We previously found that oxygen-glucose-serum deprivation/restoration（OGSD/R） induces apoptosis of spinal cord astrocytes, possibly via caspase-12 and the integrated stress response, which involves protein kinase R-...We previously found that oxygen-glucose-serum deprivation/restoration（OGSD/R） induces apoptosis of spinal cord astrocytes, possibly via caspase-12 and the integrated stress response, which involves protein kinase R-like endoplasmic reticulum kinase（PERK）, eukaryotic initiation factor 2-alpha（eIF2α） and activating transcription factor 4（ATF4）. We hypothesized that edaravone, a low molecular weight, lipophilic free radical scavenger, would reduce OGSD/R-induced apoptosis of spinal cord astrocytes. To test this, we established primary cultures of rat astrocytes, and exposed them to 8 hours/6 hours of OGSD/R with or without edaravone（0.1, 1, 10, 100 μM） treatment. We found that 100 μM of edaravone significantly suppressed astrocyte apoptosis and inhibited the release of reactive oxygen species. It also inhibited the activation of caspase-12 and caspase-3, and reduced the expression of homologous CCAAT/enhancer binding protein, phosphorylated（p）-PERK, p-eIF2α, and ATF4. These results point to a new use of an established drug in the prevention of OGSD/R-mediated spinal cord astrocyte apoptosis via the integrated stress response.展开更多
Activating transcription factor 2(ATF2)is a member of the ATF/cyclic AMP-responsive element bind-ing protein family of transcription factors.However,the information concerning ATF2 ion-mediated DNA binding module and ...Activating transcription factor 2(ATF2)is a member of the ATF/cyclic AMP-responsive element bind-ing protein family of transcription factors.However,the information concerning ATF2 ion-mediated DNA binding module and function of ATF2 in malignant pleural mesothelioma(MPM)has never been addressed.In this study,by using GRNInfer and GVedit based on linear pro-gramming and a decomposition procedure,with integrated analysis of the function cluster using Kappa statistics and fuzzy heuristic clustering in MPM,we identified one ATF2 ion-mediated DNA binding module involved in invasive function including ATF2 inhibition to target genes FALZ,C20orf31,NME2,PLOD2,RNF10,and RNASEH1,upstream RNF10 and PLOD2 activation to ATF2,upstream RNASEH1 and FALZ inhibition to ATF2 from 40 MPM tumors and 5 normal pleural tissues.Remarkably,our results showed that the predominant effect of ATF2 occupancy is to suppress the activation of target genes on MPM.Importantly,the ATF2 ion-mediated DNA binding module reflects‘mutual’positive and negative feedback regulation mechanism of ATF2 with up-and down-stream genes.It may be useful for developing novel prognostic markers and therapeutic targets in MPM.展开更多
基金supported by a grant from the Science&Technology Bureau of Changzhou City of China,No.CJ20130029
文摘We previously found that oxygen-glucose-serum deprivation/restoration（OGSD/R） induces apoptosis of spinal cord astrocytes, possibly via caspase-12 and the integrated stress response, which involves protein kinase R-like endoplasmic reticulum kinase（PERK）, eukaryotic initiation factor 2-alpha（eIF2α） and activating transcription factor 4（ATF4）. We hypothesized that edaravone, a low molecular weight, lipophilic free radical scavenger, would reduce OGSD/R-induced apoptosis of spinal cord astrocytes. To test this, we established primary cultures of rat astrocytes, and exposed them to 8 hours/6 hours of OGSD/R with or without edaravone（0.1, 1, 10, 100 μM） treatment. We found that 100 μM of edaravone significantly suppressed astrocyte apoptosis and inhibited the release of reactive oxygen species. It also inhibited the activation of caspase-12 and caspase-3, and reduced the expression of homologous CCAAT/enhancer binding protein, phosphorylated（p）-PERK, p-eIF2α, and ATF4. These results point to a new use of an established drug in the prevention of OGSD/R-mediated spinal cord astrocyte apoptosis via the integrated stress response.
基金supported by the National Natural Science Foundation of China(Grant No.60673109)the Teaching and Scientific Research Foundation for the Returned Overseas Chinese Scholars,Ministry of Education of China.
文摘Activating transcription factor 2(ATF2)is a member of the ATF/cyclic AMP-responsive element bind-ing protein family of transcription factors.However,the information concerning ATF2 ion-mediated DNA binding module and function of ATF2 in malignant pleural mesothelioma(MPM)has never been addressed.In this study,by using GRNInfer and GVedit based on linear pro-gramming and a decomposition procedure,with integrated analysis of the function cluster using Kappa statistics and fuzzy heuristic clustering in MPM,we identified one ATF2 ion-mediated DNA binding module involved in invasive function including ATF2 inhibition to target genes FALZ,C20orf31,NME2,PLOD2,RNF10,and RNASEH1,upstream RNF10 and PLOD2 activation to ATF2,upstream RNASEH1 and FALZ inhibition to ATF2 from 40 MPM tumors and 5 normal pleural tissues.Remarkably,our results showed that the predominant effect of ATF2 occupancy is to suppress the activation of target genes on MPM.Importantly,the ATF2 ion-mediated DNA binding module reflects‘mutual’positive and negative feedback regulation mechanism of ATF2 with up-and down-stream genes.It may be useful for developing novel prognostic markers and therapeutic targets in MPM.
