objective To investigate the regulative effect of p38MAPK pathway in GRP78 expression induced by CSE.
Methods In part one,24 Wister rats were divided into two groups at random:control group and COPD group. COPD rat model was established by intratracheal instillation of LPS twice and exposure to cigarette smoke daily. After the model was established, P-p38 protein expression was detected by Western blot. The correlation analysis was used to evaluate the association between P-p38 protein level and GRP78 expression. In part two, A549 cells were divided into 3 groups:control group,5%CSE group, SB203580+5%CSE group. P-p38 expression was measured by Western blot, and GRP78 expression was detected by RT-PCR and western blot.
Results Part one, the expression of P-p38 was significantly increased in the COPD group compared with the control group, and the correlation analyses showed that P-p38 protein level was positively correlated with GRP78 expression (r=0.848, P<0.01). Part two, P-p38 expression was significantly decreased in SB203580 pretreated group, demonstrated that p38MAPK pathway was successfully blocked by SB203580. The expression of GRP78 which was induced by CSE was inhibited by SB203580.
Conclusion p38MAPK pathway was activated in COPD; CSE up-regulate GRP78,which was attributed to p38 pathway.
第一章COPD大鼠肺组织内质网应激与细胞凋亡
目的观察COPD大鼠肺组织内质网应激的发生及肺泡上皮细胞的凋亡情况。
方法24只Wistar大鼠随机均分为2组：正常对照组和COPD模型组。采用被动吸烟加气管内注射脂多糖法建立COPD大鼠模型。造模完成后,测定各组大鼠的肺功能、观察肺组织病理学变化、免疫组化检测GRP78在肺组织中的表达和分布,RT-PCR检测GRP78、CHOP mRNA水平,Western blot检测GRP78、CHOP、active caspase-12蛋白水平。TUNEL法检测肺泡上皮细胞凋亡
结果COPD模型组大鼠FEV0.3/FVC (%)、动态肺顺应性(Cdyn)均较对照组明显降低,而气道阻力(RI)明显增高；免疫组化结果显示GRP78表达于肺泡上皮细胞、支气管上皮细胞、血管内皮细胞等细胞的细胞浆中,以肺泡上皮细胞明显。对照组GRP78呈弱阳性表达,阳性产物为棕黄色颗粒；模型组GRP78呈强阳性表达,阳性产物为棕褐色颗粒。与对照组相比,模型组肺组织GRP78表达显著增高；RT-PCR结果显示COPD模型组大鼠支气管肺组织中GRP78 mRNA和CHOP mRNA表达量较对照组显著增高；Western blot结果显示COPD模型组大鼠肺组织中GRP78、CHOP、active caspase-12蛋白表达较正常对照组显著增高；TUNEL法结果显示COPD模型组肺泡上皮细胞凋亡指数较正常对照组显著增高。
结论采用被动吸烟加气管内注射脂多糖的方法,成功复制出了COPD大鼠模型;COPD大鼠肺组织发生了内质网应激,尤以肺泡上皮细胞明显；COPD大鼠肺泡上皮细胞凋亡增加,内质网应激可能是介导肺泡上皮细胞发生凋亡的重要途径。
第二章香烟烟雾提取物诱导肺泡上皮细胞GRP78的表达及其抗凋亡作用
目的观察CSE对A549细胞GRP78表达的影响,并探讨GRP78抗细胞凋亡作用。
方法第一部分,体外培养A549细胞,给予不同浓度(0%-10%)和不同时间(0h-24h)的CSE干预后,以RT-PCR、Western blot分别检测GRP78 mRNA和蛋白表达；第二部分,将A549细胞分为四个处理组：对照组,5%CSE组,GRP78siRNA+5%CSE组,control siRNA+5%CSE组。以RT-PCR、Western blot分别检测GRP78 mRNA和蛋白的表达水平,Western blot检测active caspase-3蛋白表达水平,TUNEL检测A549细胞凋亡指数(AI)的变化。
结果随着CSE浓度的增加或干预时间的延长,A549细胞GRP78 mRNA及GRP78蛋白表达量逐渐增加,以5%CSE、干预12h组增加最明显,但继续增加CSE浓度或延长干预时间,GRP78表达并不增加,反而下降；小干扰GRP78后,RT-PCR、Western blot检测小干扰组GRP78表达显著下降,GRP78siRNA成功下调了GRP78基因表达；GRP78水平下调后,A549细胞active caspase-3的蛋白表达水平和细胞凋亡指数与单纯的CSE刺激组比较显著升高。
结论低浓度、短时间CSE刺激后,A549细胞启动了保护性的非折叠蛋白反应,GRP78表达上调。但高浓度、长时间CSE刺激,内质网出现功能障碍,其保护机制失代偿,GRP78表达反而下降；GRP78抵抗香烟烟雾提取物诱导的A549细胞凋亡。
第三章p38MAPK在香烟烟雾提取物诱导肺泡上皮细胞GRP78表达过程中的调控
目的明确p38MAPK在CSE诱导肺泡上皮细胞GRP78表达过程中的调控作用。
方法第一部分,24只Wistar大鼠随机均分为2组：正常对照组和COPD模型组。采用被动吸烟加气管内注射脂多糖法建立大鼠COPD模型。造模完成后,Western blot检测各组大鼠肺组织内P-p38、GRP78蛋白表达水平,并将二者进行相关性分析；第二部分,将A549细胞分为三个处理组：对照组,5%CSE组,SB203580+5%CSE组,以RT-PCR、Western blot分别检测GRP78 mRNA和蛋白的表达水平变化。
结果COPD模型组大鼠支气管肺组织中P-p38蛋白表达水平较对照组显著升高,且P-p38蛋白水平与GRP78蛋白表达呈正相关(r=0.848, P<0.01); p38MAPK抑制剂SB203580干预后,P-p38蛋白表达水平显著降低。抑制了p38MAPK通路活化后再给予CSE干预,GRP78 mRNA及GRP78蛋白表达水平较单纯的CSE刺激组显著降低。
结论COPD中p38MAPK途径发生了磷酸化激活；p38MAPK途径能上调香烟烟雾提取物诱导的GRP78表达水平。
Background The apoptosis of alveolar epithelial cell plays an important role in the pathogenesis of chronic obstructive pulmonary disease(COPD). In recent years, it has been reported that endoplasmic reticulum(ER) may be a new location which participates in intracellular pathway of cell apoptosis. That is called ER stress-mediated apoptosis pathway. GRP78, a 78kDa glucose regulated protein, is a major ER chaperone and plays a critical role in regulating ER homeostasis. Previous studies revealed that p38 mitogen-activated protein kinase (MAPK) may be involved in the induction of GRP78. Cigarette smoke, has been regarded as the main risk factor that triggers development of COPD. Some components in cigarette smoke including ROS, nicotine, heavy metals, and aldehyde may have the potential to induce ER stress. It has been reported that oxidative stress can activate p38MAPK pathway, which play an important role in the inflammation of airway in COPD. Based on these results, we speculate that cigarette smoke can cause ER stress and thereby contributes to apoptosis of lung epithelial cells. Induction of GRP78 protects cells from apoptosis, and p38 MAPK may involved in the up-regulating of GRP78. In present study, we use smoke-induced COPD rat and cigarette smoke extract (CSE) treated human alveolar epithelial cells (A549) as models, to explore the mechanisms of ER stress in COPD, the anti-apoptosis role of GRP78 and the regulative effect of MAPK pathway in this process.
Chapter One The ER stress and ER stress-mediated apoptosis in the lung tissues of COPD rat
Objective To study the ER stress and the apoptosis of alveolar epithelial cell in COPD rat model.
Methods 24 Wister rats were divided into two groups at random: control group and COPD group. COPD rat model was established by intratracheal instillation of lipopolysaccharide (LPS) twice and exposure to cigarette smoke daily. The spirometry was conducted and the pathological changes were observed after the model was established. The mRNA of GRP78 and CHOP were detected by reverse transcription-polymerase chain reaction (RT-PCR).The expression of GRP78 in the lung tissues was examined by immunohistochemistry and the protein expression of GRP78, CHOP and caspase-12 was detected by Western blot.TUNEL was used to analyze alveolar epithelial cell apoptosis.
Results Significant decrease of FEV0.3/FVC, Cdyn and increase of RI were found in the COPD group compared with the control group. Immunoperoxidase staining showed GRP78 was localized in the cytoplasm of bronchial epithelial cells, endothelial cells, especially in alveolar epithelial cells, and the GRP78 expression significantly increased in the COPD group. The levels of GRP78 and CHOP mRNA were higher in the COPD group than in the control group. The expression of GRP78, CHOP and active caspase-12 protein were increased in the COPD group. Apoptosis was observed with an in situ TUNEL assay, more apoptotic alveolar epithelial cells were found in the COPD group.
Conclusion The COPD rat models was successfully established by intratracheal instillation of LPS and exposure to cigarette smoke; ER stress was triggered in the lung tissues of COPD rat. Alveolar epithelial cell apoptosis was increased in the COPD group. The ER stress-mediated apoptosis pathway may participate in the alveolar epithelial cell apoptosis in COPD.
Chapter Two GRP78 induction by cigarette smoke extract and its anti-apoptosis effect
Objective To investigate the induction of GRP78 mediated by cigarette smoke extract(CSE), and the anti-apoptosis effect of GRP78.
Methods In part one, cultured A549 cells were exposed to CSE at various concentrations and for defferent durations. GRP78 expression was detected by RT-PCR and Western blot. In part two, A549 cells were divided into 4 groups:control group,5%CSE group, GRP78siRNA+5% CSE group, control siRNA+5% CSE group, measured the GRP78 expression by RT-PCR and Western blot, detected the active caspase-3 expression by Western blot,and TUNEL assay was used to detect apoptosis.
Results Part one, the expression of GRP78 was gradually increased as raising the CSE concentration or prolonging the treated time. When A549 cells were treated with 5% CSE for 12 hours, the GRP78 expression level reach the peak value. When continue to raise the CSE concentration or prolong the durations, the GRP78 expression was decreased. Part two, pretreated with GRP78 siRNA and then stimulated with CSE significantly reducing the GRP78 expression, indicated that GRP78 gene expression was successfully inhibited by GRP78 siRNA, accompany with the increase of active caspase-3 expression and A549 cells apoptosis.
Conclusion In A549 cells, low CSE concentration or short stimulation time up-regulate GRP78 expression via unfolded protein response. But high CSE concentration or long duration could down-regulate GRP78 expression because of the broken compensation of protection mechanism; GRP78 counteract A549 cells apoptosis induced by cigarette smoke.
Chapter Three CSE up-regulates GRP78 expression in A549 cells via p38MAPK pathway
Objective To investigate the regulative effect of p38MAPK pathway in GRP78 expression induced by CSE.
Methods In part one,24 Wister rats were divided into two groups at random:control group and COPD group. COPD rat model was established by intratracheal instillation of LPS twice and exposure to cigarette smoke daily. After the model was established, P-p38 protein expression was detected by Western blot. The correlation analysis was used to evaluate the association between P-p38 protein level and GRP78 expression. In part two, A549 cells were divided into 3 groups:control group,5%CSE group, SB203580+5%CSE group. P-p38 expression was measured by Western blot, and GRP78 expression was detected by RT-PCR and western blot.
Results Part one, the expression of P-p38 was significantly increased in the COPD group compared with the control group, and the correlation analyses showed that P-p38 protein level was positively correlated with GRP78 expression (r=0.848, P<0.01). Part two, P-p38 expression was significantly decreased in SB203580 pretreated group, demonstrated that p38MAPK pathway was successfully blocked by SB203580. The expression of GRP78 which was induced by CSE was inhibited by SB203580.
Conclusion p38MAPK pathway was activated in COPD; CSE up-regulate GRP78,which was attributed to p38 pathway.
引文
[1]中华医学会呼吸病学分会慢性阻塞性肺疾病学组.慢性阻塞性肺疾病诊治指南(2007修订版).中华结核和呼吸杂志,2007,30(1)：8-17
[2]Steiling K, Lenburg ME, Spira A.Airway gene expression in chronic obstructive pulmonary disease.Proc Am Thorac Soc,2009,6:697-700
[3]S(?)rheim IC, Gulsvik A, Bakke PS,et al. Genetics in chronic obstructive pulmonary disease.Tidsskr Nor Laegeforen,2009,129:2104-2107
[4]Horowitz JC, Martinez FJ, Thannickal VJ.Mesenchymal cell fate and phenotypes in the pathogenesis of emphysema. COPD,2009,6,201-210
[5]Roth M.Pathogenesis of COPD. Part Ⅲ. Inflammation in COPD. Int J Tuberc Lung Dis,2008,12:375-380
[6]Spurzem JR, Rennard SI.Pathogenesis of COPD. Semin Respir Crit Care Med, 2005,26(2):142-153
[7]Snider GL, Kleinerman LJ, Thurlbeck WM, et al. The Definition of Emphysema: Report of a National, Heart, Lung and Blood Institute. Division of Lung Diseases Workshop. Am Rev Respir Dis,1985,132(1):182-185
[8]Pipavath SN, Schmidt RA, Takasugi JE. Chronic obstructive pulmonary disease: radiology-pathology correlation.J Thorac Imaging,2009,24:171-180
[9]Imai K,Mercer BA,schulman LL,et al. Correlation of lung surface Area to apoptosis and proliferation in human emphysema.Eur Respir J,2005,25:250-258
[10]Aoshiba K,Yokohori N,Nagai A. Alveolar wall apoptosis induces lung destruction and emphysematous changes.Am J Respir Cell Mol Biol,2003, 28(5):555-562
[11]Kuo WH, Chen JH, Lin HH, et al. Induction of apoptosis in the lung tissue from rats exposed to cigarette smoke involves p38/JNK MAPK pathway. Chemico Biological Interactions,2005,155:31-42
[12]Eun Mi, Juliana Jung, Nuraly K,et al. Pro-oxidative DEP chemicals induce heat shock proteins and an unfolding protein response in a bronchial epithelial cell line as determined by DIGE analysis. Proteomics,2007,7:3906-3918
[13]Steven G. Kelsen, Xunbao Duan,et al. Cigarette Smoke Induces an Unfolded Protein Response in the Human Lung A Proteomic Approach.Am J Respir Cell Mol Biol,2008,38:541-550
[14]Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 1999,13:1211-1233
[15]Gomez E,Powell M.L,Bevington A, et al.A decrease in cellular energy status stimulates PERK-dependent eIF2alpha phosphorylation and regulates protein synthesis in pancreatic beta-cells. Biochem J,2008,410:485-493
[16]Yacoub Wasef S.Z, Robinson K.A,Berkaw M.N, et al. Glucose, dexamethasone, and the unfolded protein response regulate TRB3 mRNA expression in 3T3-L1 adipocytes and L6 myotubes. Am J Physiol Endocrinol Metab,2006,291: 1274-1280
[17]Schroder M, Kaufman RJ:The mammalian unfolded protein response.Annu Rev Biochem,2005,74:739-789
[18]Xu C, Bailly-Maitre B, Reed JC:Endoplasmic reticulum stress:Cell life and death decisions. J Clin Invest,2005,115:2656-2664
[19]Qian Y,Tiffany-Castiglioni E. Lead-induced endoplasmic reticulum(ER) stress responses in the nervous system. Neurochem Res,2003,28:153-162
[20]Yang GH, Li S,Pestka JJ,Down-regulation of the endoplasmic reticulum chaperone GRP78/Bip by vomitoxin (Deoxynivalenol). Toxicol Appl Pharmacol, 2000,162 (3):207-217
[21]Hitomi J, Katayama T,Taniguchi M,et al. Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. Neurosci Lett,2003,357:1 27-130
[22]Mendes CS, Levet C, Chatelain G, et al. ER stress protects from retinal degeneration. EMBO J,2009,28:1296-1307
[23]Rutkowski DT, Arnold SM, Miller CN, et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol,2006,4:e374
[24]H Liu, J Qian, F Wang. Expression of two endoplasmic reticulum stress markers, GRP78 and GADD153, in rat retinal detachment model and its implication.Eye,2010,24:137-144
[25]Jui-Ching Chen, Mei-Lin Wu, Kuo-Chin Huang, et al. HMG-CoA reductase inhibitors activate the unfolded protein response and induce cytoprotective GRP78 expression. Cardiovasc Res,2008,80:138-150
[26]Hayashi T, Saito A, Okuno S, et al. Induction of GRP78 by ischemic preconditioning reduces endoplasmic reticulum stress and prevents delayed neuronal cell death. Cereb Blood Flow Metab,2003,23(8):949-961
[27]Y. Oidaa, H. Izutaa, A. Oyagia, et al. Induction of BiP, an ER-resident protein,. prevents the neuronal death induced by transient forebrain ischemia in gerbil Brain Res,2008,1208:217-224
[28]Reddy RK, Mao C, Baumeister P, et al. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors:role of ATP binding site in suppression of caspase-7 activation.J Biol Chem 2003, 278:20915-24
[29]Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rabl rescues neuron loss in Parkinson's models. Science,2006, 313:324-328
[30]Galy A, Roux MJ, Sahel JA, et al. Rhodopsin maturation defects induce photoreceptor death by apoptosis:a fly model for RhodopsinPro23His human retinitis pigmentosa. Hum Mol Genet,2005,14:2547-2557
[31]Fonseca SG, Fukuma M, Lipson KL,et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic betacells. J Biol Chem,2005,280:39609-39615
[32]Yamada T, Ishihara H, Tamura A, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet,2006,15: 1600-1609
[33]Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J,2005,24:4368-4380.
[34]Bergren DR, Environmental tobacco smoke exposure and airway hyperrespo-nsiveness,Inflamm Allergy Drug Targets,2009,8:340-347
[35]Bartal M.COPD and tobacco smoke. Monaldi Arch Chest Dis,2005,63:213-225
[36]Ryan E. Feaver, Nicole E. Hastings, Andrew Pryor et al.GRP78 Upregulation by Atheroprone Shear Stress Via p38-,α2β1-Dependent Mechanism in Endothelial Cells. Arterioscler Thromb Vasc Biol,2008,28:1534-1541
[37]Renda T, Baraldo S, Pelaia G, et al. Increased activation of p38 MAPK in COPD. Eur Respir J,2008,31(1):62-69
[38]Brindicci C, Kharitonov SA, Ito M, et al. Nitric Oxide Synthase Isoenzyme Expression and Activity in Peripheral Lung Tissue of Patients with Chronic Obstructive Pulmonary Disease.Am J Respir Crit Care Med 2010,181(1):21-30
[39]Osoata GO, Hanazawa T, Brindicci C, et al. Peroxynitrite Elevation in Exhaled Breath Condensate of COPD and Its Inhibition by Fudosteine. Chest,2009,135 (6):1513-1520
[40]Miller M, Cho JY, Pham A, et al. Adiponectin and Functional Adiponectin Receptor 1 Are Expressed by Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease.J Immunol,2009,182(1):684-691
[41]Vernooy JHJ, Drummen NEA, Van Suylen RJ, et al. Enhanced pulmonary leptin expression in patients with severe COPD and asymptomatic smokers. Thorax, 2009,64(1):26-32
[42]Mata M, Sarria B, Buenestado A, et al. Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells.Thorax,2005,60(2):144-152
[43]Igarashi A, Shibata Y, Yamauchi K, et al.Gly80Ser Polymorphism of Phospholipase A2-IID Is Associated with Cytokine Inducibility in A549 Cells. Respiration,2009,78:312-321
[44]Qian Y,Tiffany-Castiglioni E.Lead-induced endoplasmic reticulum(ER) stress responses in the nervous system.Neurochem Res,2003,28:153-162
[45]Paschen W,Gissel C,Linden T, et al.Activation of gaddl53 expression through transient cerebral ischemia:evidence that ischemia causes endoplasmic reticulum dysfunction. Brain Res Mol Brain Res,1998,60:115-122
[46]Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature,2000, 403:98-103
[47]Momoi T. Caspases involved in ER stress-mediated cell death. J Chem Neuroanat, 2004,28:101-105
[48]宋一平,崔德健,茅培英,等.COPD大鼠模型气道重塑及生长因子的研究.中华结核和呼吸杂志,2001,24：283-287
[49]陈红梅,罗百灵,屈满英,等.红霉素对COPD大鼠MMP-9的影响.中华结核和呼吸杂志,2008,31：702-703
[50]Agusti AG.Systemic effects of chronic obstructive pulmonary disease.Proc Am Thorac Soc,2005;24(1):45-6.
[51]Wu J, Kaufman RJ. From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ,2006.13:374-384
[52]Lee AS.The glucose-regulated protein:stress induction induction and clinical applications.Trends Biochem Sci,2001,26:504-510
[53]Pryor WA, Stone K.Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann N Y Acad Sci,1993,28;686:12-27
[54]Tuder RM. Wood K. Taraseviciene L. et al. Cigarette Smoke Extract Decreases the Expression of Vascular Endothelial Growth Factor by Cultured Cells and Triggers Apoptosis of Pulmonary Endothelial Cells. CHEST,2000:117 (5) 241S-242S
[55]Yuma H,Tadashi M, Sonoko N,et al. Cytotoxic effects of cigarette smoke extract on an alveolar type II cell-derived cell line. Am J Physiol Lung Cell Mol Physiol,2001,281:L509-L516
[56]Kasahara Y. Tuder RM. Taraseviciene-Stewart L, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest,2000,106 (11):1311-9
[57]Lucky EC, Keane J, Kuang PP, et al. Severity of elastase-induced emphysema is decreased in tumor necrosis factor-alpha and interleukin-1 beta receptor-deficient mice. Lab Invest.2002;82:79-85
[58]屈满英,罗百灵,陈红梅,等.分泌型白细胞蛋白酶抑制剂对香烟烟雾提取
物诱导人支气管上皮细胞炎症介质表达的影响.中华结核和呼吸杂志,2008,31：352-355
[59]Moodie FM, Marwick JA, Anderson CS, et al.Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-κB activation and proinflammatory cytokine release in alveolar epithelial cells.The FASEB Journal,2004,18(15):1897-1899
[60]Qian Y,Tiffany-Castiglioni E.Lead-induced endoplasmic reticulum(ER) stress responses in the nervous system. Neurochem Res,2003,28:153-162
[61]Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature Cell Biol, 2000,2:326-332
[62]Harding HP, Novoa I, Zhang Y, et al. Regulated ruanslation initiation controls stress-induced gene expression in mammalian cells. Mol Cell,2000,6:1099-1108
[63]Schroder M, Kaufman RJ:The mammalian unfolded protein response.Annu Rev Biochem,2005,74:739-789
[64]Xu C, Bailly-Maitre B, Reed JC:Endoplasmic reticulum stress:Cell life and death decisions. J Clin Invest 2005,115:2656-2664,
[65]Zhuang S, Schnellmann RG. H2O2-induced transactivation of EGF receptor requires Src and mediates ERK1/2, but not Akt, activation in renal cells. Am J Physiol Renal Physiol,2004,286(5):F858-F865
[66]Park SJ,Kim Is. The role of p38 MAPK activation in auranofin-induced apoptosis of human promyelocytic leukaemia HL-60 cells. Br J Phammcol,2005,146(4): 506-513
[67]Aparna C. Ranganathan, Lin Zhang. Functional Coupling of p38-Induced Up-regulation of BiP and Activation of RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase to Drug Resistance of Dormant Carcinoma Cells. Cancer Research 2006:66,1702-1711
[68]Slevogt H, Schmeck B, Jonatat C, et al. Moraxella catarrhalis induces inflammatory response of bronchial epithelial cells via MAPK and NF-kappaB activation and histone deacetylase activity reduction. Am J Physiol Lung Cell Mol Physiol,2006,290:L818-826
[69]Chen KD, Chen LY, Huang HL, et al. Involvement of p38 mitogen-activated protein kinase signaling pathway in the rapid induction of the 78-kDa glucose-regulated protein in 9L rat brain tumor cells. J Biol Chem,1998; 273:749-755
[70]Chen KD, Lai MT, Cho JH, et al. Activation of p38 mitogen-activated protein kinase and mitochondrial Ca(2+)-mediated oxidative stress are essential for the enhanced expression of grp78 induced by the protein phosphatase inhibitors okadaic acid and calyculin A. J Cell Biochem,2000,76:585-595
[71]Goodyear LJ, Chang PY, Sherwood DJ, et al. Effects of exercise and insulin on mitogen-activated protein kinase signaling pathways in rat skeletalmuscle.Am J Physiol,1996,271 (2Pt1):E403-E408
[72]Kim BJ, Ryu SW, Song BJ. JNK and p38 kinase-mediated phosphorylationof Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem,2006,281:21256-21265.
[73]Kim HJ, Oh JE, Kim SW,et al.Ceramide induces p38 MAPK-dependent apoptosis and Bax translocation via inhibition of Akt in HL-60 cells. Cancer Lett,2008,260:88-95
[74]Jope RS, Zhang L, Song L. Peroxynitrite modulates the activation of p38 and extracellular regulated kinases in PC 12 cells. Arch Biochem Biophys,2000, 376:365-370
[1]Schultz DR, Harrington WJ Jr. Apoptosis:Programmed cell death at a molecular level. Semin Arthritis Rheum,2003,32:345-369
[2]Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rabl rescues neuron loss in Parkinson's models. Science,2006, 313:324-328
[3]Galy A, Roux MJ, Sahel JA, et al. Rhodopsin maturation defects induce photoreceptor death by apoptosis:a fly model for RhodopsinPro23His human retinitis pigmentosa. Hum Mol Genet,2005,14:2547-2557
[4]Fonseca SG, Fukuma M, Lipson KL,et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic betacells. J Biol Chem,2005,280:39609-39615
[5]Yamada T, Ishihara H, Tamura A, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet,2006,15:1600-1609
[6]Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J,2005,24:4368-4380.
[7]Eun Mi, Juliana Jung, Nuraly K,et al. Pro-oxidative DEP chemicals induce heat
shock proteins and an unfolding protein response in a bronchial epithelial cell line as determined by DIGE analysis. Proteomics,2007;7:3906-3918
[8]Steven G. Kelsen, Xunbao Duan,et al. Cigarette Smoke Induces an Unfolded Protein Response in the Human Lung A Proteomic Approach.Am J Respir Cell Mol Biol,2008; 38:541-550
[9]Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 1999;13:1211-1233
[10]Gomez E,Powell M.L,Bevington A, et al.A decrease in cellular energy status stimulates PERK-dependent eIF2alpha phosphorylation and regulates protein synthesis in pancreatic beta-cells. Biochem J,2008,410:485-493
[11]Yacoub Wasef S.Z, Robinson K.A,Berkaw M.N, et al.Glucose, dexamethasone, and the unfolded protein response regulate TRB3 mRNA expression in 3T3-L1 adipocytes and L6 myotubes. Am J Physiol Endocrinol Metab,2006, 291:1274-1280
[12]Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev. Mol. Cell Biol,2007;8:519-529
[13]Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu. Rev. Biochem,2005;74:739-789
[14]Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol,2007,8:519-529
[15]Mendes CS, Levet C, Chatelain G, et al. ER stress protects from retinal degeneration. EMBO J,2009,28:1296-1307
[16]Rutkowski DT, Arnold SM, Miller CN, et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol,2006,4:e374
[17]Qian Y,Tiffany-Castiglioni E.Lead-induced endoplasmic reticulum(ER) stress responses in the nervous system. Neurochem Res,2003,28:153-162
[18]Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature Cell Biol,2000,2:326-332
[19]Harding HP, Novoa I, Zhang Y, et al. Regulated ruanslation initiation controls stress-induced gene expression in mammalian cells. Mol Cell,2000,6:1099-1108
[20]Harding HP, Zeng H, Zhang Y, et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice revrals a role for translational contronl in secretory cell survival.Mol Cell,2001,7:1153-1163.
[21]Marciniak SJ, Garcia-Bonilla L, Hu J, et al. Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK. J Cell Biol,2006,172:201-209
[22]Lu PD, Harding HP, Ron D.Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol, 2004,167:27-33
[23]Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells.Proc Natl Acad Sci USA 2004,101:11269-11274
[24]Yaman I, Fernandez J, Liu H, et al. The zipper model of translational control:a small upstream ORF is the switch that controls structural remodeling of an mRNA leader. Cell,2003,113:519-531
[25]Harding HP, Zhang Y, Zeng H,et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell,2003,11:619-633
[26]Lin JH, Li H, Zhang Y,et al. Divergent effects of PERK and IRE1 signaling on cell viability. PLoS ONE,2009,4:e4170
[27]Yoshida H,Matsui T,Yamamoto A,et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor.Cell,2001,107:881-891
[28]Yoshida H,Okada T,Haze K,et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfoled protein protein response.Mol Cell Biol,2000,20:6755-6767
[29]Shen J, Snapp EL, Lippincott-Schwartz J,et al. Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response. Mol Cell Biol,2005,25:921-932
[30]Chen X,Shen J,Prywes R.The luminal domain of ATF6 senses endoplasmic reticulum(ER)stress and causes translocation of ATF6 from the ER to the Golgi.J Biol Chem,2002,277:13405-13052.
[31]Shen J,Chen X,Hendershot L,et al.ER stress regulation of ATF6 localization by dissociation of Bip/GRP78 binding and unmasking of Golgi localization signals.Dev Cell,2002,3:99-11.
[32]Shen J,Prywes R.Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of the luminal domain of ATF6.J Biol Chem 2004,279:43046-43051
[33]Ye J,Rawson RB,Komuro R,et al. ER stress induces cleavage of membrane-bound ATF6 by the same protease that process SREBPs. Mol Cell,2000,6:1355-1364
[34]Yamamoto K, SatoT,Matsui T,et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6a and XBP1. Dev. Cell,2007,13:365-376
[35]Wu J, Rutkowski D. T, Dubois M, et al. ATF6a optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell,2007,13:351-364
[36]Shen J,Prywes R.ER stress signaling by regulated proteolysis of ATF6. Methods, 2005,35:382-389
[37]Baltzis D, Pluquet O, Papadakis AI,et al. The eIF2alpha kinases PERK and PKR activate glycogen synthase kinase 3 to promote the proteasom al degradation of p53. J Biol Chem,2007,282:31675-3168
[38]Calfon M, Zeng H,Urano F,et al. IRE1 couples endoplasmic reticulum load to secretary capacity by processing the XBP-1 mRNA. Nature,2002,415:92-96
[39]Wang XZ, Harding HP, Zhang YH, et al. Cloning of mammalian Irel reveals diversity in the ER stress responses.EMBO J,1998,17:5708-5717.
[40]Yoshida H.Unconventional splicing of XBP-1 mRNA in the unfolded protein response. Antioxid Redox Signal,2007,9:2323-2333
[41]Oda Y, Okada T, Yoshida H, et al. Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol,2006,172:383-393
[42]Acosta-Alvear D, Zhou Y, Blais A,et al. XBP1 controls diverse cell type-and condition-specific transcriptional regulatory networks. Mol Cell,2007,27:53-66
[43]Kostova Z, Tsai Y.C, Weissman A.M. Ubiquitin ligases, critical mediators of endoplasmic reticulum-associated degradation. Semin Cell Dev Biol,2007,18: 770-779
[44]Hirao K,Natsuka Y,Tamura T,et al. EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. J Biol Chem,2006,281:9650-9658
[45]Hosokawa N,Tremblay L.O,You Z,et al. Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong alpha1-antitrypsin by human ER mannosidase I. J Biol Chem,2003,278:26287-26294
[46]Mast S.W.,Diekman K,Karaveg K, et al. Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins. Glycobiology,2005.15:421-436
[47]Ruddock LW, Molinari M. N-glycan processing in ER quality control. J Cell Sci,2006.119:4373-4380
[48]Denic V, Quan EM, Weissman JS.A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell,2006,26:349-359
[49]Oyadomari S, koizumi A, Takeda K, et al. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest,2002,109: 525-532
[50]Mccullough KD, Martindale JL,Klotz LO,et al.Gadd153 Sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol,2001,21:1249-1259
[51]Ortis F,Cardozo AK,Crispim D,et al. Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-kappaB activation.MolEndocrino,2006,20: 1867-1779.
[52]Paschen W,Gissel C,Linden T,et al.Activation of gaddl53 expression through transient cerebral ischemia:evidence that ischemia causes endoplasmic reticulum dysfunction.Brain Res Mol Brain Res,1998,60:115-122
[53]Averous J, Bruhat A, Jousse C,et al. Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. J Biol Chem,2004,279:5288-5297
[54]Ma YJ, Brewer JW, Diehl JA, et al. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol,2002,318:1351-1365
[55]Puthalakath H,O'Reilly LA, Gunn P, et al. ER stress triggers apoptosis by activating BH3-only protein Bim.Cell,2007,129:1337-1349
[56]Haynes CM, Titus EA, Cooper AA. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell,2004,15:767-776
[57]Marciniak SJ, Yun CY, Oyadomari S,et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev,2004.18:3066-3077
[58]Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem,2004,279:45495-45502
[59]Puthalakath H,O'Reilly LA, Gunn P, et al.ER stress triggers apoptosis by activating BH3-only protein Bim. Cell,2007.129:1337-1349
[60]Ohoka N, Yoshii S, Hattori T, et al.TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J,2005, 24:1243-1255
[61]Hu P, Han Z, Couvillon AD, et al. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE 1 alpha-mediated NF-kappa B activation and down-regulation of TRAF2 expression. Mol Cell Biol,2006,26:3071-3084
[62]Hatai T,Matsuzawa A,Inoshita S,et al.Execution of apoptosis signal regulating kinase I(ASK1)-induced apoptosis by the mitochondria-dependent caspase activation.J Biol Chem.2000.275:26576-26581
[63]Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature,2000,403:98-103.
[64]Kalai M,lamkanfi M,Denecker G,et al.Regulation of the expression and processing of caspase-12.J Cell Biol.2003.162:457-467
[65]Momoi T. Caspases involved in ER stress-mediated cell death. J Chem Neuroanat,2004,28:101-105
[66]Morishima N,Nakanishi K,Takenouchi H,et al.An endoplasmic reticulum stress-specific caspase casade in apoptosis.Cytochrome c-independent activation of caspase-9 by caspase-12.J Biol Chem,2002,277:34287-34294
[67]Rao RV,Castro-Obregon S,Frankowski H,et al.Coupling endoplasmic reticulum stress to the cell death program.An Apaf-1-independent inreinsic pathway.J Biol Chem,2002,277:21836-21842
[68]Cheung HH, Lynn Kelly N, Liston P,et al. Involvement of caspase-2 and caspase-9 in endoplasmic reticulum stress-induced apoptosis:a role for the IAPs. Exp Cell Res,2006,312:2347-2357
[69]Eva S,Una F,Afshiin S.Caspase-12 and ER-stress-mediate apoptosis the stoyso far.Ann NY Acad Sci,2003,1010:186-194.
[70]Tan Y, Dourdin N, Wu C,et al. Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum stress-induced apoptosis. J Biol Chem,2006,281:16016-16024
[71]Chua BT,Guo K, Li P. Direct cleavage by the calcium-activated protease calpain can lead to inactivation of caspases.J Biol Chem,2000,275:5131-5135
[72]Nieves D, Moreno JJ. Epoxyeicosatrienoic acids induce growth inhibition and calpain/caspase-12 dependent apoptosis in PDGF cutured 3T6 fibroblast.Apoptosis,2007,12:1979-1988
[73]Masud A,Mohapatra A, Lakhani SA,et al. Endoplasmic reticulum stress-induced death of mouse embryonic fibroblasts requires the intrinsic pathway of apoptosis. J Biol Chem,2007,282:14132-14139
[74]Nakagawa T,Yuan J.Cross-talk between two cysteine protease families.Activation of caspase-12 by calpain in apoptosis. J Cell Biol,2000,150:887-894
[75]Hitomi J,Katayama T,Eguchi Y, et al.Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and a beta_induced cell death. J Cell
Biol,2004,165(3):347-356.
[76]Urano F,Wang X,Bertolotti A,et al.Coupling of stress in the ER to activation of JNK protein kinase by transmembrane protein kinase IRE1. Science, 2000,287:664-666
[77]Pizzo P, Pozzan T.Mitochondria-endoplasmic reticulum choreography:structure and signaling dynamics. Trends Cell Biol,2007.7:511-17
[78]Chami M, Oules B, Szabadkai G,et al. Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress. Mol Cell,2008,32:641-651
[79]Wei MC, Zong WX, Cheng EH,et al.Proapoptotic BAX and BAK:a requisite gateway to mitochondrial dysfunction and death. Science,2001,292:727-730
[80]Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+:a control point for apoptosis. Science,2003,300:135-139
[81]Yasumasa ,Pramod P,Neerad M,et al.Targeting of the c-Abl Tyrosine Kinase To Mitochondria in Endoplasmic Reticulum Stress-Induced Apoptosis.Molecular And Cellular Biology,2001,18:6233-6242
[82]Nishitoh H,Matsuzawa A,Tobiume K.et al.ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats.Genes Dev,2002,16:1345-1355
[2]Steiling K, Lenburg ME, Spira A.Airway gene expression in chronic obstructive pulmonary disease.Proc Am Thorac Soc,2009,6:697-700
[3]S(?)rheim IC, Gulsvik A, Bakke PS,et al. Genetics in chronic obstructive pulmonary disease.Tidsskr Nor Laegeforen,2009,129:2104-2107
[4]Horowitz JC, Martinez FJ, Thannickal VJ.Mesenchymal cell fate and phenotypes in the pathogenesis of emphysema. COPD,2009,6,201-210
[5]Roth M.Pathogenesis of COPD. Part Ⅲ. Inflammation in COPD. Int J Tuberc Lung Dis,2008,12:375-380
[6]Spurzem JR, Rennard SI.Pathogenesis of COPD. Semin Respir Crit Care Med, 2005,26(2):142-153
[7]Snider GL, Kleinerman LJ, Thurlbeck WM, et al. The Definition of Emphysema: Report of a National, Heart, Lung and Blood Institute. Division of Lung Diseases Workshop. Am Rev Respir Dis,1985,132(1):182-185
[8]Pipavath SN, Schmidt RA, Takasugi JE. Chronic obstructive pulmonary disease: radiology-pathology correlation.J Thorac Imaging,2009,24:171-180
[9]Imai K,Mercer BA,schulman LL,et al. Correlation of lung surface Area to apoptosis and proliferation in human emphysema.Eur Respir J,2005,25:250-258
[10]Aoshiba K,Yokohori N,Nagai A. Alveolar wall apoptosis induces lung destruction and emphysematous changes.Am J Respir Cell Mol Biol,2003, 28(5):555-562
[11]Kuo WH, Chen JH, Lin HH, et al. Induction of apoptosis in the lung tissue from rats exposed to cigarette smoke involves p38/JNK MAPK pathway. Chemico Biological Interactions,2005,155:31-42
[12]Eun Mi, Juliana Jung, Nuraly K,et al. Pro-oxidative DEP chemicals induce heat shock proteins and an unfolding protein response in a bronchial epithelial cell line as determined by DIGE analysis. Proteomics,2007,7:3906-3918
[13]Steven G. Kelsen, Xunbao Duan,et al. Cigarette Smoke Induces an Unfolded Protein Response in the Human Lung A Proteomic Approach.Am J Respir Cell Mol Biol,2008,38:541-550
[14]Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 1999,13:1211-1233
[15]Gomez E,Powell M.L,Bevington A, et al.A decrease in cellular energy status stimulates PERK-dependent eIF2alpha phosphorylation and regulates protein synthesis in pancreatic beta-cells. Biochem J,2008,410:485-493
[16]Yacoub Wasef S.Z, Robinson K.A,Berkaw M.N, et al. Glucose, dexamethasone, and the unfolded protein response regulate TRB3 mRNA expression in 3T3-L1 adipocytes and L6 myotubes. Am J Physiol Endocrinol Metab,2006,291: 1274-1280
[17]Schroder M, Kaufman RJ:The mammalian unfolded protein response.Annu Rev Biochem,2005,74:739-789
[18]Xu C, Bailly-Maitre B, Reed JC:Endoplasmic reticulum stress:Cell life and death decisions. J Clin Invest,2005,115:2656-2664
[19]Qian Y,Tiffany-Castiglioni E. Lead-induced endoplasmic reticulum(ER) stress responses in the nervous system. Neurochem Res,2003,28:153-162
[20]Yang GH, Li S,Pestka JJ,Down-regulation of the endoplasmic reticulum chaperone GRP78/Bip by vomitoxin (Deoxynivalenol). Toxicol Appl Pharmacol, 2000,162 (3):207-217
[21]Hitomi J, Katayama T,Taniguchi M,et al. Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. Neurosci Lett,2003,357:1 27-130
[22]Mendes CS, Levet C, Chatelain G, et al. ER stress protects from retinal degeneration. EMBO J,2009,28:1296-1307
[23]Rutkowski DT, Arnold SM, Miller CN, et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol,2006,4:e374
[24]H Liu, J Qian, F Wang. Expression of two endoplasmic reticulum stress markers, GRP78 and GADD153, in rat retinal detachment model and its implication.Eye,2010,24:137-144
[25]Jui-Ching Chen, Mei-Lin Wu, Kuo-Chin Huang, et al. HMG-CoA reductase inhibitors activate the unfolded protein response and induce cytoprotective GRP78 expression. Cardiovasc Res,2008,80:138-150
[26]Hayashi T, Saito A, Okuno S, et al. Induction of GRP78 by ischemic preconditioning reduces endoplasmic reticulum stress and prevents delayed neuronal cell death. Cereb Blood Flow Metab,2003,23(8):949-961
[27]Y. Oidaa, H. Izutaa, A. Oyagia, et al. Induction of BiP, an ER-resident protein,. prevents the neuronal death induced by transient forebrain ischemia in gerbil Brain Res,2008,1208:217-224
[28]Reddy RK, Mao C, Baumeister P, et al. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors:role of ATP binding site in suppression of caspase-7 activation.J Biol Chem 2003, 278:20915-24
[29]Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rabl rescues neuron loss in Parkinson's models. Science,2006, 313:324-328
[30]Galy A, Roux MJ, Sahel JA, et al. Rhodopsin maturation defects induce photoreceptor death by apoptosis:a fly model for RhodopsinPro23His human retinitis pigmentosa. Hum Mol Genet,2005,14:2547-2557
[31]Fonseca SG, Fukuma M, Lipson KL,et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic betacells. J Biol Chem,2005,280:39609-39615
[32]Yamada T, Ishihara H, Tamura A, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet,2006,15: 1600-1609
[33]Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J,2005,24:4368-4380.
[34]Bergren DR, Environmental tobacco smoke exposure and airway hyperrespo-nsiveness,Inflamm Allergy Drug Targets,2009,8:340-347
[35]Bartal M.COPD and tobacco smoke. Monaldi Arch Chest Dis,2005,63:213-225
[36]Ryan E. Feaver, Nicole E. Hastings, Andrew Pryor et al.GRP78 Upregulation by Atheroprone Shear Stress Via p38-,α2β1-Dependent Mechanism in Endothelial Cells. Arterioscler Thromb Vasc Biol,2008,28:1534-1541
[37]Renda T, Baraldo S, Pelaia G, et al. Increased activation of p38 MAPK in COPD. Eur Respir J,2008,31(1):62-69
[38]Brindicci C, Kharitonov SA, Ito M, et al. Nitric Oxide Synthase Isoenzyme Expression and Activity in Peripheral Lung Tissue of Patients with Chronic Obstructive Pulmonary Disease.Am J Respir Crit Care Med 2010,181(1):21-30
[39]Osoata GO, Hanazawa T, Brindicci C, et al. Peroxynitrite Elevation in Exhaled Breath Condensate of COPD and Its Inhibition by Fudosteine. Chest,2009,135 (6):1513-1520
[40]Miller M, Cho JY, Pham A, et al. Adiponectin and Functional Adiponectin Receptor 1 Are Expressed by Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease.J Immunol,2009,182(1):684-691
[41]Vernooy JHJ, Drummen NEA, Van Suylen RJ, et al. Enhanced pulmonary leptin expression in patients with severe COPD and asymptomatic smokers. Thorax, 2009,64(1):26-32
[42]Mata M, Sarria B, Buenestado A, et al. Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells.Thorax,2005,60(2):144-152
[43]Igarashi A, Shibata Y, Yamauchi K, et al.Gly80Ser Polymorphism of Phospholipase A2-IID Is Associated with Cytokine Inducibility in A549 Cells. Respiration,2009,78:312-321
[44]Qian Y,Tiffany-Castiglioni E.Lead-induced endoplasmic reticulum(ER) stress responses in the nervous system.Neurochem Res,2003,28:153-162
[45]Paschen W,Gissel C,Linden T, et al.Activation of gaddl53 expression through transient cerebral ischemia:evidence that ischemia causes endoplasmic reticulum dysfunction. Brain Res Mol Brain Res,1998,60:115-122
[46]Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature,2000, 403:98-103
[47]Momoi T. Caspases involved in ER stress-mediated cell death. J Chem Neuroanat, 2004,28:101-105
[48]宋一平,崔德健,茅培英,等.COPD大鼠模型气道重塑及生长因子的研究.中华结核和呼吸杂志,2001,24：283-287
[49]陈红梅,罗百灵,屈满英,等.红霉素对COPD大鼠MMP-9的影响.中华结核和呼吸杂志,2008,31：702-703
[50]Agusti AG.Systemic effects of chronic obstructive pulmonary disease.Proc Am Thorac Soc,2005;24(1):45-6.
[51]Wu J, Kaufman RJ. From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ,2006.13:374-384
[52]Lee AS.The glucose-regulated protein:stress induction induction and clinical applications.Trends Biochem Sci,2001,26:504-510
[53]Pryor WA, Stone K.Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann N Y Acad Sci,1993,28;686:12-27
[54]Tuder RM. Wood K. Taraseviciene L. et al. Cigarette Smoke Extract Decreases the Expression of Vascular Endothelial Growth Factor by Cultured Cells and Triggers Apoptosis of Pulmonary Endothelial Cells. CHEST,2000:117 (5) 241S-242S
[55]Yuma H,Tadashi M, Sonoko N,et al. Cytotoxic effects of cigarette smoke extract on an alveolar type II cell-derived cell line. Am J Physiol Lung Cell Mol Physiol,2001,281:L509-L516
[56]Kasahara Y. Tuder RM. Taraseviciene-Stewart L, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest,2000,106 (11):1311-9
[57]Lucky EC, Keane J, Kuang PP, et al. Severity of elastase-induced emphysema is decreased in tumor necrosis factor-alpha and interleukin-1 beta receptor-deficient mice. Lab Invest.2002;82:79-85
[58]屈满英,罗百灵,陈红梅,等.分泌型白细胞蛋白酶抑制剂对香烟烟雾提取
物诱导人支气管上皮细胞炎症介质表达的影响.中华结核和呼吸杂志,2008,31：352-355
[59]Moodie FM, Marwick JA, Anderson CS, et al.Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-κB activation and proinflammatory cytokine release in alveolar epithelial cells.The FASEB Journal,2004,18(15):1897-1899
[60]Qian Y,Tiffany-Castiglioni E.Lead-induced endoplasmic reticulum(ER) stress responses in the nervous system. Neurochem Res,2003,28:153-162
[61]Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature Cell Biol, 2000,2:326-332
[62]Harding HP, Novoa I, Zhang Y, et al. Regulated ruanslation initiation controls stress-induced gene expression in mammalian cells. Mol Cell,2000,6:1099-1108
[63]Schroder M, Kaufman RJ:The mammalian unfolded protein response.Annu Rev Biochem,2005,74:739-789
[64]Xu C, Bailly-Maitre B, Reed JC:Endoplasmic reticulum stress:Cell life and death decisions. J Clin Invest 2005,115:2656-2664,
[65]Zhuang S, Schnellmann RG. H2O2-induced transactivation of EGF receptor requires Src and mediates ERK1/2, but not Akt, activation in renal cells. Am J Physiol Renal Physiol,2004,286(5):F858-F865
[66]Park SJ,Kim Is. The role of p38 MAPK activation in auranofin-induced apoptosis of human promyelocytic leukaemia HL-60 cells. Br J Phammcol,2005,146(4): 506-513
[67]Aparna C. Ranganathan, Lin Zhang. Functional Coupling of p38-Induced Up-regulation of BiP and Activation of RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase to Drug Resistance of Dormant Carcinoma Cells. Cancer Research 2006:66,1702-1711
[68]Slevogt H, Schmeck B, Jonatat C, et al. Moraxella catarrhalis induces inflammatory response of bronchial epithelial cells via MAPK and NF-kappaB activation and histone deacetylase activity reduction. Am J Physiol Lung Cell Mol Physiol,2006,290:L818-826
[69]Chen KD, Chen LY, Huang HL, et al. Involvement of p38 mitogen-activated protein kinase signaling pathway in the rapid induction of the 78-kDa glucose-regulated protein in 9L rat brain tumor cells. J Biol Chem,1998; 273:749-755
[70]Chen KD, Lai MT, Cho JH, et al. Activation of p38 mitogen-activated protein kinase and mitochondrial Ca(2+)-mediated oxidative stress are essential for the enhanced expression of grp78 induced by the protein phosphatase inhibitors okadaic acid and calyculin A. J Cell Biochem,2000,76:585-595
[71]Goodyear LJ, Chang PY, Sherwood DJ, et al. Effects of exercise and insulin on mitogen-activated protein kinase signaling pathways in rat skeletalmuscle.Am J Physiol,1996,271 (2Pt1):E403-E408
[72]Kim BJ, Ryu SW, Song BJ. JNK and p38 kinase-mediated phosphorylationof Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem,2006,281:21256-21265.
[73]Kim HJ, Oh JE, Kim SW,et al.Ceramide induces p38 MAPK-dependent apoptosis and Bax translocation via inhibition of Akt in HL-60 cells. Cancer Lett,2008,260:88-95
[74]Jope RS, Zhang L, Song L. Peroxynitrite modulates the activation of p38 and extracellular regulated kinases in PC 12 cells. Arch Biochem Biophys,2000, 376:365-370
[1]Schultz DR, Harrington WJ Jr. Apoptosis:Programmed cell death at a molecular level. Semin Arthritis Rheum,2003,32:345-369
[2]Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rabl rescues neuron loss in Parkinson's models. Science,2006, 313:324-328
[3]Galy A, Roux MJ, Sahel JA, et al. Rhodopsin maturation defects induce photoreceptor death by apoptosis:a fly model for RhodopsinPro23His human retinitis pigmentosa. Hum Mol Genet,2005,14:2547-2557
[4]Fonseca SG, Fukuma M, Lipson KL,et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic betacells. J Biol Chem,2005,280:39609-39615
[5]Yamada T, Ishihara H, Tamura A, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet,2006,15:1600-1609
[6]Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J,2005,24:4368-4380.
[7]Eun Mi, Juliana Jung, Nuraly K,et al. Pro-oxidative DEP chemicals induce heat
shock proteins and an unfolding protein response in a bronchial epithelial cell line as determined by DIGE analysis. Proteomics,2007;7:3906-3918
[8]Steven G. Kelsen, Xunbao Duan,et al. Cigarette Smoke Induces an Unfolded Protein Response in the Human Lung A Proteomic Approach.Am J Respir Cell Mol Biol,2008; 38:541-550
[9]Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 1999;13:1211-1233
[10]Gomez E,Powell M.L,Bevington A, et al.A decrease in cellular energy status stimulates PERK-dependent eIF2alpha phosphorylation and regulates protein synthesis in pancreatic beta-cells. Biochem J,2008,410:485-493
[11]Yacoub Wasef S.Z, Robinson K.A,Berkaw M.N, et al.Glucose, dexamethasone, and the unfolded protein response regulate TRB3 mRNA expression in 3T3-L1 adipocytes and L6 myotubes. Am J Physiol Endocrinol Metab,2006, 291:1274-1280
[12]Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev. Mol. Cell Biol,2007;8:519-529
[13]Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu. Rev. Biochem,2005;74:739-789
[14]Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol,2007,8:519-529
[15]Mendes CS, Levet C, Chatelain G, et al. ER stress protects from retinal degeneration. EMBO J,2009,28:1296-1307
[16]Rutkowski DT, Arnold SM, Miller CN, et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol,2006,4:e374
[17]Qian Y,Tiffany-Castiglioni E.Lead-induced endoplasmic reticulum(ER) stress responses in the nervous system. Neurochem Res,2003,28:153-162
[18]Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature Cell Biol,2000,2:326-332
[19]Harding HP, Novoa I, Zhang Y, et al. Regulated ruanslation initiation controls stress-induced gene expression in mammalian cells. Mol Cell,2000,6:1099-1108
[20]Harding HP, Zeng H, Zhang Y, et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice revrals a role for translational contronl in secretory cell survival.Mol Cell,2001,7:1153-1163.
[21]Marciniak SJ, Garcia-Bonilla L, Hu J, et al. Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK. J Cell Biol,2006,172:201-209
[22]Lu PD, Harding HP, Ron D.Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol, 2004,167:27-33
[23]Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells.Proc Natl Acad Sci USA 2004,101:11269-11274
[24]Yaman I, Fernandez J, Liu H, et al. The zipper model of translational control:a small upstream ORF is the switch that controls structural remodeling of an mRNA leader. Cell,2003,113:519-531
[25]Harding HP, Zhang Y, Zeng H,et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell,2003,11:619-633
[26]Lin JH, Li H, Zhang Y,et al. Divergent effects of PERK and IRE1 signaling on cell viability. PLoS ONE,2009,4:e4170
[27]Yoshida H,Matsui T,Yamamoto A,et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor.Cell,2001,107:881-891
[28]Yoshida H,Okada T,Haze K,et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfoled protein protein response.Mol Cell Biol,2000,20:6755-6767
[29]Shen J, Snapp EL, Lippincott-Schwartz J,et al. Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response. Mol Cell Biol,2005,25:921-932
[30]Chen X,Shen J,Prywes R.The luminal domain of ATF6 senses endoplasmic reticulum(ER)stress and causes translocation of ATF6 from the ER to the Golgi.J Biol Chem,2002,277:13405-13052.
[31]Shen J,Chen X,Hendershot L,et al.ER stress regulation of ATF6 localization by dissociation of Bip/GRP78 binding and unmasking of Golgi localization signals.Dev Cell,2002,3:99-11.
[32]Shen J,Prywes R.Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of the luminal domain of ATF6.J Biol Chem 2004,279:43046-43051
[33]Ye J,Rawson RB,Komuro R,et al. ER stress induces cleavage of membrane-bound ATF6 by the same protease that process SREBPs. Mol Cell,2000,6:1355-1364
[34]Yamamoto K, SatoT,Matsui T,et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6a and XBP1. Dev. Cell,2007,13:365-376
[35]Wu J, Rutkowski D. T, Dubois M, et al. ATF6a optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell,2007,13:351-364
[36]Shen J,Prywes R.ER stress signaling by regulated proteolysis of ATF6. Methods, 2005,35:382-389
[37]Baltzis D, Pluquet O, Papadakis AI,et al. The eIF2alpha kinases PERK and PKR activate glycogen synthase kinase 3 to promote the proteasom al degradation of p53. J Biol Chem,2007,282:31675-3168
[38]Calfon M, Zeng H,Urano F,et al. IRE1 couples endoplasmic reticulum load to secretary capacity by processing the XBP-1 mRNA. Nature,2002,415:92-96
[39]Wang XZ, Harding HP, Zhang YH, et al. Cloning of mammalian Irel reveals diversity in the ER stress responses.EMBO J,1998,17:5708-5717.
[40]Yoshida H.Unconventional splicing of XBP-1 mRNA in the unfolded protein response. Antioxid Redox Signal,2007,9:2323-2333
[41]Oda Y, Okada T, Yoshida H, et al. Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol,2006,172:383-393
[42]Acosta-Alvear D, Zhou Y, Blais A,et al. XBP1 controls diverse cell type-and condition-specific transcriptional regulatory networks. Mol Cell,2007,27:53-66
[43]Kostova Z, Tsai Y.C, Weissman A.M. Ubiquitin ligases, critical mediators of endoplasmic reticulum-associated degradation. Semin Cell Dev Biol,2007,18: 770-779
[44]Hirao K,Natsuka Y,Tamura T,et al. EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. J Biol Chem,2006,281:9650-9658
[45]Hosokawa N,Tremblay L.O,You Z,et al. Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong alpha1-antitrypsin by human ER mannosidase I. J Biol Chem,2003,278:26287-26294
[46]Mast S.W.,Diekman K,Karaveg K, et al. Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins. Glycobiology,2005.15:421-436
[47]Ruddock LW, Molinari M. N-glycan processing in ER quality control. J Cell Sci,2006.119:4373-4380
[48]Denic V, Quan EM, Weissman JS.A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell,2006,26:349-359
[49]Oyadomari S, koizumi A, Takeda K, et al. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest,2002,109: 525-532
[50]Mccullough KD, Martindale JL,Klotz LO,et al.Gadd153 Sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol,2001,21:1249-1259
[51]Ortis F,Cardozo AK,Crispim D,et al. Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-kappaB activation.MolEndocrino,2006,20: 1867-1779.
[52]Paschen W,Gissel C,Linden T,et al.Activation of gaddl53 expression through transient cerebral ischemia:evidence that ischemia causes endoplasmic reticulum dysfunction.Brain Res Mol Brain Res,1998,60:115-122
[53]Averous J, Bruhat A, Jousse C,et al. Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. J Biol Chem,2004,279:5288-5297
[54]Ma YJ, Brewer JW, Diehl JA, et al. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol,2002,318:1351-1365
[55]Puthalakath H,O'Reilly LA, Gunn P, et al. ER stress triggers apoptosis by activating BH3-only protein Bim.Cell,2007,129:1337-1349
[56]Haynes CM, Titus EA, Cooper AA. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell,2004,15:767-776
[57]Marciniak SJ, Yun CY, Oyadomari S,et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev,2004.18:3066-3077
[58]Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem,2004,279:45495-45502
[59]Puthalakath H,O'Reilly LA, Gunn P, et al.ER stress triggers apoptosis by activating BH3-only protein Bim. Cell,2007.129:1337-1349
[60]Ohoka N, Yoshii S, Hattori T, et al.TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J,2005, 24:1243-1255
[61]Hu P, Han Z, Couvillon AD, et al. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE 1 alpha-mediated NF-kappa B activation and down-regulation of TRAF2 expression. Mol Cell Biol,2006,26:3071-3084
[62]Hatai T,Matsuzawa A,Inoshita S,et al.Execution of apoptosis signal regulating kinase I(ASK1)-induced apoptosis by the mitochondria-dependent caspase activation.J Biol Chem.2000.275:26576-26581
[63]Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature,2000,403:98-103.
[64]Kalai M,lamkanfi M,Denecker G,et al.Regulation of the expression and processing of caspase-12.J Cell Biol.2003.162:457-467
[65]Momoi T. Caspases involved in ER stress-mediated cell death. J Chem Neuroanat,2004,28:101-105
[66]Morishima N,Nakanishi K,Takenouchi H,et al.An endoplasmic reticulum stress-specific caspase casade in apoptosis.Cytochrome c-independent activation of caspase-9 by caspase-12.J Biol Chem,2002,277:34287-34294
[67]Rao RV,Castro-Obregon S,Frankowski H,et al.Coupling endoplasmic reticulum stress to the cell death program.An Apaf-1-independent inreinsic pathway.J Biol Chem,2002,277:21836-21842
[68]Cheung HH, Lynn Kelly N, Liston P,et al. Involvement of caspase-2 and caspase-9 in endoplasmic reticulum stress-induced apoptosis:a role for the IAPs. Exp Cell Res,2006,312:2347-2357
[69]Eva S,Una F,Afshiin S.Caspase-12 and ER-stress-mediate apoptosis the stoyso far.Ann NY Acad Sci,2003,1010:186-194.
[70]Tan Y, Dourdin N, Wu C,et al. Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum stress-induced apoptosis. J Biol Chem,2006,281:16016-16024
[71]Chua BT,Guo K, Li P. Direct cleavage by the calcium-activated protease calpain can lead to inactivation of caspases.J Biol Chem,2000,275:5131-5135
[72]Nieves D, Moreno JJ. Epoxyeicosatrienoic acids induce growth inhibition and calpain/caspase-12 dependent apoptosis in PDGF cutured 3T6 fibroblast.Apoptosis,2007,12:1979-1988
[73]Masud A,Mohapatra A, Lakhani SA,et al. Endoplasmic reticulum stress-induced death of mouse embryonic fibroblasts requires the intrinsic pathway of apoptosis. J Biol Chem,2007,282:14132-14139
[74]Nakagawa T,Yuan J.Cross-talk between two cysteine protease families.Activation of caspase-12 by calpain in apoptosis. J Cell Biol,2000,150:887-894
[75]Hitomi J,Katayama T,Eguchi Y, et al.Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and a beta_induced cell death. J Cell
Biol,2004,165(3):347-356.
[76]Urano F,Wang X,Bertolotti A,et al.Coupling of stress in the ER to activation of JNK protein kinase by transmembrane protein kinase IRE1. Science, 2000,287:664-666
[77]Pizzo P, Pozzan T.Mitochondria-endoplasmic reticulum choreography:structure and signaling dynamics. Trends Cell Biol,2007.7:511-17
[78]Chami M, Oules B, Szabadkai G,et al. Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress. Mol Cell,2008,32:641-651
[79]Wei MC, Zong WX, Cheng EH,et al.Proapoptotic BAX and BAK:a requisite gateway to mitochondrial dysfunction and death. Science,2001,292:727-730
[80]Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+:a control point for apoptosis. Science,2003,300:135-139
[81]Yasumasa ,Pramod P,Neerad M,et al.Targeting of the c-Abl Tyrosine Kinase To Mitochondria in Endoplasmic Reticulum Stress-Induced Apoptosis.Molecular And Cellular Biology,2001,18:6233-6242
[82]Nishitoh H,Matsuzawa A,Tobiume K.et al.ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats.Genes Dev,2002,16:1345-1355