Song Jae J, Lee Yong J
Department of Surgery and Cancer Institute, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Biochem J. 2003 Aug 1;373(Pt 3):845-53. doi: 10.1042/BJ20030275.
Redox-sensing molecules such as thioredoxin (TRX) and glutaredoxin (GRX) bind to apoptosis signal-regulating kinase 1 (ASK1) and suppress its activation. Glucose deprivation disrupted the interaction between TRX/GRX and ASK1 and subsequently activated the ASK1-stress-activated protein kinase/extracellular-signal-regulated kinase kinase-c-Jun N-terminal kinase 1 (JNK1) signal-transduction pathway. L-Buthionine-( S, R )-sulphoximine, which decreases intracellular glutathione content, enhanced glucose deprivation-induced activation of JNK1 by promoting the dissociation of TRX, but not GRX, from ASK1. Treatment of cells with exogenous glutathione disulphide ester resulted in the dissociation of GRX, but not TRX, from ASK1 and the subsequent activation of JNK1. Nonetheless, overexpression of calatase, an H(2)O(2) scavenger, inhibited JNK1 activation and cytotoxicity as well as the dissociation of TRX and GRX from ASK1 during combined glucose deprivation and L-buthionine-( S, R )-sulphoximine treatment. Taken together, glucose deprivation-induced metabolic oxidative stress may activate ASK1 through two different pathways: glutathione-dependent GRX-ASK1 and glutathione-independent TRX-ASK1 pathways.
氧化还原感应分子，如硫氧还蛋白（TRX）和谷氧还蛋白（GRX），可与凋亡信号调节激酶1（ASK1）结合并抑制其激活。葡萄糖剥夺破坏了TRX/GRX与ASK1之间的相互作用，随后激活了ASK1-应激激活蛋白激酶/细胞外信号调节激酶激酶-c-Jun氨基末端激酶1（JNK1）信号转导通路。L-丁硫氨酸-（S，R）-亚砜亚胺可降低细胞内谷胱甘肽含量，通过促进TRX而非GRX与ASK1的解离，增强葡萄糖剥夺诱导的JNK1激活。用外源性谷胱甘肽二硫化物酯处理细胞会导致GRX而非TRX与ASK1解离，随后激活JNK1。尽管如此，过氧化氢酶（一种H2O2清除剂）的过表达在联合葡萄糖剥夺和L-丁硫氨酸-（S，R）-亚砜亚胺处理期间抑制了JNK1激活和细胞毒性以及TRX和GRX与ASK1的解离。综上所述，葡萄糖剥夺诱导的代谢性氧化应激可能通过两种不同途径激活ASK1：谷胱甘肽依赖性GRX-ASK1途径和谷胱甘肽非依赖性TRX-ASK1途径。
